NEUROPSYCHOLOGY OF AGING

All highly developed nations in the world are experiencing substantial increases in the proportion of elderly adults in the
population due to falling birth rates combined with increased longevity.We are an old population. We well face in older adult: by
250 there will be many older adults in wealthy and developed countries (26%) than children u8nder 15 (about 16% of total
population). Adults aged 85 and older have a dementia rate of nearly 50% (typically in the form of Alzheimer’s disease).

Really impressed about some data: by 2050

there will be more old adults than young
adults and children. Adults aged over 85
have a rate of dementia about 50%: half of
them have a kind of dementia.

The prospective and the framework of this course is the COGNITIVE NEUROSCIENCE OF AGING.
We will see aging in relation to the brain: which is the result of functional and structural changing. We have always to look at
brain not only in a structural changing (like atrophy or tumours) but also in changing of its functions and cognition. You cannot
say what came first: the cognition and social ability are in bidirectional relationship; we can do much more than we think to our
brain. For this reason, in this picture, what is missing? We have to consider also health (physical status, environment, culture,
the high of cultural level, mental state, emotions) that can postpone the cognitive decline. All those aspects have a huge impact:
we can’t ignore the rule of mental state in our cognition. The rule of genes is also very important.

It’s important to consider a holistic overview of aging!

From a lifespan perspective, many of the statements made by psychologists about normal development in the last third of life
have been clouded by what can only be described as buying into common societal stereotypes that we now call ageism. Such
ageism seems to be informed by the assumption of universal declines in cognitive competence and the development of other
undesirable psychological characteristics with advanced age. When we talk about ageism there is a prejudice or discrimination
based on a person’s age. There is the assumption of universal declines in cognitive competence and the development of other
undesirable psychological characteristic with advanced age. Classically all people outside psychology think that ageing entail a
reduction of ability and neural connection (less flexibility, neural plasticity, physical strength, working memory and attentional
aspects, executive functions). There is a prejudice and a pessimistic view: what we want to emphasize that this process is linked
not only to something that is lost, but also a gain (experience, wisdom, good mood, positive bias) and a functional
reorganization. The true is probably that aging is associated with a decline (during ageing the myelin around the nerves
deteriorated and so the processing slowing down) but in most of the time also a stable or even an increasing of ability.
Perhaps one of the most serious assumptions made by many psychologists is that of universal cognitive decline. While it is true
that the proportion of individuals who show cognitive decline increases with each decade after the 60s are reached, it is equally
true that many individuals do not show such decline until close to their demise, and that some fortunate few, in fact, show
selective ability gains from midlife into old age.

In the brain, the key locus of working memory and

executive function are pre-frontal cortex: the last
region to reach maturity and the first to show
deterioration. Pre-frontal cortex and frontal lobes are
so more vulnerable to aging. Word knowledge instead
remains mostly stable.

So, what does it really mean “to age”?

This graph reveals the truth only partially because it

depends on cross-sectional studies: if we see the same
result in a longitudinal study, we will see a quite
different story. In cross-sectional (two group taken at
the same time) study we cannot say if the difference
found depend on age-related change or something else. In a rapid changing society, we also continue to confuse differences
between old and young that are a function of greater educational and other opportunity structures for the younger cohorts with
age-related changes.

Cross sectional vs longitudinal studies: they tell a different story. Of course, there are differences in recruitment methods. Cross
sectional has a problem with the difference between the subject (for example in cultural difference between who is 20 and who
is 80 at the same time) and overestimate age-related differences.
Longitudinal study is very long and expensive study. It also has dropout problem (sometimes people have problem of health or
they die) and we have the practise effect, so an underestimate age-related difference.
In a rapidly changing society, we also continue to confuse differences between old and young that are a function of greater
educational and other opportunity structures for the younger cohorts with age-related changes.
This confusion leads to language in the scientific literature that interprets age differences that reflect complex population
differences as “aging decline”.

[For example, numerical ability→ in cross sectional it seems that there is not difference because of cohort effect: environmental
changing masks a difference]
CROSS-SECTIONAL LONGITUDINAL
A large body of behavioural research on the effects of ageing on human cognition has found at least three descriptive patterns
of age-related change in cognitive behaviour — life-long declines, declines that occur late in life, and relative stability across life.
The contrasts among these patterns indicate that, although ageing might have global effects, it influences certain cognitive
functions disproportionately.

o LIFE-LONG DECLINE → it starts to decline early in life, processing speed, working memory and encoding of
information into episodic memory (sometimes older adults have problems in memory because they have problem to
encode the information) tend to decline across the adult lifespan.
There are differences in the results between cross-sectional and longitudinal studies:
Cross sectional data showed that these functions decline from age 20 to 60.
Longitudinal data showed that these functions decline only after 60 years.

o LATE-LIFE DECLINE → well-practiced tasks or tasks that involve knowledge show little or no decline in performance
until very late in life:
• Short-term memory (phonological storage, measured using digit span) shows declines after the age of 70
• Measures of vocabulary and semantic knowledge are also stable until late in life

There are some functions that are pretty stable for a long time until later life. There is a plateau and then after 57 years
old they show a decline. The relative stability of semantic memory and knowledge until late in life indicates that life
experience might breed knowledge, and that the combination of these might lead to the wisdom that is often exhibited
by older adults11. One possibility is that older adults use preserved knowledge and experience to form more efficient or
effective strategies when performing tasks in which younger adults rely on processing ability

o LIFE-LONG STABILITY → function that seem to be unchanged throughout life:

• Autobiographical memory (we know for example that older adults have a good memory for the past event)
• Emotional processing (e.g. theory of mind)
• Automatic memory processes (familiarity for example to drive)

When performance is plotted as a function of time to mortality, there is an acceleration of cognitive decline that begins 3–6
years before death. In a sort of sense death can be predicted from a slowing down or decline of processing. This acceleration
indicates that pathology influences estimates of age-related cognitive changes in advanced age, whereas normal ageing
processes might be manifest in linear slopes.

AGE-RELATED NEURAL CHANGES

As we grow older, we may grow wiser, but we can also experience memory loss and cognitive slowing that can interfere with our
daily routines. The cognitive neuroscience of human ageing, which relies largely on neuroimaging techniques, relates these
cognitive changes to their neural substrates, including structural and functional changes in the prefrontal cortex, medial
temporal lobe regions and white matter tracts. Much remains unknown about how normal ageing affects the neural basis of
cognition, but recent research on individual differences in the trajectory of ageing effects is helping to distinguish normal from
pathological origins of age-related cognitive changes.

There is a general atrophy of the brain, but this atrophy is not due to a neuronal lost but on a reduce of synaptic density:
neurons themselves die but is in communication that there is impairment. There is an atrophy, but some regions are more
sensitive to aging than others.
In post-mortem and in vivo studies, the brains of older adults tend to have lower volumes of grey matter than do the brains of
younger adults. This is not due to cell death, but rather from lower synaptic densities in older adults (neocortical synapse density
declines steadily between the ages of 20). Communication in the synaptic reducing in the volume. Besides regional changes in
volume are not uniform: for example, the primary visual cortex is preserved during life. Pre-frontal cortex→ shows a decline. So
you can see that from 20 years old it starts to reduce in the volume.
 Hippocampus→
shows a decline
which is after 50
years old: it’s pretty
stable until 45 years
old.
Primary visual
cortex→ is the first
to reach the
maturity and it’s the
last to loss volume.

The logic is that if I see deterioration in the brain probably, I would see a deterioration in the corresponding cognitive function.
There is a high variability about cognitive functions but there is also a high variability in aging.

THERE ARE 4 PATTERNS OF AGING:

1. Individuals who age successfully (called the super-normals) → unfortunately low number of people. Independent
people who have good physical and mental active. Is a small sub-group. Genetically and socioeconomically both
advantaged. While they too show some very modest decline on highly speeded tasks, they are likely to maintain their
overall level of cognitive functioning until shortly before their demise. Good genes and also they remains active and
engage themselves in social, mental and physical activities during life. They are also less neurotic and more open to
new experiences most of their age peers.
(In most of older adults the reduce of cognitive flexibility is reflected in a more conservative and neurotic personality
and they became closer).
2. Normal aging → the largest part of individuals. This pattern is characterized by most individuals reaching an
asymptote in early midlife, maintaining a plateau until the late 50s or early 60s, and then showing modest decline on
most cognitive abilities through the early 80s, with more marked decline in the years prior to death. There is a
parallelism to opinion, attitudes and personality. Among those whose cognitive aging can be described as normal, we
can distinguish two subgroups. The first include those individuals who reach a relatively high level of cognitive
functioning who, even if they become physically frail, can remain independent until close to their demise (better
prognosis). The second group who only reach a modest asymptote in cognitive development, on the other hand, may
in old age require greater support and be more likely to experience a period of institutional care.
3. Mild Cognitive Impairment (MCI) → borderline condition. Experience greater than normative cognitive decline. 3
matters of controversy:
I. Definition of MCI→ Some have argued for a criterion of 1 SD of performance compared to the young adult
average, while others have proposed a rating of 0.5 on a clinical dementia rating scale, where 0 is normal and 1.0
is probable dementia.
II. Memory loss as a necessary feature? → Earlier on, the identification of MCI required the presence of memory
loss, in particular. However, more recently the diagnosis has been extended to decline in other cognitive abilities
and clinicians now distinguish between amnestic and non-amnestic MCI patterns.
III. Does MCI inevitably progress to dementia? Or whether this group of individuals represents a unique entity;
perhaps one that could be denoted as unsuccessful aging.
4. Dementia → dramatic impairment in each kind of cognitive functioning (pervasive). There are different causes and
post-mortem diagnosis reveals different neural changes depending on the type of dementia.

SOME THEORIES OF PSYCHOLOGICAL AGING

SOC THEORY (Baltes, 1977). In order to compensate for the loss there is a focus, a restriction of the interests and domains.
Selection, optimization and compensation are thought to advance the maximization of gains and minimization of losses
associated with aging. SOC theory represents a dialectical lifespan approach. Psychological gains and losses occur at every life
stage, but in old age losses far exceed the gains. SOC, however, can also be seen as strategies of life management, and thus may
be indicators of successful aging.
The second one is the ERIKSON’S STAGE MODEL (not for aging especially).
Erik Erikson remains the primary theorist coming from a psychoanalytic background who has consistently pursued a lifespan
approach. How can we have a hole sense of our life? The question of greatest priority in the study of ego development is: “How,
on the basis of a unique life cycle and a unique complex of psychosocial dynamics, each individual struggles to reconcile earlier
themes in order to bring into balance a lifelong sense of trustworthy wholeness and an opposing sense of bleak fragmentation”

All of us came across these stages or phases of life:

o Identity consolidation (starts in the adolescence)

o Intimacy crisis (future, chance to face big question)
o Generativity versus stagnation (middle age, education of one’s children, productivity and creativity in one’s work).
Successful resolution of the generativity crisis involves the human virtues of caring, giving, and teaching, in the home, on
the job, and in life in general.
o Integrity versus despair crisis (final years): is my life meaningful? Those who despair approach the end of life with the
feeling that death will be one more frustration in a series of failures. In contrast, the people with integrity accept their
lives (including their deaths) as important and on the whole satisfying. In a sense, ego integrity is the end result of the
lifelong search for ego identity, a recognition that one has coped reasonably successfully with the demands of both the
id and society.
o An exploration of personal grounds for faith. The experience of ultimate confidence is provided for the older person by
the confirmation of the distinctiveness of their integrated life and by its impending transcendence.

Administering an inventory of psychological development to three cohorts of college students followed-up after 11 and 22
years. Not only inner personality changes, but also effects of exposure to particular historical, cultural and social realities of
environment. This model is not unidirectional.

SCHAIE AND WILLIS’ STAGE THEORY OF COGNITION

o Acquisition stage
o Achieving stage (from the acquisition to the application of knowledge). It represents most prominently the application of
intelligence in situations that have profound consequences for achieving long-term goals.
o Responsible/executive stage (application of cognitive skills in situations involving social responsibility). Typically, the
responsible stage occurs when a family is established and the needs of spouse and offspring must be met. Similar
extensions of adult cognitive skills are required as responsibilities for others are acquired on the job and in the
community.
o Reintegration (from 60-65; reintegration of interests, attitudes and values). The information that elderly people acquire
and the knowledge they apply become a function of their interests, attitudes, and values. It requires, in fact, the
reintegration of all of these. Restriction of interest:
“The most important thing I discovered a few days after turning 65 is that I can't waste any more time doing things I
don't want to do”. (The great beauty)
o Reorganizational stage (maintenance of flexible cognitive styles to restructure the context and content of life after
retirement). The skills required for the reorganizational stage require the maintenance of reasonably high levels of
cognitive competence. In addition, maintenance of flexible cognitive styles is needed to be able to restructure the
context and content of life after retirement, to relinquish control of resources to others and to accept the partial
surrender of one’s independence.
o Legacy-creating stage (in the end of the life to conduct a life review).

CO-CONSTRUCTIVE PERSPECTIVE
Three principles are proposed regarding the relative contributions of biology and culture influences across the lifespan (more
and more influence of experience and cultural aspects across the lifespan).

1. Beneficial effects of the evolutionary selection process occur primarily in early life and are less likely to optimize
development in the later half of life.
2. Further advances in human development depend on ever-increasing cultural resources. From a historical perspective,
increases in cultural resources have occurred via cumulative cultural evolution and have resulted in humans reaching
higher levels of functioning. At the individual level, increasing cultural resources are required at older ages for further
development to occur or to prevent age-related losses.
3. The efficacy of increasing cultural resources is diminished in old age, due to decline in neurobiological functions.

It is based on a triarchic view of culture, Li (2003) proposes a triarchic view of culture involving three aspects of culture that are
related to the co-constructionist perspective: resource, process, and developmental relevancy.
 o Culture as social resources involves the knowledge, values and material artefacts accumulated by a society and
transmitted to future generations. these resources continue to develop and change through cumulative cultural
evolution (Tomasello)
o Culture as ongoing social process involves the routines, habits and performances of the individual in daily life that take
place in the individual’s proximal developmental context and that are shaped by the momentarily shared social reality.
o Developmental relevancy, that is the impact of particular cultural resources/processes on an individual is partially
determined by the individual’s developmental stage.

The increased influence of neurobiological factors in old age is thought to be based in part on the assumption among
evolutionary theorists that positive selection effects are most clearly manifest early in the lifespan and that the expression of
deleterious genes in old age has been less constrained by the evolutionary process.

NEUROIMAGING OF HEALTHY COGNITIVE AGING

Recently, advances in the area of neuroimaging have allowed for the examination of the relationship between cognitive and
neural differences in the aging brain. Given that cognitive processes depend on brain anatomy and physiology, it is natural to
expect that previously observed behavioral differences in aging are intimately linked to age-related changes in the integrity of
cerebral architecture and function. Main neural changes associated with aging. We don’t have to think that aging is simply
associated with macroscopic morphologic changes. We have to keep in mind that aging has an effect on different levels.
Aging is associated with alterations that are:

1. Morphological macro alterations: volume, white matter: we have a general reduction of the volume. The
volume decreases because of both grey matter and white matter decrements. Rate of volumetric loss is not
homogenous either across age or across structures.
AGE: The rate of volume e decline increases after 52-55 years. The decline starts but the rate of decline is higher during
the increasing of the age.
BRAIN STRUCTURES: Greatest shrinkage across the lifespan occurs in the caudate, cerebellum, hippocampus, and
prefrontal areas.

This line representing the same

subject: there is a decline in the
same subject at 5 years of
latency. The graph represents
many different participants with
different ages. What can we
infer? It represents the
reduction of the volume during
age. All those regions show a
declining in the volume during
age. The decline is larger with
increasing age but there is a
variability.

In those regions there are indeed not a clear decline. There is a minimal shrinkage in the entorhinal
cortex and the visual
cortex volume remains
stable across the
lifespan.
The entorhinal cortex
mediates familiarity
effect. The familiarity is
the feeling of have
already know something.
 Wat does it means? That aging is associated with the spear process in familiarity.
Hippocampus mediates the controlled memory processing and in this case there
is a reduction in memory performance. Is importanto to understend how decline
in a structure leds to a decline in the corrisponding cognitive function. So the
ability to remember in a controlled way is mediated by hippocampus. Familiarity
is an authomatic memory process: aging doesn’t have an effect in enthorinal
cortex and so neither to the familiarity effect.

Every time one study found something and another one found the opposite. Mixing results concerning the age-related shrinkage
in visual cortex: in general, visual cortex seems to be preserved (as well as visual processing). There are some contrasting
evidences. For example, Salat et al., (2004): age-related atrophy in the calcarine cortex, an area near primary visual cortex.

WHITE MATTER AND GREY MATTER

White matter loss: Diffusion tensor imaging (DTI) measures the rate and direction at
which water diffuses through white matter and provides an index of the density or
structural integrity of the white matter. Ii allows to detect how water passes in the
nerves (axons like rivers). If the rivers have not the barriers (myelin) the water come
out of the axons. Myelin is a lipid-rich substance that surrounds nerve cell axons to
insulate them and increase the rate at which information (encoded as electrical
impulses) is passed along the axon. This technique shows how the molecules of
water pass into the axon. In young individual we can see a clear and well-defined
signal of white matter, in older adult white matter appears smoothie because of the
deterioration of the myelin.

There is a deterioration of white matter but there is a progression

of the kind of deterioration: typically deterioration occurs first in
anterior regions, then in the posterior regions and finally the
occipital regions.
Results suggest an anterior–posterior gradient for decline in the
structural integrity of white matter.

Declines in white matter volume and integrity

are more evident in anterior regions.

o Rate decline in white matter is not constant during the lifespan

Young adults: 0.12% per year and in middle age (> 52 yrs): 0.35 % → the decline is more prominent
o Ventricles expand because of the deterioration of white matter.
We can observe a rate of 0.43% in younger adults and a rate of 4.25% after the age of 70.

WHITE MATTER INTEGRITY is explored using number of white matters hyperintensities (WMHs) present in a structural scan.
You will see in the scan some little spots of whitness. Also in thise case the most vulnerable reagion is the frontal cortex. Only
many of them are a phatological sign.
We can observe the same deterioration in grey metter: there is a decline that is larger and the rate of decline is higer for the
frontal, temporal and finally occipital regions.
But also in some subregions, for example in the basial ganglia, we
can observ that caudatum start to be deteriorated first. Is still not
clear why. Why in the same subregion of the same sisyem there
are some structure more vulnerable than others? Probably
because of trasmettitors or expression of genetic influences, it’s a
question mark.
Also in the deeper and inner regions of the brain we can see first cerebellum, vermis and finally pons.
In the corpus callosum we can see fascium that connect the right to the left part of the brain: also in this case we observ an
anter-posterior gradiant. The anter part declines earlier than the posterior part.

What about the functional deterioration?

2. Functional (macro) alteration: Measures of resting blood flow and metabolism suggest age-related difference
also in the activity of cerebral regions.

1. Cerebral Blood Flow (CFB)

2. Blood Oxygenation Level Depend (BOLD)
3. Hemodynamic Response Amplitude (HDR)

CBF and metabolic activity decline with age. Basically, all the techniques (fMRI, PET) explore the degree of oxygenation
in brain: the logic is that the regions there are active need to have blood (oxygen and nutrients). Comparing this
pattern of for example blood signal or HDR signa we can see how the brain works. Respect to a baseline we can see the
regions active and the regions deactivated. In general, there is a decline of the brain but then we will see in more details
what happen: not all the regions show a decline. Paradoxically some regions increase their activation to compensate for
deterioration of other regions.

3. Functional (micro) alterations:

The system that is mostly affected by age is dopaminergic system.
We can see in blue the pathway from the inner part of the brain goes
to the frontal regions and then backword to the posterior regions
(system dispreads over the brain).
What are the cognitive functions or aspect that are mediated by
dopaminergic system?
What is the role of DOPAMINERGIC RECEPTORS?
They play an important role regulation attention, the decision
making, cognitive and motor processes and in modulating response to contextual (e.g. emotional, reward) stimuli.
[Marshmallow test→ the ability to postpone a reward is a controlled function (frontal) and is associated to intelligence,
society, social ability…].
They can be measured using a radioligands (a radioactive substance that, when injected, binds to dopamine and allows
imaging of areas where receptors are located).
There is a strong relationship among age, the number of receptors and cognition.
Age-related decrease in Dopamine (DA) neurotransmitter concentration and in pre- and post- receptors, D1 and D2. (7-
10% per decade). We have a reduction in neurotransmitters, in the receptors, in the proteins what binds dopamine: we
can see a general hypoactivation of this system.
We can see a reduction in striatal DA transporter
protein binding. DA loss in aging also been INTERIM SUMMARY
observed in extra-striatal regions: in frontal,
temporal and occipital cortices, 1. Both white and grey matter decline show similar
in hippocampus and thalamus patterns in aging.
(always antero-posterior gradient). 2. Structural decline appearing most prominent in
Deficit in striatal DA have been associated advanced aging and anterior regions.
with reduction in: 3. Pre- and post- synaptic DA markers also tends to
▪ Episodic Memory follow this anterior-posterior gradient of decline.
▪ Executive functions 4. Greater age-related performance decrements in
▪ Motor performance cognitive functions mediated by frontal functioning
Taken together, resting neuroimaging measures suggest significant agerelated differences. Both white and gray matter decline show similar
patterns in aging, with structural decline appearing most prominent in advanced aging and anterior regions showing greater decline compared
to posterior regions. Age-related decline in both pre- and post-synaptic DA markers also tends to follow this anterior–posterior gradient of
decline. Both patterns coincide with behavioral data findings that show greater age-related performance decrements in cognitive functions
mediated by frontal functioning (see West, 1996) and greater cognitive decline in advanced aging (for a review see Park, 2002). Furthermore,
resting blood flow and metabolism measures (i.e., in rCMRglc, rCMRO2 and CBF) also show age-related decline in healthy adults. However,
caution should be used when interpreting these findings, for they also may reflect changes caused by age differences in cerebral atrophy. In
addition to resting neuroimaging measures, several studies have also examined cognitive performance—finding significant correlations
between structure and function. Thus, results underscore the need to not only consider age-related differences within a given measure, but
also to assess its relationship with behavioral measures of cognition.

It’s only a part of the story: there are some compensative phenomenon, especially in high performing individuals.

FOCUS ON CEREBRAL AGING

1. Is Aging a mere phenomenon of DECLINE: reduced activation, grey and white matter decline, loss of neurons? Or is it a
more complex process?
2. Which is the relationship between cerebral and cognitive aging?

Cerebral aging is a complex phenomenon. We can find 2 patterns of

activation: the PASA pattern and the HAROLD pattern.

PASA PATTERN is a posterior-anterior shift in aging. If you put an older adults in a fMRI
and you make him doing a task respect to a young individual you see that there is a
reduction of the activation in the occipital regions but an increasing activation of the
prefrontal cortex (especially adults that performance successfully in their life).
An age-related decrease in occipital activity is coupled with an age-related increase in
pre-frontal cortex (PFC) activity.
Older adults compensate for visual processing deficits (occipital decrease) by recruiting
higher cognitive processes (PFC increase).
How is it possible? In a difficult task, at the beginning we need a lot of control (PFC), but
when the task became easier, we don’t need to put so much control, it became like an
automatic function. Older adults need a lot of control to do a task that probably for a
young individual us an automatic task.

HAROLD PATTERN is a Hemispheric Asymmetry Reduction in OLDer Adults. Older

adults recruit in a similar way both the hemisphere.
e.d.: Working memory visual-spatial task in fMRI. The right pre-frontal cortex is more
activated in young individual but in older adults there is a reduction in the right pre-
frontal cortex and increase of activation of the left.
The other hemisphere helps the most specialized one to do the task.
- More bilateral (less asymmetric) pattern of PFC activity
- Compensatory mechanism
- Correlates with successful cognitive performance
- An alternative account: such a widespread activation pattern reflects a difficulty in
engaging specialized neural mechanisms
(it’s difficult to recruit a specific region for Fabiani et al).

In which kind of domains this pattern is shown?

Other studies have shown an age-related reduction of

MTL (medial temporal lobes) activation coupled with
an increased frontal activation.
 VISUAL PERCEPTION
In general, we have seen that older adults recruit less the occipital visual regions: there is a

o reduction of the activation in the posterior regions (especially the visual cortex)

o increase of the activation in the anterior regions of the ventral pathway.

Older adults have sometime an attenuation in emotions. This may be due to a reduction in amygdala activation. The reduction in
those posterior regions are associated with increase in more anterior brain regions: PFC, anterior cingulate, insula.

ATTENTION! Compensation is shown in the form of:

o PASA pattern
o Activation of deep grey matter regions (striatum, thalamus, insula)

E.g.: when cueing selective attention → both spatial and colour visual stimuli elicited weaker occipital activity but stronger PFC
activation.

However, not all attention studies show anterior increase: in odd-ball task no age-related differences in frontal activation.

LANGUAGE/SEMANTIC PROCESSING
If the task is easy or if the cognitive functions are preserved there is no need to recruit frontal cortex, indeed in language and
semantic that are preserved in aging → No PASA compensatory phenomenon. Respect to other cognitive functions language is
shield.

Task: sentence comprehension across different WM loads

both younger and older adults recruited a similar set of regions, regardless of WM demands (for example left temporal and
ventrolateral PFC regions, bilateral occipital cortex).

Overall, however, older adults showed weaker activation in parietal cortex and greater activation in left dorsal PFC, right
temporal lobe, bilateral anteromedial PFC regions.

WORKING MEMORY
Memory is a difficult and controlled function. Involves several cognitive operations: maintenance, manipulation and
monitoring of information + executive processes involved in problem solving and reasoning

Older adults Older adults

reduced right and reduced left and
increased left PFC increased right
activity. PFC activity
 EXECUTIVE FUNCTIONS
A set of processes: Inhibition, Switching and Updating

IMPLICIT MEMORY
Investigated using tasks such as:
o Word stem completion priming
o Repetition priming
o Sequence learning
o Probabilistic categorical learning
In older adults, implicit memory is relatively preserved (entorhinal is preserved in healthy aging): similar regions are
activated in younger and older adults but there is a reduced activity within these regions in older adults. We can see age-
related decreases in frontal and striatal regions.

EPISODIC MEMORY
Cabeza et al. (2004) confirmed a pattern if increases frontal bilaterality and decreased hippocampal activation in older
adults. This pattern was shared across tasks of attention, working memory and long-term memory, demonstrating the
global nature of this pattern.
Episodic memory is one of the cognitive functions most affected by aging.
As older adults cannot maintain/retrieve information from hippocampus, they need more control to source from the
memory → so they recruit the frontal cortex.

ENCODING

Young adults recruit the left prefrontal cortex, the

low-functioning old adults recruit less the left
prefrontal cortex and the high-
functioning old adults recruit right and
left prefrontal cortex. This is a
compensatory mechanism to
remembering, to encoding and retrieve
information.

In memory we have 3 phases: encoding information, maintain information and retrieving information. In aging the most
affected stage is encoding information. What is seems is that we have:
o An increased activity in the right PFC regions → first HAROLD PATTERN only in high-performing group
o Reduction in left PFC and MLT activity that seems to reflect a disturbed encoding network (because of the difficult to
encode the specificity of the stimulus, problems in elaborating in a propriate way each part of the stimulus).
o Decreases in posterior parietal and visual regions (deficit encoding of visuospatial information).
 RETRIVAL
Age effects are more pronounced for encoding than retrieval.

PASA PATTERN:

o Decreases in occipital and parietal regions

o Increases in PFC and MTL
Overactivation of prefrontal regions has been specifically linked to improved memory in older adults.

HAROLD PATTERN:
o More bilateral pattern of PFC and MTL
Has also been observed in MTL regions during recall of words and autobiographical memories. Several studies reported
increases in MTL activity with age (only for high-performing old adults).
Cabeza et al. (2004) found a dissociation between hippocampus, which showed weaker activity in older adults, and the
para-hippocampal gyrus which showed greater activity in older adults.
o Hippocampus → recollection
o Cortical MTL regions → familiarity

TMS study (Rossi et al., 2004)

If I put a magnetic field over the brain, which is an electrical
structure, and I stimulate the brain with a little magnetic current →
there is an interference: TMS leads to a reversable and temporary
perturbation of brain activity.
In this way you can tell if a region is important for a task.
TMS is probably the most important technique that allows to
investigate causal links.

Encoding: young and older adults studied pictures while rTMS was applied to the subject’s left or right DLPFC.
Recognition phase: the subjects then made recognition judgments while rTMS was again applied to the left or right DLPFC.

YOUNG ADULTS: memory retrieval accuracy MOST affected when the rTMS was applied to the left compared to the right
hemisphere → the right is not involving, and nothing changes.

OLDER ADULTS: retrieval equally impaired → they need both the 2 hemispheres to execute the test.
 COMPENSATION for what? Several hypotheses that are not mutually exclusive.
1. Deficient hippocampal activations→ Frontal overactivation compensates structural and functional changes in
medial temporal regions, being associated with hippocampal shrinkage and memory loss and decreased
hippocampal/para-hippocampal activations.
However, we have different view, for example Buckner (2004):
Normal aging – frontal shrinkage along with increases in frontal activation
Pathological aging – declining hippocampal/entorhinal volume and activation

2. Differentiation as an impetus for compensation → Young adults show activations that are highly specific to
category: Faces in left and right fusiform areas of ventral visual cortex
Pictures of places, houses and outdoor scenes in the para-hippocampus
Words and numbers in the left fusiform gyrus and collateral sulcus
Older adults show activations that is aspecific: less neural specificity in the fusiform face area, para-hippocampal place
area and the lateral occipital area specialized for letters.
Therefore, increased activation of frontal cortex provides additional compensatory processing to recognize and
differentiate categories as we age. As they lose specificity, they recruit everything but this necessary led to an aspecific
representation of the reality: only with the help of prefrontal cortex they can manage.
3. Difficult suppression of the default network* → Activated when we are directed in our inner world, but when we
have to pay attention the default network is suppressed, and the dorsal attention network becomes to be active. Older
adults show significantly less suppression of the default network than young adults: the shift is quick and stable in
young, indeed in older adults the default network keep being active. They fail to suppress irrelevant stimuli and
intrusions. The failure to suppress is actively related to lower performance on some cognitive tasks.

Increased frontal activity in older adults due to a failure to shift from default network to active networks.

[*or default state network, is a large scale brain network of interacting brain
regions known to have activity highly correlated with each other and distinct from
other networks in the brain. It was initially assumed that the default mode network
was most commonly active when a person is not focused on the outside world and
the brain is at wakeful rest, such as during daydreaming and mind-wandering.
However, it is now known that it can contribute to elements of experience that are
related to external task performance. It is also active when the individual is thinking
about others, thinking about themselves, remembering the past, and planning for
the future. Though the DMN was originally noticed to be deactivated in certain goal-oriented tasks and is sometimes referred to
as the task-negative network, it can be active in other goal-oriented tasks such as social working memory or autobiographical
tasks. The DMN has been shown to be negatively correlated with other networks such as attention networks.]

INTERIM SUMMARY

1. PASA and HAROLD pattern shown in many

cognitive domains.
2. Especially in:
- High-performing older individuals
- High-demanding tasks
3. Compensatory mechanism
 LINKING BRAIN DATA AND COGNITIVE AGING THEORIES
➢ SENSORY DEFICIT THEORY (Lindenberger & Baltes, 1994)
Older adults show considerable deficits in basic sensory functioning (both vision and auditory processing).
Three views:
1. Cascade view → sensory organ degeneration leads to sensory deficits and, eventually, to cognitive decline.
2. Common cause view → sensory and cognitive deficits are both mediated by widespread neural degeneration.
3. Decline-Compensation view → deterioration of sensory processing may be compensated by over-recruitment of
top-down processes mediated by PFC.

NEUROIMAGING EVIDENCE
PASA pattern is an
evidence supporting
sensory deficit theory:
• Decrease in posterior
activity coupled with an
age-related increase in PFC
activity
• Has been found across a
variety of cognitive
functions à sensory deficits
have a global impact on
cognitive functions.

➢ RESOURCHES DEFICIT THEORY (Craik et al., 1983)

Aging is associated with a reduction in tha amount of attentional resources.

NEUROIMAGING EVIDENCE
Deficits in processes are related to a reduction in the efficiency of frontal lobe functioning.
This theory predicts HAROLD PATTERN: Weaker activity in older adults in the PFC hemisphere
usually recruited by younger adults. They may compensate by recruiting contralateral PFC
regions.

➢ SPEED DEFICIT THEORY (Salthouse, 1996)

Older adults’ cognitive deficits reflect a general reduction in the speed of cognitive processes.
Low processing speed impairs performance because of 2 mechanisms:
o the time required by early operations reduces the time available for later operations (limited time mechanism)
o the products of early operations are lost or irrelevant by the time later operations are completed (simultaneity
mechanism)
 NEUROIMAGING EVIDENCE
One possible neural mechanism for age-related slowing → white matter deterioration.
The myelin sheath increases speed of neural
transmission along axons, and hence its
deterioration can lead to a slowing in neural
communication.

White matter alterations evidenced

by DTI

➢ INHIBITION DEFICIT THEORY (Hasher & Zacks, 1988)

Cerebral regions can be distinguished in:

➢ RECOLLECTION DEFICIT THEORY

It is specific to the episodic memory domain.
Episodic memory deficits are larger for recollection than for familiarity.

NEURAL CORRELATES:
o Recollection→ HIPPOCAMPUS
o FAMILIARITY →CORTICAL MTL REGIONS (such as Perirhinal cortex).

NEUROIMAGING EVIDENCE

INTERIM CONCLUSION

• Brain undergoes significant change with age

• Age-related atrophy differs across and within regions
• Correlations between these measures and cognitive functions emphasize the importance these changes have
on cognitive functions.

Two consistent patterns of age-related differences in brain activity, PASA and HAROLD pattern, seem to reflect
compensatory mechanisms and they are more evident in high-performers than low-performers.
 ➢ Scaffolding theory of aging and cognition (Park & Reuter-Lorenz)
The authors argue that the unprecedented opportunity to look into the operation of the mind afforded by
neuroimaging indicates the brain and cognitive system to be more dynamic and adaptive then was ever previously
suspected. For this model the brain is a dynamic organism seeking to maintain homeostatic cognitive function. With
age, the number of dopaminergic receptors declines; many brain structures show volumetric shrinkage; white matter
becomes less dense; and brains of even very highly functioning individuals are frequently characterized by destructive
neurofibrillary plaques and tangles. We argue that the brain responds to these neural insults by engaging in continuous
functional reorganization and functional repairs that result in selfgenerated support of cognitive function.

Scaffolding? A homeostatic process

that results in changes in brain
function through:
o Strengthening of existing connections
o Formation of new connections
o Disuse of connections (weak or faulty)

Behavior is maintained at a relatively high

level with age, despite neural challenges and
functional deterioration, due to the
continuous engagement of compensatory
scaffolding: the recruitment of additional
circuitry.

Assumption:

▪ It is not merely the brain’s response to normal aging; it is the brain’s normal response to challenge. It’s a process across
lifespan.

▪ Prefrontal cortex is the primary locus for scaffolding Scaffolding provides supplementary, complementary, and, in some
cases, alternative ways to achieve a particular behavioral output or cognitive goal Thus requires a versatile brain
structure: PREFRONTAL CORTEX

▪ Scaffolding is a way of facing challenges The case of right DLPFC in verbal working memory tasks (which typically involve
left DLPFC)
▪ Scaffolded Networks are less efficient than honed cognitive networks

▪ The Aged Brain is Less Efficient at Generating Scaffolding, and Pathology May Entirely Limit Scaffolding Operations.
Normal aging: As aging proceeds, the need for compensatory scaffolding exceeds the capacity for plasticity and
reorganization, leading to the more frank expression of cognitive loss in the oldest old .
Neural Pathology: penetrates the scaffolding, leading to total collapse of the scaffolding.
▪ Individual Variability and the Factors that Promote Scaffolding.
Inter-individual differences in:
• Magnitude of decline
• Amount of protective scaffolding

Because of:

▪ Genetic susceptibility (hetero- or homozygosity for APOE4)

▪ Disease (hypertension)
▪ Adverse experiences (e.g., chemotherapy)
▪ Advanced age
▪ Cognitive/social experiences
▪ Scaffolding is Promoted by Training and Cognitive Activity.
Studies with nonhuman animals:
✓ Adult rats that had degraded auditory cortices early in life were able, with intensive discrimination training in
adulthood, were shown to develop normal auditory function.
✓ Old rats maintained in complex visual and play environments showed birth of new neurons in the
hippocampus in old age and a decrease in atrophy in the dentate gyrus.

Possible mediators in animals? Possible mediators in human?

Highly educated people who tend to be involved in more cognitively

stimulating activities

✓ Increased intellectual functioning

✓ More protect against the risk of Alzheimer’s disease
✓ More cognitively resilient in the early stages of Alzheimer’s disease
 AGING AND PHYSICAL ACTIVITY
Why a lecture on physical activity?
1. Expected increase over the next several decades in the proportion of adults over the age of 65 à concomitant increase
in the proportion of age-related diseases.
2. Growing need to identify factors earlier in life that either precipitate the onset of cognitive decline or protectagainst
decline.
3. Presence of factorsthat influence the trajectory of cognitive losses.
4. The non-pharmaceutical products marketed as tools to potentially mitigate cognitive losses and dementia in late life
revealed to be not so effective.
5. Natural capacity for brain plasticity in late adulthood and that physical activity has the capacity to take advantage of
this natural characteristic of the brain.

A diminished capacity for plasticity may suggest that physical activity or cognitive training interventions could have limited
effects in altering cognitive and brain outcomes in late adulthood.

however

There is considerable promise for non-pharmaceutical approaches that focus on health behaviors, and in particular physical
activity.

PHYSICAL ACTIVITY is any activity that may be aerobic or non-aerobic in nature and independent of the type, dose, or
frequency of the activity.

We can use self-reported questionnaires: e.g., “how many city blocks do you walk per day?” Pros and cons of Self-reported
questionnaires?
Pros: easy to administered à large number of participants
Cons: social desirability

More recently: more objective studies (devises as accelerometers, pedometers).

Maximal oxygen capacity (VO2max)→ is the maximum rate of oxygen consumption as measured during incremental
exercise. It’s a measure of cardiovascular fitness and maximal aerobic power and it’s often used to assess the efficacy of
interventions to improve cardio-vascular fitness. It’s a measure of aerobic capacity that is modifiable by participation in
aerobic activities. Absolute values of VO2 max are typically 4060% higher in men than in women.

Why a lecture on physical activity?

Seminal studies (Larson et al. (2006)):
1) 1740 participants over the age of 65 without cognitive impairment They reported the number of times per week that
they performed physical activities for at least 15 min over the past year.
After a follow-up period of 6.2 years, the incidence rate of AD was significantly higher for individuals that engaged in
physical activity fewer than three times per week.
2) Retrospective studies have found that self-reported physical activity during early to midlife is associated with a
reduced risk of dementia and mild cognitive impairment (MCI)
3) In a meta-analysis of 15 prospective longitudinal studies including more than 33,000participants that were followed for
1–12 years, greater engagement in physical activity was associated with nearly a 40 % reduced risk for cognitive
decline.

PROBLEMS of these studies:

I. Which kind of measures?

o Self-reports non sensitive and reliable.
o Objective fitness measures were significantly associated with reduced cognitive decline.

Objective measures more sensitive to physical activity patterns throughout the day and less susceptible to biases associated
with self-reports.

II. Correlation not causality - what comes first?

Individuals with subtle losses in cognitive function may choose to avoid engagement in physical activity or that loss in
physical functions is a prodromal marker for cognitive decline and dementia-related pathology.
HOW TO SOLVE ‘Correlation not causality’ PROBLEM?
Randomized controlled studies, that assign individuals to one of two conditions:
(i) a treatment condition that receives moderate intensity physical activity such as brisk walking or resistance training.
(ii) a control condition (light stretching)

SEMINAL STUDIES:
1. Dustman et al. (1984)→ 43 sedentary, cognitively healthy, older adults assigned to one of three groups for a 4-
month period:
a. Aerobic training group (three 1-h walking and slow jogging sessions per week)
b. A control group that received light strength and flexibility exercises
c. A non-exercise control group.
➔ They found that the aerobic exercise condition showed improvements on measures of memory, processing speed, and
inhibitory control while each of the control groups did not improve on any of these measures.
2. Kramer et al. (1999)→ 124 cognitively healthy, but low-fit older adults that were randomized to 6 months of.
a. A brisk walking conditions
b. Stretching-and-toning control condition
➔ They found that the aerobic exercise group, compared with the control group, demonstrated improvements on
EXECUTIVE FUNCTIONS: including task-switching, response compatibility, and stopping tasks.

Effects of exercise on cognitive function: general and specific? BOTH!

GENERAL, because nearly all cognitive domains improved after exercise, but SPECIFIC in the sense that executive functions were
affected more than other cognitive domains.

Which kind of physical activity? Aerobic exercise programs were the most effective, especially when combined with resistance
training. Different effects of open-skill versus closed-skill physical interventions.

Effects of Exercise on Impaired Populations:

✓
33 older adults with MCI
1) an aerobic exercise group
2) a stretching control group
For 4 days per week for 6 months
➔ SEX-SPECIFIC EFFECTS: Women showed improvements, men showed only marginal improvements.
 ✓ 86 women with MCI
1) aerobic exercise group
2) resistance training group
3) a balance and toning control group
For 2 days per week
➔ Aerobic exercise improved verbal learning memory; Resistance training improved associative memory and executive
functions.

Effects of Exercise on brain structures:

o Gray Matter Volume

o White Matter Integrity
o Self-reported measures of physical activity greater engagement in physical activity was associated with greater volume
of the prefrontal cortex (even in those with low amounts of physical activity)
o Objective measures of cardiorespiratory fitness levels.
o Higher fitness levels were associated with greater hippocampal volumes and that larger hippocampi were associated
with better spatial memory performance→ PREFRONTAL AND HYPPOCAMPUS.

COLCOMBE et al. (2006)→ Randomized studies: Aerobic Exercise Training Increases GRAY MATTER Volume
AIM: examined whether aerobic fitness training of older humans can increase brain volume in regions associated with age-
related decline in both brain structure and cognition.
METHOD: 59 healthy but sedentary community-dwelling volunteers, aged 60–79 years.

o 6-months randomized clinical trial: HALF OF THEM→Aerobic

HALF OF THEM à Toning and stretching

MRI images were collected before and after the 6-month fitness intervention.

RESULTS: Significant increases in brain volume, in gray matters (PREFRONTAL AND ANTERIOR CINGULATE CORTEX) for the older
adults who participated in the aerobicfitness training but not for the older adults who participated in the stretching and toning
(nonaerobic) control group.

ERIKSON et al. (2011)→ Randomized studies: Aerobic Exercise Training

o 120 cognitively healthy older adults (brisk walking VERSUS stretching-toning).
o 12 months.

RESULTS: They found that the brisk walking condition increased the size of the hippocampus while the stretching control group
showed a decline over the same period.ù

WEINSTEIN et al. (2012)→ The association between aerobic fitness and executive function is mediated by prefrontal cortex
volume.

Do fitness-related increases in GRAY METTER volume lead to elevated cognitive function?

METHOD: Subjects: 142 older adults (mean age = 66.6 years)

▪ Structural magnetic resonance imaging (MRI) scans

▪ Cardio-respiratory fitness assessments
▪ Stroop and spatial working memory (SPWM) tasks.

RESULTS: Higher cardiorespiratory fitness levels were associated with:

o Better performance on both the Stroop and SPWM tasks,

o Greater gray matter volume in several regions (e.g., prefrontal, anterior cingulate cortex).
• Volume of the right inferior frontal gyrus and precentral gyrus mediated the relationship between CRF and Stroop
interference
• DLPFC mediated the association between CRF and SPWM accuracy.

Aerobic Exercise Training Increases WHITE MATTER Volume?

Tseng et al. (2013) using diffusion tensor imaging (DTI) examined white matter integrity in ten older adult athletes compared to
ten sedentary controls. Athletes had greater white matter integrity and fewer white matter lesions.
Exercise Training and fMRI

▪ Higher cardiorespiratory fitness levels associated with greater brain activation during an attentionally demanding task in the
prefrontal and parietal cortices and reduced activation in the anterior cingulate cortex.
▪ Resistance training increased neural activation in the anterior portion of the left middle temporal gyrusand the left anterior
insula extending into lateral occipital and frontal cortex.

MEDIATORS & MODERATORS

MEDIATORS:

➢ Increasing the rate of angiogenesis

➢ The production of new capillary beds in several brain areas à more nutrients and oxygen
➢ Proliferation and survival of new neurons in the dentate gyrus of the hippocampus→ learning
and memory
➢ Increased BDNF (brain-derived neurotrophic factor (BDNF)
➢ Decreases in proinflammatory cytokines § changes in neurotransmitter systems including dopamine and serotonin

Moderator: APOE ε4→ APOE ε4 carriers benefited more than non-carriers from physical activity.

COGNITIVE FUNCTIONS IN A ULTRA-MARATHON

Details of the race:

▪ Trans d’Havet (‘Piccole Dolomiti’)

▪ 80 Km § 5500 mD+
▪ Maximum altitude: 2238 m
▪ Race started at midnight (25 July 2014)

o 30 subjects (males; M= 43 years, D. S.= 8.6) 15 with ‘high score’ (high-performers) 15 with ‘high score’ (low-performers)
o Cognitive tests - Inhibitory Control Task (response speed, attention, working memory, response inhibition)
o Dual task paradigm (external versus internal focus of attention)
o Inhibitory Control Task (attention, working memory, response
inhibition)

o Dual task paradigm

ENCODING: ‘ENCODE THESE 5 PICTURES’

DUAL TASK: 1°TASK: N-BACK TASK

2°TASK: ‘IF YOU SEE ONE OF THE PREVIOUS 5

PICTURES, PRESS ANOTHER KEY’

RESULTS: Comparingthe performance betweenhigh-performers and lowperformers.

Inhibitory Control Task

o High performers have higher levels of accuracy in the no-go trials, where the inhibition of
response was required
o No difference in attention and working memory

Dual task paradigm

• High performers are faster in performing the first task as they are less distractable by the information of the second task.

Factors that influence the performance:

▪ Good motor inhibition → Agility

▪ External focus of attention → Being focused on the external stimuli, and not being distracted by internal, irrelevant,
thoughts.
 PREVENTION OF COGNITIVE DECLINE

Ten percent of persons older than 65 years, 50% of those older than 85 years have AD.
By 2050, the prevalence of AD in the USA is expected to triple. The risk of dementia nearly doubles with every 5 years of age.

Prevalence→ static picture of percentual people who develop AD in a year. refers to a condition that tells us how widespread a
disease is in a population whereas incidence refers to new cases of the disease in the population in a year.
Incidence→ is the ratio of total new cases in a population divided by total population

The US Medicare economic cost of caring for people with dementia in 2008 was 91 billion dollars, and it is expected to nearly
double by 2015.in the onset of AD can be delayed by 5 years, the expected prevalence would decrease by more than 1 million
cases after 10 years and more than 4 million cases after 50 years.

ALZHEIMER’S DISEASE. Early pathological change:

o Deposition of beta amyloid (Aβ 42)

o Related tau accumulation

In vulnerable brain areas such as the hippocampus and the entorhinal cortex.

APP (amyloid precursor protein) generates beta amyloid ranging from 39- to 42- amino acid peptide.

Later pathological change:

o The Aβ 42 and tau aggregates progress to plaques and tangles that are eventually widespread in the brain.
o Synaptic dysfunction
o Neuronal loss
▪ Oxidative damage
▪ Excessive glutaminergic activity
▪ Energy failure
▪ Inflammation
▪ Apoptosis

Later pathological change:

o Degeneration of some regions due to neurotransmitter deficiencies

(degeneration of the basal forebrain is associated with decrements in
acetylcholine- mediated neuronal activity involved in memory).

RISK FACTORS:

▪ Genetic
▪ Clinical
▪ Environmental
▪ Vascular risk factors
o Diabetes mellitus (DM)
o Hypertension (HTN)
o Dyslipidaemia (Dys)
o Smoking
Different prophylaxes for different stages
Primary prophylaxis→ avoidance of age-associated cognitive decline.
Secondary prophylaxis→ prevention or slowing of progression from MCI to dementia.
Tertiary prophylaxis→ treatment of dementia (gaining of function, stabilization of the decline, or slowing of the progression).

Since the most prevalent of the dementias is Alzheimer’s Disease → interventions based on AD.
Intervention also related (to a lesser degree) to vascular dementia.

SO, DIFFERENT PROPHYLAXES FOR DIFFERENT PATHOPHYSIOLOGICAL PROCESS:

COMBINATION OF:

- Aβ and TAU aggregation inhibitors

- Antioxidants
- Anti-inflammatory compounds
- Cognitive enhancers or facilitators
- Neuroprotective agents

The failure of recent trials to prevent cognitive decline and the complexity of the cascade leading to AD
suggest that pleiotropic interventions may be more likely to succeed.

VITAMINS AND MINERALS

B vitamins

➔
Vitamin B1 (thiamine) and vitamin B2 (riboflavin) exist in a variety of food soures:
o Enriched and whole grain cereals
o Organ meats
o Milk
o Vegetables
➔ Vitamin B6 (pyridoxine) and vitamin B12 (cobalamin) come from meat, poultry, seafood, eggs, enriched cereals.
➔ Folates (e.g. vitamin B9)
o Major source of folates in the green leafy vegetables. “folium” from latin: spinach, turnip greens, bok choy, parsley and
romaine lettuce are all rated by our system as excellent sources of folate.
o Other vegetables can be strong sources as well, and we see asparagus, cauliflower, broccoli and beets.
o Several legumes do very well for this nutrient. At the top of the list here are lentils, which achieve a rating of “excellent”
for folate.

B VITAMINS
Antioxidant and anti-inflammatory proprieties: vitamin B12, folate and vitamin B6 interact together in the metabolism of
homocysteine → high levels can be deleterious due to neurotoxic and vasotoxic effects. Risk factor for vascular disease and
dementia.

Studies: interaction between folate, vitamin B6, B12 and cognitive decline. Folate levels are associated with different degrees of
cognitive decline independent of the homocysteine and vitamin B levels.

VITAMIN B1 (Thiamine)
Studies using animal models:

o Rats with low thiamine diet have impaired cognitive performance.

o Repetitive episodes of thiamine deficiency can cause worsening of cognitive performance and severe brain damage.
o Blood-brain barrier (BBB) dysfunction
o Intracellular edema

Studies in humans: older individuals supplemented with 3-8 g/day of oral thiamine showed statically significant improvement in
the ADAS in the initial months with slowing of the cognitive decline rate during 22-13 months after the trial stopped. [ADAS=
Alzheimer's Disease Assessment Scale].
Was found a improvement in scores on the MMSE but no evidence that low B1 leads to AD.
VITAMIN B2 (Riboflavin)
Dietary B2 intake improve cognitive performance in some cognitive domains. Better MMSE score (but only in women) and low
B2 is not associated with AD.

VITAMIN B6 (Pyridoxine)
In rodents→ low pyridoxine was associated with worse motor skills.
In humans→ high-dose pyridoxine associated with improved long-term memory and low pyridoxine was associated with AD (but
interpretation bias, so not clear).

VITAMIN B12 (Cobalamin)

A more specific marker for vitamin B12 deficiency (high methylmalonic acid level) eas associated with a faster rate of cognitive
decline, especially in APOEe 4 carries. The administration of coblamin was associated with improvement on a 12-word list
learning test at 15 min.

o The supplementation of cobalamin for the prevention or treatment of cognitive decline is not supported at this point
o However, vitamin B12 levels are part of the workup for reversible causes of dementia as well as other neurological
diseases, and deficiencies should be a target of clinical intervention.

Folate
In folate deficient mice: no differences in Ab deposition but in cornus ammonis (CA)3 [a region of the hippocampus] had at least
20% fewer neurons compared to controls.
Apolipoprotein E gene (ApoE)-deficient mice, a model of increased susceptibility to oxidative damage.

Two groups: fed with folate-free diet in one group and folate-supplemented diet in the other one.
Folate-supplemented→ decrement in the amount of oxidative.

In humans, contrasting results:

1. One study shows that high dietary folate offered protection against cognitive decline
2. Another study showed that high folate intake from food or supplements was associated with faster cognitive decline
3. Most of the cross-sectional and case-control studies suggest that lower levels of serum folate or higher-prevalence of
folate deficiency is found in patients with AD.
o Folate supplementation improved cognitive scores in aged patients with cognitive impairment and low folate levels.
o Folate supplementation improved cognition in the older women.
4. Recent systematic reviews and meta-analysis do not support the use of folate with or without
vitamin B supplements for the prevention or treatment of cognitive decline in the short term.

Vitamine C and D
o Powerful antioxidant
o Better cognitive performance associated with vitamin C

Study (older than 65 followed on average for 7 years)

Higher intake of vitamin E and C→ higher MMSE scores.
Low intake of vitamin E and C → higher rate of decline in MMSE

Chromium
Chromium is an essential trace mineral used in insulin receptor signalling, and it is thought to amplify the insulina action.

➔ Individuals with chromium supplementation had increased activation in multiple regions of the brain, including the
thalamus and the frontal cortex; however, areas of activation did not correspond to the improved cognitive
performance.
 POLYPHENOLIC COMPOUNDS (Flavonoids)
• Wine related myricetin (MYR)
• Curcumin
• Nordihydroguaiaretic acid (NDGA)
• Rosmarinic acid (RA)

(berries, onions, dark chocolate, broccoli, apples, tea, red wine, purple grape juice, soybean and tomatoes)

• Antioxidative, antiviral and anticarcinogenic properties

• Strong anti-Ab aggregation properties in vitro

Barriers
Against the oxidative and inflammatory process associated with aging

➔ In blueberry-fed rats improved cognitive performance, increased neurogenesis in the dentate gyrus

Curcumin
It’s a potent antioxidant an effective anti-inflammatory compound. It can inhibit the formation of Ab oligomers and fibrils, bind
plaque and reduce plaque burden.

➔ Promising results with rats, still tentative results with humans.

Omega-3 (Docosahexaenoic Acid (DHA))

It’s polyunsaturated fatty acid we can find in marine algae, fatty fish and fish oil. Pleiotropic mechanism:

o Preservation of debrin, a vital component for the adequate synaptic function

o Ani-inflammatory activity, neuroprotection, neuro-genesis, antioxidant, metabolic enhancer and weak amyloid
aggregation inhibitor.
➔ Studies have failed to identify unequivocal evidence suggestive of a protective effect of DHA on cognitive decline. BUT
the association of DHA with slower cognitive decline seems to be somewhat consistent across studies: a potential role
in the prevention of cognitive decline, more evident in APOE e 4-negative patients.

DIET
What is the best diet for preventing cognitive decline? “Mediterranean diet” rich in fruits, vegetables, whole grains, olive oil,
cheese and yogurt, low-to-moderate consumption of wine and fish or seafood products.

➔ A higher Mediterranean diet score was associated with better cognition. Many covariates associated with a healthier
diet, such es education, exercise and less prevalent cardiovascular risk factor. The final impact of the Mediterranean
diet on cognition is still debatable.

Other supplements or Diet-Related Items

▪ Garlic: reduces cardiovascular risk factors and their impact on the development of AD. Supplying important
antioxidants that counteract the ongoing neurogenerative process.
➔ In animal models can reduce homocysteine
▪ Ginkgo biloba: affect inflammation and oxidative processes in the human body.
➔ A recent meta-analysis on nine trials using standardized formulation of ginkgo biloba in the treatment of dementia
showed statistically significant improvement in cognitive scales. BUT contrasting results.
▪ Alcohol: low-to-moderate alcohol consumption has been associated with decrease risk of dementia.
▪ Caffeine: in humans, caffeine reaches a peak in plasma 45-120 min after oral ingestion and has a half-life that ranges
from 2.5 to 4.5 hours. Caffeine facilitates learning on tasks in which information is presented passively. Caffeine confers
a boost for cognitive performance among fatigued individuals. Caffeine appears to have a differential effect across the
age span (more effective in older adults). The relationship between AD and caffeine has been more elusive to grasp:
maybe a protective effect of caffeine in individual consuming more than three cup per day (confounding variables?
Social class? IQ?)
CARDIOVASCULAR RISK PROFILE: what is good for our heart is good for our brain.
▪ Cardiovascular risk factors seem to be strongly associated with cognitive decline and dementia.
▪ Carry the great advantage of being modifiable
▪ Cardiovascular risk factors
o Hypertension
o Diabetes
o Dyslipidaemia
o Smoking
▪ Vascular disease is associated with cerebral hypoperfusion, oxidative stress, neurodegeneration and cognitive decline
▪ The pure cases of AD account for less than 20% of all the cases and that AD with various components of vascular
disease are much more common than AD alone.
▪ Hypertension and Hypercholesterolemia
✓ There is a time period where exposure is more fundamental for subsequent risk
✓ Higher levels of systolic pressure in midlife are associated with higher risk of dementia later in life, but lower
levels of systolic pressure later in life, but lower levels of systolic pressure later in life can also be associated
with dementia.
✓ The same effect has been described for cholesterol levels
▪ Diabetes and Insulin Resistance
✓ Insulin facilitates cognition when given concomitantly with glucose to support metabolism.
✓ Defects in insulin signalling are associated with increased deposition of Ab and hyperphosphorylated tau.
✓ Patient with diabetes have lower hippocampal and prefrontal volumes when compared with non-diabetic
controls.
▪ Smoking
✓ Dose-effect relationship of higher exposure to nicotine and lower incidence of dementia
✓ Elderly smokers have increased risk of dementia and cognitive decline
✓ Here is a dose-effect gradient with higher odds for heavier smokers

Protective factors are:

o Physical Exercise
o Cognitive Engagement
COGNITIVE TRAININGS: engaging in highly complex mental activities is a protective factor against the development of
dementia, with a dose-dependent effect.
➔ The ACTIVE trial (2002) was a major study in this field that randomized 2,832 patients to four groups and three
intervention arms:
1. Memory training group;
2. Reasoning training group; 3.
Processing speed training group;
4. Control
A 5-year follow-up of the same population showed that compared with the control group, cognitive-trained subject
had improved cognitive abilities specific to the abilities trained that persisted after the intervention was stopped.
In MCI patients, multimodal intervention is more effective (than unimodal memory training).
o Social Engagement

DEPRESSION: it’s difficult to isolate depression from dementia:

o Patients with dementia have a higher prevalence of depression than nondemented populations
o Depression could be a prodromal sign of dementia
➔ Depression may be a risk factor for AD.

PHARMACOLOGICAL STRATEGIES:
1. HORMONES→ the apparent slower degeneration in women in early adulthood reverses in the postmenopausal stage,
with greater odds of dementia for women when compared with men.
Memory problems are frequently associated with menopause.
Estrogens influence verbal fluency, verbal memory, performance in spatial tasks and fine motor skills.
Mediate the oxidative processes, neuroprotective. However, the studies did not show that a therapy consisting in
estrogen in combination with progesterone offers a protective effect against cognitive decline in the form of MCI or
 probable dementia. On the contrary, they found an elevated risk of developing either MCI or dementia in patients using
this therapy that almost double the risk for those not using it.
2. PIRACETAM→ the word comes from ancient Greek making “for or toward the mind”.
Piracetam is the most studied compound as a cognitive enhancer.
➔ Promising results: protection against cognitive decline in various clinical settings like traumatic brain injury,
cerebrovascular insufficiency, cardiac bypass cognitive deficit and MCI.
Part of its efficacy can be attributed to the offset of depressive symptoms.
3. ACETYLCHOLINESTERASE INHIBITORS→ among the widespread neurodegeneration in AD and MCI, the basal forebrain
is affected (this region secretes acetylcholine).
Acetylcholine deficiency is responsible for memory dysfunction in AD and MCI.
Acetylcholinesterase (AChE) inhibitors are drugs that block or inhibit the enzyme in charge of degrading acetylcholine,
thus favouring larger amount of acetylcholine present at the synaptic level. The administration of Ache inhibitors is
recommended for patients with AD or vascular dementia, NO evidence for recommending them for healthy adults.
4. MEMANTINE→ memantine is approved for moderate to severe dementia and can be used in combination with AChE
inhibitors when indicated.
5. NOVEL THERAPIES→ Immune Therapy (vaccination with antibodies against Ab to reduce deposition and/or increase
clearance of Ab in the brain. Intravenous immunoglobulins (IVIG) have been used in trials to treat Alzheimer’s
dementia) and Gamma Secretase Inhibitors.

CLINICAL PEARLS
o Treating vitamins/mineral deficiencies
o What is good for the heart is good for the brain (controlling CV risk factors)
o Recommendations under physician supervision
o A diet rich in vegetables, fruit, nuts and fish is advisable to everybody
o Patients should remain active physically and mentally
o Patients with diagnosis of Alzheimer’s dementia should be considered medical therapy unless contraindicated.

COGNITIVE AND PHYSICAL AGING: Genetic Influences and Gene-Environment Interplay

What is the impact of genes on aging?
Differences in aging because there are a lot of pieces of this puzzle.

There are 2 levels: the baseline (starting point) and

the change during time. It’s possible that the influence
of genes has a different impact in different period of life.
TWIN STUDIES
Differences in performance between:

o Monozygotic twins (sharing 100% DNA)

o Heterozygotes twins (50% DNA)
o Brothers/sisters not twin (sharing family and DNA but with less extent)
o Individuals not in the same family (eg. twins vs not family-related).

COGNITION: GENETIC INFLUENCES

General Cognitive Ability

Heritability of IQ is about 50% in young adulthood, reaching estimates as high as 80% in middle adulthood.
Although mixing results, the heritability in late adulthood seems to decline, with associated increases in environmental variance.

Specific Cognitive Abilities

Stability in heritability estimates for some cognitive domains, but changes in heritability for other domains.
Heritability estimates within specific domains lower than estimates for general cognitive ability (50% to 70%)
→ more influences of environment on specific functions.

Most of the genetic influences on change are shared across domains, with specific genetic variance on change ONLY for memory
and spatial ability
Regardless of the different abilities tapped by each domain, the genetic influences on cognitive change appear to be more global
than specific.

COGNITION: ENVIRONMENT
Indeed rearing environment has little impact on cognitive function in the second half of the lifespan.

FACTORS (for mean cognitive performance and rates of decline):

o Education
o Socioeconomic status
o Occupational complexity These are themselves
o Lung function influenced by genetic factors!
o Leisure activities
o Social participation
 PHYSICAL FUNCTION
To fully understand the mechanisms of cognitive aging, it is important to consider the physical context in which aging occurs.

o Physiological functioning includes obesity, cardiovascular health, and lung function.

o BODY MASS INDEX (BMI)
Normal (19-25 kg/m2) in midlife is related to better health and survival
Slightly elevated BMI (25–30) in late adulthood is associated with better health prognoses than normal BMI →
“OBESITY PARADOX”, WHY?
Heritability estimates remain fairly constant at 70 % throughout the second half of the lifespan.
o BLOOD PRESSURE (BP)
Moderate genetic influences on BP: heritability near 45% for systolic BP and 34% for diastolic BP. Decreasing
genetic influences on BP with increasing age
Heritability estimates for elevated BP (hypertension) are higher (46-63%)

Environmental influences on cardiovascular health include: caffeine, smoking, BMI, medications.

GENETIC INFLUENCES ON:

- Serum lipids (e.g. cholesterol and triglycerides): between 30% - 80%
- Lung function (in late adulthood): from 30% to 50%

o Behavioral physical functioning includes muscle strength and functional ability.

o Physical strength in adulthood: Heritability estimates for this range from 30% to 60%
o Heritability estimates for physical functioning in ecological setting (walking, balance, and chair stands) tend to
be mixed, with evidence for significant age and gender effects.

INTERRELATIONSHIPS BETWEEN COGNITIVE AND PHYSICAL AGING

Strong relationship between genetic influences on lung function and genetic influences on measures of fluid intelligence ability.
Genetic variance in lung function at baseline was correlated with genetic variance in cognitive function 6 years later.
Correlation between BMI at midlife and cognitive scores in late life was primarily genetically mediated.

Longitudinal twin analyses indicated significant shared genetic variance between functional ability and cognition: POSSIBLE
MECHANISMS?

1. Physical illness impacts subsequent cognitive function

2. Cognitive function as a contributor to the ability to maintain good health and lifestyle habits
3. A biological process of aging that affects both

BRAIN STRUCTURES
Genetic influences account for 40–95% of individual differences in brain structures and function. Genetic influences on change in
brain volume over time appear to be minimal (associations between white matter hyperintensities and cognitive function
resulted for the most part from shared genetic variance).

SPECIFIC GENES IMPORTANT TO COGNITIVE AND PHYSICAL AGING

The search for genes that may potentiate or moderate normative cognitive aging, and the extent to which these overlap with
physical functioning.

▪ Association studies → correlational relationships between a variant of a particular gene, i.e., an allele, and cognitive
change traits.
▪ Linkage strategies trace the extent to which a genetic marker or mutation co-occurs with a disorder or trait, within
families.

Gene that has been studied most extensitvely is the gene encoding apolipoprotein E (APOE) Not only as susceptibility factor for
late-onset for Alzheimer’s disease but also for non-pathological (normative) cognitive aging. But there are 20 additional genes
that are studied.

These gene pathways include: • cholesterol and lipid metabolism (e.g., APOE, ABCA7, CLU, SORL1), • cellular endocytosis or
adhesion which play a role in protein absorption (BIN1, CD2AP, FERMT2, PICALM), • immune/inflammatory response (e.g., CR1,
HLA-DRB5– DRB1 region, INPP5D, MEF2C, MS4A4E/MS4A6A), • cell- signaling or synaptic functioning processes in hippocampal
regions (e.g., MEF2C, PTK2B, SLC24A4), neural development (e.g., cell migration, PTK2B).

APOE→ The risk allele, APOE ɛ4, is associated with increased beta-
amyloid (Aβ) protein deposition (a hallmark neuropathology observed
in those with AD). Beta-amyloid (Aβ) protein deposition is also
observed at
autopsy among
aged individuals with no dementia (APOE important also in normal aging).

➔ THE LINK BETWEEN COGNITION AND PHYSICAL

SORL1→ Plays a dual role:

o Protein sorting and binding to the low-density lipoprotein (LDL)

o Participates in the transport of the amyloid precursor (APP) protein - a relatively greater number of associations with
rate of cognitive change versus performance levels, particularly for spatial as well as episodic memory and verbal ability
domains.
➔ The lipid pathway may be an important pathway underlying association between cognition and physical traits.

PRRC1 (on chromosome 5)

o IS important to fluid ability performance in late adulthood

o Altered PRRC1 expression was observed in the temporal cortical region

Genes influences on Physical aging:

o Fat Mass and Obesity Associated (FTO) gene: shows strengthening associations with BMI across childhood and into early
adulthood but may lessen in impact into older adulthood
o The gene responsible for encoding brain-derived neurotrophic factor (BDNF*) has been implicated in BMI
o Other genes were found important for:
✓ Blood pressure,
✓ Serum lipid profiles,
✓ Heart rate

*brain-derived neurotrophic factor (BDNF) gene: is expressed in the prefrontal cortex and hippocampal regions, is implicated in
synaptic plasticity processes that occur during memory formation and the persistence of memories. It may predict late life
cognitive change (only in females?) and may predict hippocampal atrophy
Moderators:
- Females?
- Age?
- Exercise?

INFLUENCE OF genetic (G), environmental (E), and G × E processes

• In a high physical activity context those with the APOE ɛ4 allele show comparable activation to those not at risk.
• Physical activity did not lead APOE ɛ4 individuals to surpass non-ɛ4 individuals in positive outcomes, however the
mitigation of risk via physical activity was notable.

BIOMARKERS OF G X E INTERPLAY DIRECTLY

Why do we age? The role of Telomeres:

o DNA segments that cap the ends of chromosome

o Telomeres shorten after each cell division
o Telomeric loss associated with increased risk of somatic mutation and damage

Telomeres:

o Shorter telomere lengths are predicted by increasing age, low education, illness, social stress and adversity
 o Telomere lengths are heritable based on studies of twins.
o Longer telomere lengths correlate with higher working and episodic memory performance.

AGING, GENES AND SEX DIFFERENCES

Complex sex- plus age-dependent effects may be evident over the entire life course:

o Men’s and women’s cognitive trajectories may be differentially influenced by serum cholesterol and lipoprotein
o Men may be more likely to be diagnosed with MCI
o Women with AD, including a greater risk conferred by carrying the APOE e4 allele

MEMORY: BEHAVIOR AND

NEURAL BASIS
How can we study age-related changes in aging?

o Task-view→ major factors influencing the

presence and size of negative age differences:
• controlled versus automatic
processing
• cognitive load
• demands for associative versus item processing
• use of environmental support or compensation

o Brain-view
• “Front to back” or “Last in, first out” pattern→ Prefrontal regions are the last to reach full maturity, are
also those that show the earliest age-related decline, whereas posterior sensory regions that reach mature
states within the first few years of life show relatively little decline in healthy aging.
• Prefrontal regions vs. posterior cortex→ Prefrontal regions vs. posterior cortex and item recognition vs.
free recall.
• Hippocampus and medial temporal regions Deterioration→ association processes that depend on the
hippocampus and other medial temporal lobe structures.
• Anterior temporal lobe→semantic memory is preserved and may even increase until the final decades of
life, consistent with the relatively preserved volume of the anterior temporal lobes However ‘tip-of-the-
tongue errors’

o Neurocognitive process-view. The most exhaustive prospective

• Any memory task requires multiple processing components.
• Young and older adults often differ not only in the efficiency of specific components but also the degree to
which they rely on them.
• Not simply deterioration but we can see compensatory mechanisms (HAROLD, PASA, STAC)

MAJOR INFLUENCES ON AGE DIFFERENCES IN MEMORY

AUTOMATIC VS CONTROL:

o SPARED performance in memory tasks that rely largely on automatic processing

o DECLINE in controlled memory tasks with higher degree of control
o Older adults are more reliant on top-down control at earlier stages of processing and lower levels of task difficulty
Repetition priming paradigm - Rely upon automatic processes, repetition of previous stimuli/information leads to faster
responses (facilitated or biased as a result of prior exposure) and largely spared in aging but: Increasing control demands of the
tasks is associated with decline in performance.
Largely spared in aging but increasing control demands of the tasks is associated with decline in performance

Older adults had similar repetition-related reductions in

left inferior frontal cortex during a semantic decision
task. Age-related differences in right prefrontal and
inferior temporal regions that may have reflected
engagement and repetition-related change in
compensatory processing.

Nondeclarative memory (e.g., procedural memory, probabilistic learning)

o Behavioral: good performance unless the task is very demanding

o Neural: the likelihood of age-related deficits increases the more that experience-related change depends on regions
associated with controlled processing

Episodic memory

o Familiarity (more automatic) versus recollection (controlled effortful)

o Behavioral: familiarity more spared, deficits in recollection
o Neural: increased activity in rihinal cortex (familiarity) + reduced activity in hippocampal regions (recollection)

BUT

1. For older adults the familiarity signal may be less specific, increasing vulnerability to false memories
2. Older adults show more extensive activation than do young adults, especially in prefrontal and parietal regions,
perhaps in compensation for reduced modulation of other regions

Reduction in controlled processing at encoding

Difficulty to self-initiated encoding.

1. less distinct, elaborated representations

of the to-be-remembered item
2. 2. the “accidental” encoding of irrelevant items, which compete with the target and interfere with its retrieval
BUT

SINGLE ITEM VS ASSOCIATIONAL MEMORY

Older adults have more difficulties in recalling associations between items or with the context (source memory).
(At least) two major components to older adults’ associative memory deficits:

o Frontal component→ influence on information to bind in WM

o Temporal memory-related component → the binding/association process itself is likely more strongly influenced by a
medial temporal lobe/hippocampal activity
 COMPENSATION FOR WHAT?
Increased activation is usually related to better performance. Possible explanations:

1. Deterioration of cognitive control-related structures → reduced efficiency or power of the cognitive control regions→
the homologous region of the other hemisphere may be recruited to help out.
2. Deterioration of memory-related structures→ reduced activation of hippocampus + frontoparietal cognitive control
network
3. Deterioration of sensory-related structures and less specialized neural representations in regions associated with
higher-level visual processing→ degraded representation.

DEFAULT NETWORK DYSREGULATION

Our brain is organized in 12 networks,
regions functionally connected each other.

It’s a sort of flip.

Older adults don’t encode the information

because of the difficulty to change from a
default mode to an active mode.

Aging→ failure to deactivate the

Default network

This network supports task-unrelated

thoughts

This network is more active→ task-unrelated thoughts are

more active and can interfere with the ongoing, memory tasks.

Worse performance in memory task.

The default network plays a special

role in memory–cognitive control
interaction.

Posterior cingulate/retrospenial cortex is the PRIMARY HUB of this network (interconnected

with medial temporal and frontal regions).

[encoding→ attention allocated externally,

retrieval→ attention allocated internally.]

Posterior cingulate/retrospenial cortex shows a unique, particular, pattern:

“encoding-retrieval flip”: decreases in activity during successful encoding, increases in activity during episodic retrieval. Both
sides of the flip are smaller in older adults, but age deficits in the encoding–deactivation component appear especially large in
older adults (and associated with unsuccessful memory).

WHY STUDYING DEFAULT NETWORK?

1. Failures to deactivate during encoding are linked to failures to encode regardless of age.

2. Failures to deactivate the default network may be related to older adults’ increased distractibility.
 MODIFYING FACTORS
✓ Culture→ Culture may have greater effects on qualitative aspects of memory. That is, rather than affecting how much
people remember, cultural influences may be more evident in what they pay attention to. The performance in memory
is maybe the same but the quality is different (es: individualistic vs community prospective).
There is still some debate as to whether the size of these cultural differences is larger or smaller in older adults as
compared to younger ones:
- Older adults have spent longer internalizing their own culture and thus may be more strongly influenced by it
_ BUT _
- Age-related declines in neuroplasticity may become a more overwhelming contributor to individual differences in
brain structure and function.

✓ Emotional content→ An interesting exception to age-related reductions in cognitive control!

Compared to young adults, older adults show a positivity bias towards remembering positive information. They
remember more positive details because they are focus on the past (young individuals are focus on the present).
Strategic process aimed at maintaining positive mood and emotional balance in the face of limited (life) time.
o Older adults show reduced subcortical but increased cortical responses to emotional stimuli, suggesting top-
down regulation of the emotional response.
o Prefrontal regions associated with emotional control show less structural decline in aging than do those
associated with other forms of. Problem in cognitive control but emotional cognitive control is preserved (near
to limbic system).

“USE IT AND DON’T LOSE IT”

Older adults may engage emotional regulation more consistently than young adults.

✓ Type of processing→ Increasing the depth of processing increases the likelihood that the information is remembered
(creation of a strategy).
(asking participants to engage in a semantic decision task that encourages deep processing rather than simply telling
them to memorize items).
BUT If it’s too demanding→ the reverse effect

✓ Environmental support→ Older adults often perform as well or even better than young adults in real-world
situations. Errors were very rare in situations where routine, reminders, or maps could provide supportive guidance or
cues.

✓ Inter-individual factors and difference→ Cognitive reserve and Genetic background has DIFFERENT PATHWAYS:
o Cognitive reserve→ larger bank of neural or cognitive resources/compensation to reduce the negative effects
of pathology.
o Genetic→ prevent that pathology from occurring in the first place.

INTERVENTIONS: HOPE FOR IMPROVEMENT?

Brain/cognitive enhancements: exercise (cardiovascular system), nutrition, pharmaceuticals treatment, behaviorally based
training.

Cardiovascular training→ modest but reliable effects on memory, perhaps in part through its larger effects on executive
function and cognitive control.

Behaviorally-based interventions→ small but significant effects on a

number of cognitive functions including memory (less generalisable).
Strong caution when considering the often-exaggerated claims of
commercially based programs. Duration and transfer of the effects?
(the ACTIVE study→ moderate benefits to memory performance that
lasted for 5 years, but not in everyday life).
ENCODING! What is the problem? They have less control, an aspecific representation and activation in brain.

Bottom-up vs top-down? Trying to improve perceptual processing and thus the distinctiveness of to-be-encoded representations
or top-down approaches that try to train older adults to engage more attention and control at encoding. Encourage the external
prospective.

RECOLLECTION! Recollection processes that help distinguish between cue-

appropriate responses and other items that are familiar but incorrect.

INFLUENCE OF INDIVIDUAL CHARACTERISTICS. The same training can have different effects because of the individual’s
characteristics.

o In cardiovascular training, several studies now suggest that the benefits are especially large for those at genetic risk for
dementia.
o High- vs low-ability participants: Low–ability → difficulty with the training but more room of improvements.
➔ Choose the training based on individual
Adaptive programs that allow the participant to begin at a high level of performance and gradually increase demand on the to-
be-trained processes as performance improves may help foster benefits in both groups.
Training in which individuals could choose their strategy works more.
[Minor number of self-reported everyday memory errors when allowed participants to choose their own strategies.]

SUMMARY
1. Best view/approach→ Neurocognitive approach.
2. Controlled versus automatic→ Controlled more impaired.
3. Single item versus associative→ Associative task more impaired.
4. Decline in neural structures→ Prefrontal, medio-temporal.
5. Preservation of other functions→ Semantic memory, emotion.
6. Why some individuals maintain high levels of functioning→ Cognitive reserve, Environmental support, Genes
7. Type of intervention→ Multidisciplinary, especially cardiovascular, behavioural intervention.
 EXECUTIVE FUNCTIONS
EFs are multifaceted control HIGH LEVEL (top-down) processes that regulate thought and behavior. It’s family of general-
purpose mechanisms (i.e., updating, inhibiting, switching, working memory, prioritizing, sequencing).
Are critical to other higher cognitive abilities including planning, reasoning, long-term memory, decision
making, and problem solving. Mediated mainly by prefrontal cortex but we cannot assume that a so
complex functions are related with a single region. Not modularism but connesionism! But also… the
parietal lobes, and subcortical regions, including the thalamus, basal ganglia, limbic system, mid-brain, and
the cerebellum.

TEST → Wisconsin card sorting test (WCST), N-back, Trail making test B, Stroop Task, Stop signal, AX-CPT and many others... To
identify the specific process responsible for age-related differences in cognitive tasks!

WCST: - one task, multiple processes.

- a variety of measures

MIYAKE’S MODEL:
A successive study (Fisk & Sharp, 2004) tested the Miyake and collaborators ’s factor structure, including also older people. The
authors confirmed the Miyake’s model age-related deficits on all of
those factors. Nonetheless, except for shifting tasks, which showed a
less degree attenuation, such age effects were reduced to below
statistical significance after controlling for age-related differences in
information processing speed.

BADDELEY’S MODEL (1986, 2003):

Complex tasks require that information is stored and
manipulated in a short-term storage system. Older adults have a
reduction in WM storage capacity. This led to deficits in several
cognitive tasks…. BUT… tasks that seem to tap into the function
of WM capacity (e.g., digit span) show minimal effect of age.

Tasks that seem to tap into the function of WM capacity (e.g.,

digit span) show minimal effect of age but complex span tasks
(reading span) do show robust effect of age So it is not just the
reduction in the
storage capacity,
But rather an interaction of storage and control mechanisms→ Age deficits in
complex WM span tasks seem to mainly reflect a decline in executive control,
rather than a decline in storage capacity.

EXECUTIVE DEFICIT THEORIES OF COGNITIVE AGING

1. Inhibitory Deficit Theory (Hasher & Zacks)
2. Frontal Lobe Hypothesis of Cognitive Aging
3. Goal Maintenance Deficit (Braver & West)

GOAL MAINTENANCE THEORY

(Braver & West, 2008; Barch et al., 2001)
Older adults have deficits in executive control, which consists of the internal representation, maintenance, and updating of goal
information in the service of exerting control over thoughts and behavior.
Many executive control tasks rely on internal representations of tasks-set goals:
Stroop task→ “remembering to respond to color ink”
WCST→ “remembering the rule for the decision of the card”

o Critical role of the lateral PFC in executive control processes: Goal representations are formed, actively maintained over
time and used to control the behavioral output by biasing (i.e., modulating) the flow of ongoing processing in other
brain regions.
 o Critical role of the dopamine (DA) in executive control processes: DA
modulates PFC function by regulating the way that goal representations are
maintained and updated DA regulates the access of afferent inputs to lateral
PFC. There is a critical role of the dopamine (DA) in executive control
processes: DA modulates PFC function by regulating the way that goal
representations are maintained and updated DA regulates the access of
afferent inputs to lateral PFC.
Thus… lateral PFC is important to maintain in mind the goals of the task and
to transform goal representations into a plan to respond to upcoming stimuli.
➔ This function is particularly required when: Multiple conflicting responses are activated, but some are irrelevant or
inappropriate.

This theory clarifies the relationship between attention , working memory and inhibition, and the role of lateral PFC in these
domains.

➔ in situations of behavioral inhibition (e.g., in stroop tasks) the top-down control may have a suppressive effect.

THE EXAMPLE OF THE STROOP TASK:

- Multiple perceptual dimensions that compete for attention
- A tendency to make an inappropriate response

Age-related declines in lateral PFC and dopamine function result in

a specific impairment in the ability of older adults to actively
represent and maintain goal information over time.

WORKING MEMORY
3 phenomena concerning age effects on WM can be explained by the older adults’ reduced ability to maintain goal
representations in working memory

1. Increased susceptibility to interference.

PROACTIVE INTERFERENCE: interfering information presented before the occurrence of the target information
previously relevant to the task Previous stored information interfere with processing and retrieval of actual target
information.
RETROACTIVE INTERFERENCE: the interfering information is presented successively with respect to the target
information. However, when recalling the target information, following information interfere with the retrieval.
Increased susceptibility to interference Minimizing Proactive Interference → reduced age-related differences
 2. Age-related declines in the ability to control the focus of attention within working memory
Structure of WM (Cowan,2001; McElree, 2001; Oberauer, 2002)
The short-term memory zone is very close to the
conceptualization of actively maintaining goal
representations within the goal maintenance account.
The ‘embedded process model of WM’ (focus of
attention).
Ex. N-back task: ‘judge if the stimulus is the same or
different of the stimulus presented two slides ago’.
Older adults have a decline in refreshing and updating
the focus of attention, thus in switching between the
processing of no more relevant items and now relevant
items.

3. Strong age-related memory impairments occurring in task condition that require the binding of arbitrary stimulus
features together in working memory.
Older adults exhibit a disruption in the ability to bind together the various elements of a representation within working
memory.
Memory tasks that require to:
o Retrieve/recognize items based on one single feature→ no age effect
o Retrieve/recognize items based on a conjunction of more features → age effect

Decline in left anterior hippocampus and right rostral prefrontal cortex: goal representations act by top-down drive how
different features are integrated together!

INHIBITION OF RESPONSES
Different INHIBITORY paradigms:
Common feature→ To inhibit irrelevant, inappropriate, but dominant or prepotent responses.

➢ STROOP TASK (Stroop, 1935)

There is an interference in naming the color of incongruent color-words because of a prepotent tendency to read the
word (green). This interference effect accelerates in an exponential fashion from the sixth to eighth decades.
- Reduced inhibition abilities?
- Slowing down of speed of processing?
- Impairments in low-level visual processing?
- Impaired executive control processes?
➢ ANTISACCADE TASK
OLDER ADULTS:
- Higher number of errors in antisaccade
condition
- Similar number of errors in prosaccade
condition
- Slower saccade onset latency,
especially for antisaccade condition
Impaired goal maintenance? Older adults tend to rely greatly on onset of the stimulus, rather than maintain actively in mind the
goal. (i.e., they decide when they see the stimulus despite of being driven by internal rules) When all the target positions are
filled by stimuli (even if not target), the age-related differences are reduced.

TASK MANAGEMENT
Older adults have difficulties in managing and coordinating multiple task demands. These difficulties can not be accounted
simply by a generalized slowing-down of processes The classical measure is the subtraction: (Performance in a dual task
condition – Performance in a single task condition)

TASK UTILIZED:

o Task switching
o Psychological Refractory period (PRP)

Task switching:
Similar to a dual-task, but one task at a time. We need to change the task trial-by trial: there are cues, that can occur in a
predictable or unpredictable way. 2
1 task → Judge if the letters in the second and fourth
position are same or different 2 task → judge if the letters
in the second and fourth position are written in the same or
different way (lowercase/uppercase).

MEASURES TAKEN INTO ACCOUNT IN A CLASSICAL TASK SWITCHING PARADIGM:

1. SWITCHING COSTS→ reduction in performance that occurs on trials where the task has switched from the previous trial
2. MIXING COSTS→ reduction in performance when comparing trials NOT REQUIRING A TASK SWITCH but in a task-switching
block relative to the same trials presented in a single-task block
3. AGING→ increased mixing costs (Verhaeghen et al., 2005) Inconsistent results about the effect of aging on switching costs

Both younger and older adults are facilitated by this

long interval. But… residual switch costs greater in
older adults.

Consistent with the goal maintenance account: Older

adults are less able to use such information to
appropriately select the currently relevant task-set
and de-select the currently irrelevant set.

How can we explain the minimal effect of aging on

local switch cost? It seems to be opposite to the predictions of the theories of cognitive control (according to which task-set
management is a core executive process that declines with
increasing age).
 ERP AND BRAIN IMAGING STUDIES
In general, Lateral anterior PREFRONTAL CORTEX (PFC) plays a key role in maintaining task goals active in mind
In task switching blocks→ activation of Lateral PFC, which resulted associated with mixing costs
IN OLDER ADULTS______________REDUCED activation of lateral PFC during task-switching blocks

Goal maintenance theory seems able to explain age related deficits in:
1) Working memory
2) Episodic Memory
3) Prospective Memory
4) Inhibition of responses
5) Task management

A test for the Goal maintenance theory

Paradigm: AX-CPT (Braver et al., 2002)
Similar to a Continuous performance test Participants are required to respond to an
X-probe, but only when it follows an A-cue. Target trials (AX) occur very frequently.
AX-CPT requires to maintain contextual cue information (A or B cues) to guide
responding (or inhibiting response) to subsequent ambiguous probes (e.g., X or Y).
Age-related deficits in contextual information maintenance (i.e., forgetting the
preceding letter): led to an increased number of errors in BX trials [MORE ERRORS
FOR OLDER ADULTS]

and to an ‘apparently’ paradoxical facilitation effect in AY trials [MORE ERRORS FOR YOUNGER ADULTS].

- IN YOUNGER ADULTS: activation in lateral PFC → active prefrontal goal representations. It tends to lead to both successful
BX inhibition but also to an increase in the AY errors.

- IN OLDER ADULTS, reversed pattern to young adults (in AY trials, not only they had a less number of errors, but also faster
RTs, compared to younger adults).

Support for context processing deficits in older adults, due to impairments in goal representation and maintenance

➔ Correlations between AX-CPT impairments in older adults and performance declines in neuropsychological tasks of
executive control domains (e.g., verbal-fluency task etc)

A key idea of goal maintenance theory is that impairments in the use of context information in older adults are caused by
changes in lateral PFC (and/or dopamine) function.

➔ Reduced cue-related activation of lateral PFC in older adults

TEMPORAL DYNAMIC OF EXECUTIVE CONTROL & AGING

• Dual Mechanisms of Control (DMC) account (T. S.

Braver, Gray, & Burgess)
Cognitive control can occur in two distinct modes:
Proactive Control→ sustained active maintenance of goal
representations and anticipatory preparatory attention to
the onset of imperative events
Reactive Control→ transient, stimulus-driven reactivation of
goal information only in situations where such information is
critical to avoid inappropriate performance.
Older adults may have a reduced tendency to use proactive control, but a relatively spared or even enhanced
tendency to engage in reactive control.

EXECUTIVE FUNCTIONS: A SINGLE OR MULTIPLE PROCESSES

Recent cognitive and neuroimaging studies showed that EXECUTIVE CONTROL

Error / Performance Monitoring

Error-related negativity (ERN)

1) A specific ERP brain wave component sensitive to error monitoring and detection
2) is an electrophysiological signal associated with this ACC monitoring process, occurring approximately 100 ms after an
error is made

3) ERN- like brain-

waves are activated not only by error commission itself, but also by the occurrence of response conflict, or by other
kinds of feedback signals

Botvinick is one of the most important investigators of ERN and cognitive control.

ERN activity (ACC activity) provides a signal to PFC about the correctness of the behavior Thus…. Enables the system to learn
about task situations requiring a high degree of cognitive
control and lateral PFC can adjust the actions (exerting
control), based on the ACC signals.

o The amplitude of ERN is attenuated in older adults

o A reduction in the magnitude of a dopamine-
mediated error feedback signal from the basal
ganglia to the anterior cingulate.
➔ DECLINE IN DOPAMINE ACC-PFC MONITORING SYSTEM
 AFFECT-COGNITION INTERACTIONS IN EXECUTIVE CONTROL
“Somatic marker” theory (Bachara and Damasio are the most
influent investigators)

HOW CAN WE DECIDE? IS IT JUST DRIVEN BY OUR RATIO? NO!

affective bodily signals can bias (modulate) our decisions! These
affective bodily signals are represented within ventromedial (VM)
regions of PFC.

Affect-dependent decision-making and VM-PFC function in aging:

MIXING RESULTS

o No clear age-related changes in the tasks used to measure

VM-PFC function (Iowa Gambling Task) (MacPherson et al.,
2002) (but robust aging effects on measures of DLPFC function (e.g., WCST)
o Older adults show slower learning curves from negative feedback and a higher tolerance for risk (Deakin, et al., 2004)
o Compared to young adults, older adults are able to exert equivalent or even better control over their emotions, and as
such show a reduced impact of negative (vs. positive) information on memory and attention (Mather & Carstensen,
2005).

➔ EVEN if VM regions of PFC are not directly impacted by age, older adults however can display same deficits in
‘affective-directed tasks because of an impairment of Lateral PFC.

INTEGRATION
✓ Anterior PFC→ executive processes related to the integration of higher-order goal information actively maintained in
working memory with other internally represented information.
✓ Anterior PFC→ when the subtask had to be integrated with information previously stored in working memory (T. S.
Braver & Bongiolatti, 2002).
➔ This process underlies many planning and reasoning tasks

Older adults?

Age differences in reasoning and higher-order thinking and planning tasks are well established
Integration processes dependent on anterior PFC function
Decline on PFC function may underlie age-related changes in integration, and hence in high-order tasks

CONCLUSION
• The Goal Maintenance Account can explain the majority of the age-related differences evidenced in cognitive tasks • Executive
Control cannot be defined as a single process, but encompasses a series of different processes .
• Age-related alterations in regions within Lateral PFC seem to be critical to determine cognitive decline in aging.
 AGE-RELATED CHANGES IN PROSPECTIVE MEMORY
How many times did you meet the following situations? After having sent an e-mail, you realized that you forgot to attach the
file containing the results of one of your experiments. Or, after having prepared a delicious meal, the smell of burning
remembered you that you forgot to take that out of the oven.

What is prospective memory?

“ability of remembering to perform intended actions at a particular time in the future”.
When we talk about failure, we often talk about prospective memory. Many times, this function is
crucial in our life because it’s essential for independent and successful life.

Why Prospective Memory?

o Kliegel and Martin (2003) showed that 50-80% of everyday memory problems involve
difficulties with appropriate execution of planned intentions.
o In old age, in particular, an efficient PM has been found to be a major prerequisite for successful independent living
(health-care, medications).
o One-third of older adults take three or more medications on a regular basis (Morell et al.,1997).
o Deficits in PM in several neuropsychological disease (Parkinson’s dis., Alzheimer’s dis. etc.. )

TYPES OF PROSPECTIVE MEMORY

It can be identify in 3 classes of PM cue:

1. Event-based task (remember to perform an intended action when a particular event, the PM cue, occurs)
2. Time-based task (remember to perform an intended action at a particular time, or after a delay)
3. Activity-based task (in relation of a particular activity. E.g., after lunch)

In LAB:

Ongoing task→ What we are doing by now, such as making lexical decisions, making picture or word ratings, answering
questions, reading or taking a video tour of a town.

PM task→ When a specific event, the PM cue, appears (e.g., a word, face, concept, or category of elements), participants must
execute overt responses to show that they have recollected the previously formed intention.

PROSPECTIVE MEMORY: 2 big COMPONENTS

It’s a sort of bridge between memory and executive function.

• Retrospective component→ “What to do” Processes belonging to other kinds of explicit episodic memory (the content
of the action: you open the fridge, but you can’t remember what you suppose to take from it).
• Prospective component→ “When to do” mediated by executive control.

Distinct cognitive functions have been shown to underpin the different phases of PM. In general, intention formation, intention
initiation, and intention execution phases can be assumed to involve specific executive functions, whereas the intention
retention phase seems to be mainly related to retrospective component.

1. I conceive the intention

2. I have to mantain the intention
3. As soon as possible I have to retrieve the
intention
4. I realise the intention: the execution
 MODELS
1. THE MULTIPROCESS VIEW

What is the neural system of those two kinds of strategy? In the second case the intention automatically pop up, you don’t
allocate attention to remember it.

FACTORS INFLUENCING THE ENGAGEMENT OF STRATEGIC MONITORING VERSUS SPONTANEOUS RETRIEVAL:

o Salience of the pm cue

o Importance of the ongoing and the pm task
o Load of the ongoing task
o Association between cue-intention
o Number of intentions
o Individual features
o Focality of the task

2. THE TEST-WAIT-TEST-EXIT (TWTE) MODEL

▪ Individuals intermittently test time (by checking the clock) to see whether the required time has come for
executing the intended action.
▪ If the time is not correct, individuals wait for a period of time until another test seems appropriate.
▪ The exit of this loop happens when the critical time occurs and the intention is executed.
 AGING AND PM
Implications of failures in PM can be dramatic under some circumstances, especially for older individuals for whom medication
adherence, as example, represents often an important part of daily living.

‘‘puzzle of inconsistent age-related declines in prospective memory’’.

- Laboratory-based prospective memory tasks

- Naturalistic tasks (e.g., email to researchers, envelope...): in remembering to telephone the experimenters at a specific
time over 5 days, 2 weeks, and 4 weeks in sending the experimenter mail postcards; or to log the time on electronic
organizers.

Younger adults outperform older adults in laboratory-based prospective memory tasks.

Older adults outperform younger adults in naturalistic tasks.

Why?
The greater use of reminders and external cues by older adults in naturalistic settings, higher motivation, less busy everyday life,
structuredness of life, personality factors such as attitudes of politeness, more experience with time management, generational
differences in attitude to punctuality, fewer distractions, awareness of their memory’s failurer or more efficient utilization of PM
reminder aids.

Craik (1986) argued that PM is characterized by a higher recruitment of self-initiated processes and the lowest extent of
environmental support as compared to retrospective memory tasks (for example recognition or free recall) __________
BUT__________ Larger age-related impairment for retrospective than for prospective memory.

Age effects may be a function of whether the prospective memory tasks depend:

a) On strategic, attention-demanding processes, which would lead to an age deficit

b) On spontaneous retrieval, thus more automatic processes, which would lead to spared age-related performances.

Does aging affect mainly the prospective or the retrospective component of PM?

For some authors, retrospective component (memory problem):

- Two indices of retrospective memory explained 68% of the age-related variance (the difference in performance can be
explain) in PM tasks performance.
- Age-related differences in PM tasks increased as a function of retrospective memory load (e.g., number of
cues/intentions).
- Increment in false alarms to stimuli that were similar to PM cues but another similar cue.

For other authors, prospective component:

- Age-related differences in executive functions and working memory capacity mediate the effects of aging on
prospective memory.
- Measures of these functions were shown to account for 30% up to 100% of the age-related variance in PM tasks.
- Age-related differences in strategic monitoring.

Braver & West (2008) ‘GOAL MAINTENANCE ACCOUNT’ (intentions are goals):

▪ Age-related decline in PM performance is due to difficulties in executive control, conceptualized as the ability to
maintain and update goal-related contextual information to guide task performance.
▪ Seems to be related to a decline in efficiency of prefrontal cortex (PFC)→ less efficient in the maintaining of intentions.

Does aging affect mainly the time-based or the event-based PM tasks?

Age-related deficits are usually (but not always) more pronounced in time-based than in event-based tasks.
(No cues, no external reminders, higher degree of controlled and self-initiated cognitive processes).

AGE DEFICIT IN TIME-BASED PM TASKS: THE ROLE OF TIME CHECK-IN

How older adults manage time? In general, they check the clock less frequently.
The number of clock checking was lower for older relative to younger adults, and that such effect was accentuated during the
period just preceding a PM action. Age-related differences in time-based performance might be due to an inefficient use of
these clock checking strategies.

Factors influencing the magnitude of age-related differences in PM tasks

More depend on the type of ongoing task: it can absorb all the individual’s attention.
The Multiprocess View suggested that the following variables may influence age-related deficit:

1. Salience of PM cue,
2. Strength of the relation between the PM cue and the intended action,
3. Focality of PM cue*,
4. Demands of the ongoing task

*Focality of PM cue→ A PM cue is focal when the features of the PM cue are easily extracted from the information relevant for
the ongoing task (i.e., PM cues overlap with the information features relevant to execute the ongoing task). A PM cue is non-
focal when the ongoing activity does not encourage the processing of the PM cue. Age effect in PM tasks was larger in non-focal
PM tasks, but evident also in tasks with focal PM cues.

Low-demanding versus high-demanding ongoing tasks→ Age effects typically increased if the cognitive demands of the ongoing
task were high.

Mäntylä and collaborators (2009)→ time-based tasks

In the low-demanding conditions: older adults produced similar levels of PM performance by increasing clock checking as
respect to younger participants.
In the high-demanding conditions: older adults were not able to check the clock frequently, which led in turn to a worse PM
performance.

NEURAL BASES OF PM

The aPFC mediates competition between stimulus-oriented (e.g., monitoring the

traffic) versus stimulus-independent (e.g., maintaining the intention) processing.

A lot of different regions for this complex ability:

➢ Superior parietal lobule

➢ Precuneus
➢ Inferior parietal lobule
➢ DLPFC
➢ Cingulate cortices
➢ Insula
➢ Medial temporal regions
THE ATTENTION TO DELAYED INTENTION (AtoDI) MODEL (Cona et al)

NEURAL DISSOCIATION BETWEEN MAINTENANCE AND RETRIEVAL PHASE

Any activation of
hippocampus!

THE CRUCIAL ROLE OF

PREFRONTAL CORTEX
(McDaniel et al., 1999)
Relationship between individual differences PM and various neuropsychological tests associated with frontal and medial
temporal lobe function: memory and executive function.

The critical discrimination is the frontal function

McFarland & Glisky, 2009

Relationship between individual differences PM and various neuropsychological tests associated with frontal and medial
temporal lobe function.

Again, the key point: frontal function is the important ability due to PM
AGE-RELATED IMPAIRMENTS IN TIME-BASED PM TASKS?
Accounts for age-related impairments in time-based tasks:

▪ Resource deficit account (Craik, 1986)

Age-related reduction of self-initiated resources, which are
highly required in time-based tasks
▪ Goal maintenance account (Braver & West, 2008)
Age-related deficits in goal maintenance processes mediated
by prefrontal regions.

AMIS OF THE STUDY: To evaluate if time-based PM is spared

by aging or is impaired and investigate neural and cognitive mechanisms underlying possible agerelated differences in PM.

PARTICIPANTS:
15 Younger adults (age: 23± 2 years; education: 13 yrs)
18 Older adults (age: 67± 5 years; education: 11 yrs)

ONGOING TASK:
To judge if the letters in the second and fourth position were same (e.g., DFDFD) or different (e.g., DFDGD)

PM TASK:
To remember to press a key every 5 minutes.

METHODS:

BEHAVIOURAL RESULTS

No significant age-related differences in

the number of clock checks

Slower RTs in older adults in both

baseline and PM block (p < .01)
No age-related difference in PM
interference effect (p > .05)

Within the older group, however, a significant negative correlation was found between number of clock checks and age,
indicating that as the age increased the number of checks decreased.

Older adults had an impaired PM performance, likely because the ongoing task was demanding, so they had no enough
resources to increase clock checking (they would need to monitor more the time).
 ERP RESULTS

DISCUSSION

Critical role of frontal regions in explaining age-related differences in PM.

INTERVENTIONS

Intention implementation→ developed during

intention formation. We ‘‘When situation X occurs

[i.e., the target event], then I will perform response
[i.e., the intended action]’’
It’ important teaching older adults in implementing the
intention

External aids: now we have apps and for (youg) older adults this may be the key.

MILD COGNITIVE IMPAIRMENT

About normal aging it is generally accepted that some degree of cognitive decline associated with aging is inevitable. Slowed
processing speed is a key cognitive change in the aging brain. Moreover, we can observe decreased efficiency in working
memory, short-term and episodic memory, executive control.

An autopsy study on clinically nondemented oldest old (age > or = 85 at death; n = 9) found neurofibrillary tangles (tau) (i.e.,
aggregates of hyperphosphorylated tau protein) in one or more limbic regions in all study participants.
Senile plaque (SP) formation observed in this group and was found to affect all brain regions equally, with the exception of
relative sparing of the occipital cortex.

About Mild Cognitive Impairment, Neuropsychological referrals are often made on the basis of a patient’s or their family’s
perceived (i.e., subjective) report of a decline in cognitive ability. An integral part of the neuropsychologist’s role is to determine
normal cognitive aging process or an objective impairment in cognitive functioning relative to the patient’s same-age peers.
MCI is a decline in cognitive performance greater than would be expected for the person’s age but not sufficient to meet criteria
for a diagnosis of dementia. They show a pattern of decline in one or some abilities, but they can manage a pretty independent
and successful life. For Petersen MCI is an intermediate stage between normal aging and the development of dementia. It is
conceptualized as a PATHOLOGICAL condition. This is due with the sociality aspect (drive, work...). Incidence and prevalence
differ according to the study (depend on diagnostic criteria, assessment procedures, sample characteristics) Prevalence rates
have been found to range from 1 to 19%.
The original criteria for MCI proposed by Petersen et al. (1999) are:

• Presence of a memory complaint (subjective report): for him this aspect was important (like a prequel of Alzheimer
disease). By now we know that is not a prerequisite.
• Normal activities of daily living
• Normal general cognitive function
• Abnormal memory for age
• Not demented (in MMSE or MOKA or other screening test they reach the “normal performance”)

Revised criteria were proposed by a multidisciplinary, international group of experts, in light of the heterogeneity of MCI clinical
presentations:

- Some patients have a primary impairment in the memory domain only,

- Memory impairment in addition to other domain impairment(s)
- Others have impairments in single or multiple nonmemory cognitive domains

The heterogeneity of MCI etiology: degenerative, vascular, metabolic, traumatic, psychiatric.

The most updated clinical diagnostic criteria for MCI:

o Concern regarding change in cognition

o Impairment in one or more cognitive domains
o Preservation of independence in functional abilities
o Not demented
➔ Not necessary memory problems

SUBTYPES:

1. Single-domain amnesic MCI (a-MCI)→ Within the a-MCI groups, two new subtypes identified:
▪ Hippocampal atrophy
▪ White matter hyperintensities

Relatively selective decline in episodic memory Impairments in attentional/cognitive control

contingent on disruption of primary mnemonic processes critical for working memory, which in
processes dependent on the hippocampus. turn give rise to episodic memory decline.

2. Single-domain non-amnesic MCI (Na-MCI)→ Non-amnesic MCI is characterized by a subtle decline in functions not
related to memory, affecting executive functions, attention, use of language, or visuospatial skills. Na-MCI is probably
less common than the amnestic type. May be the forerunner of dementias that are not related to AD, such as
frontotemporal dementia, or dementia with Lewy bodies.
3. Multiple-domain MCI: md-MCI + a (amnesic)
md-MCI – a
MULTIPLE ETIOLOGIES:

Petersen suggested four

main etiologies:
a. Degenerative
(e.g., Alzheimer’s
disease),
b. Vascular
(e.g., cerebro-
vascular disease),
c. Psychiatric
(e.g., depression),
d. Traumatic
(e.g., head injury)

Others etiologies:

- Toxic factors
- Metabolic factors
(e.g., thyroid
dysfunction,
vitamin B12
deficiency)→
reversible if take
care on time with
supplementation.
- Medication side
effects

MCI AND DEMENTIA

Patients with a-MCI are more likely to convert to Alzheimer’s disease than patients with Na-MCI.
Patients with Na-MCI, with impairments in nonmemory domains such as executive function and visuospatial skills may be more
likely to convert to dementia with Lewy bodies.
Patients with Na-MCI in one domain were least likely to convert to any form of dementia.

Follow-up data from the initial Petersen et al. study (N = 220 MCI patients) found:

- A rate of progression from MCI to dementia of 12% per year

- At a 6-year follow-up, approximately 80% of MCI patients were reported to have progressed to dementia.

Other studies have found:

- Conversion rates of 10–19% per year from MCI to Alzheimer’s disease (1–2% of the general population develop
Alzheimer’s disease per year)
- When considering a general diagnosis of MCI, patients are found to have a three times greater risk of developing
Alzheimer’s disease

________________However

Other MCI patients:

- Remain stable with this diagnosis or revert to normal.

- In a clinical sample, 41% remained stable over an average 3.5-year follow-up and 17% returned to normal cognitive
status.
 ➔ Patients with reversible causes of cognitive dysfunction, such as metabolic abnormalities or substance use.

PATHOPHYSIOLOGY AND NEURODIAGNOSTIC FINDINGS

Neuroimaging data lends support for MCI as a unique diagnostic entity:
Retention of Pittsburgh compound B (PIB), used to image beta-amyloid plaques in neuronal tissue examined using PET in
persons with normal cognition, MCI, and Alzheimer’s disease:

- AD > MCI > normal cognition

- MCI converting to dementia > MCI not converting

MRI: volumetric brain loss in a healthy aging sample over a 15-year period:

• Ventricular expansion was found to be faster in persons developing MCI years prior to the emergence of clinical
symptoms (faster 2 years prior to the clinical diagnosis of MCI).
• Greater volume loss for who develops AD than a stable MCI group

Specific MRI abnormalities also have been identified in MCI subjects who ultimately convert to AD, vascular dementia, and Lewy
body dementia, MCI is a prodrome to multiple dementing processes.

ASSESSMENT: REFERRALS

Common questions from patients or caregivers:

_Differential diagnosis_ _Etiology_ _Treatment_

(usually involves a question of Cognitive enhancing

Alzheimer’s disease pathology
versus other causes such as
vascular cognitive impairment,
frontotemporal dementia, a
Parkinson’s syndrome.
medication or psychotropic
drugs for treatment of
mood disorders à referring
to a physician

Neuropsychological evaluation is important for creating a baseline

- Assessment of functional independence
- Assessment of mood
- Assessment of driving abilities

Clinical interview, what to assess?

1. Subjective cognitive complaint
2. Functional independence
3. Changes in behavior or personality
4. Medical history and assessment of the patient’s current health status
5. Patient’s sleep quality
6. Medications
7. Recreational substances
8. Cognitive reserve

Subjective cognitive complaint

It is a diagnostic criterion for MCI. It complaints corroborated by the collateral informant (familiar, friend) and providing
examples of cognitive problems the patient is experiencing in everyday life.
IMPORTANCE OF EARLY SYMPTOMS→ early and prominent emergence of language symptoms may be indicative of a primarily
aphasic dementing process. Early memory difficulties may signal mesial temporal lobe involvement.
Functional independence
The key factor in the differential diagnosis of MCI or early dementia. Evaluation of intact basic activities of daily living (ADLs):

o Hygiene, dressing, and feeding oneself

o Keeping appointments, financial management, driving abilities, and medication management
▪ Self-report or clinician-administered ADL scales can also be employed but do not replace a careful detailed interview.
Although carry out ADLs is essentially normal:
o Minor inconveniences
o Some degree of decline in their ability to handle daily task (trouble remembering shopping items, recalling
conversations, or prioritizing tasks by importance, retaining new information)
▪ Poorer memory performance on cognitive testing has been found to predict future difficulties in financial management.
▪ Attention and executive functioning, but not memory, are associated with difficulties managing multiple-step financial
tasks.
▪ Subtle functional declines in driving abilities
▪ MCI patients tend to perform functionally on a level intermediate between persons with normal cognition and
dementia patients

Changes in behavior or personality

▪ Apathy, disinhibition, perseveration, or behaviors that are out of the ordinary for the person.
▪ 35–75% of patients with MCI endorse at least one neuropsychiatric symptom.
▪ The most commonly endorsed symptoms include depression/dysphoria, apathy, anxiety, and agitation.
▪ Other common symptoms: poor concentration, inner tension, pessimistic thoughts, lassitude, reduced sleep, thoughts
of death, inability to feel, and reduced appetite.

Medical history and assessment of the patient’s current health status.

▪ For consideration in the differential diagnosis
▪ Hypertension, hypercholesterolemia, and diabetes is essential when considering etiology of cognitive decline .

COGNITIVE IMPAIRMENT
Objective measurements of deficits in cognitive functioning. An
exact cutoff for what constitutes “mild” impairment has not been
set but in Petersen et al.’s original study (1999), the cut off score set
to identify MCI was 1.5 SD below age norms.

The most recent consensus criteria notes that scores on cognitive tests for
patients with MCI are typically 1–1.5 SD below the mean for age and
education matched peers on culturally appropriate normative data.

IMPORTANT:

• Evaluation of cultural level (CRIq)

• Evaluation of premorbid functioning (e.g., word reading)
• Evaluation of the patient’s performance in all major cognitive
domains
• Evaluation of mood (depression and anxiety symptom)

COMMON NEUROCOGNITIVE DEFICITS

The most common neuropsychological impairment seen in MCI patients who
ultimately convert to Alzheimer’s disease is a decline in episodic learning and
memory early in the disease process.
Than (in a-MCI): reduced learning, rapid forgetting, poor recognition
discrimination, and elevated intrusion errors.
Md-MCI patients show the most severe impairments!
 1. Semantic knowledge: a severe decline does not typically occur at the MCI stage, but poorer performance than
controls.
2. Attention domain: MCI patients who ultimately convert to AD demonstrate poorer immediate serial recall and
divided attention than their MCI counterparts who remain cognitively stable.

FEEDBACK, Information to give:

- Degree of cognitive impairment associated with the diagnosis
- Patient’s increased risk for converting to dementia in the future (especially if a-MCI or amnestic md-MCI)
- Areas of difficulty and the real-world implications for these deficits
- Cognitive and other personal strengths
- Context of developing compensatory strategies

Scoring Interpretation: For ADLs, the total score ranges from 0 to 6, and for IADLs, from 0 to 8. In some categories, only the
highest level of function receives a 1; in others, two or more levels have scores of 1 because each describes competence that
represents some minimal level of function. These screens are useful for indicating specifically how a person is performing at the
present time. When they are also used over time, they serve as documentation of a person's functional improvement or
deterioration.

FOLLOW UP
Follow-up depends on multiple factors:
- MCI subtypes: If a-MCI is diagnosed, retesting may be recommended in 1 year.
- The severity and number of domains impaired
- The patient’s functional status.
- Negative changes

Perhaps the safest benchmark for retesting is a 1-year follow-up period, in conjunction with the recommendation that the
patient return for testing earlier should he or she (or family members) notice a significant decline in cognitive ability or
functional status prior to the 1-year mark.

RECOMMENDATIONS:
o Follow-up with the patient’s neurologist or psychiatrist to discuss potentially beginning a trial of anti-dementia
medication, such as an acetylcholinesterase inhibitor.
o Management of risk factors associated with cognitive decline
o Patients should be encouraged to remain cognitively and socially active
o Patients and their families to continuously monitor functional status

PSEUDODEMENTIA
Late-life depression can be accompanied by significant cognitive impairments. These depression-related changes are often
similar to those associated with dementia. Historically, a psychiatric illness that mimicked dementia symptoms was referred to
as “pseudodementia”. The cognitive symptoms of pseudodementia were assumed to be related to transient mood symptoms
and therefore reversible with adequate psychiatric treatment.
 ALZHEIMER’S DISEASE
A few facts about dementia:
There are 800,000 people in the UK with a form of dementia in 2012

The well-established prevalence rates for dementia in the UK are:

40-64 years: 1 in 1400

70-79 years: 1 in 25
65-69 years: 1 in 100
80+ years: 1 in 6

Alzheimer's disease is the most common form of dementia. The proportions of those with different forms of dementia can be
broken down as follows:

Alzheimer's disease 62%

Vascular dementia 17%
Dementia with Lewy bodies 4%
Fronto-temporal dementia 2%
Death usually occurs within 10-12 years of diagnosis.

Pathological signs:
I. PLAQUES
• Small extracellular protein [beta-amyloid] deposits.
• Deposits especially in medial temporal memory structures (entorhinal cortex, hippocampus) and frontal cortex
• Abnormal proteins continue to aggregate, particularly in the frontal lobes, anterior cingulate, posterior
cingulate, precuneus and striatum.
 Beta amyloid causes toxic amyloid
fibrils as many as 20–30 years before
any clinical symptoms of the disease
are manifested.

Bateman et al., 2012

II. NEUROFIBRILLARY TANGLES

• Twisted intracellular [axon] protein [tau] filaments
• Initially prevalent in medial temporal memory structures (entorhinal cortex, hippocampus), before spreading
throughout cortex.

Two of these neurons contain filaments called neurofibrillary tangles (NFTs). They are
magenta colored and have been described as looking like flames (arrows).

Here the NFTs stain black within the neurons.

III. GRANULOVACUOLAR DEGENERATION (GVD) BODIES

Granulovacuolar degeneration involves the accumulation of large, double
membrane-bound bodies within certain neurones during the course of
Alzheimer's disease (AD) and other adult-onset dementias.

The arrows point out some of the GVD

 WHAT IS THE RELATIONSHIP BETWEEN AMYLOID DEPOSITION AND NEURODEGENERATION?

1. Synaptic dysfunction→ amyloid deposition disrupts network circuitry in the brain, particularly in the default
network. Decreases the ability to modulate or control brain networks in response to task demands associated with
episodic memory.

FDG-PET

• Provides an overall measure of how metabolically active

different regions are by measuring how much glucose the
regions are utilizing for energy
• High amyloid burden has been associated with lower
metabolic activity in temporoparietal brain regions known
to be impaired in AD patients
• Individuals transition from healthy to demented by first
depositing amyloid and then exhibiting signs of neuronal
dysfunction.

2. Neuronal loss→ Decreases in cortical thickness across many brain regions and a specific decline in hippocampal
volume.
Amyloid and tau: a small amount of tau is present in the medial temporal lobe in healthy adults before amyloid
deposition, it is hypothesized that amyloid induces the spread of tau. Tau tangles literally kill neurons, so that tau
deposition should be a particularly potent marker of neurodegeneration.

KEY BRAIN STRUCTURES AFFECTED IN ALZHEIMER’S

DISEASE
 Begins in the entorhinal cortex of the medial temporal lobe memory system and temporal lobe beyond

On to the basal forebrain and frontal lobes

COGNITIVE PROFILE MAPPED ONTO NEUROPATHOLOGY

- Initial cognitive symptoms → Memory decline

• Recall, recollection of anterograde episodic memories;
AD patients have recent memory deficits while still able to recall information from the past.
Entorhinal cortex
• Becomes progressively worse as pathology spreads to the
Hippocampal complex

Cognitive symptoms of AD will first become apparent in the face of stressful life events which tax an individual’s cognitive
reserve.

“Very often I wander around looking for something which I know is very pertinent, but then after a while I forget about it
is I was looking for....Once the idea is lost, everything is lost and I have nothing to do but wander around trying to figure
out what is was that was so important earlier.”

- As Alzheimer’s becomes more severe, other impairments emerge..

• Language problems such as word finding difficulties;
Temporal lobe
• Dysexecutive syndrome
• Emotional changes such as apathy, disinhibition
• Attentional, problem-solving and decision-making impairments
• Semantic memory
• Praxis
• Spatial disorientation
Frontal lobe
 DOES AMYLOID DEPOSITION INVARIABLY LEAD TO COGNITIVE DECLINE?

MEMORY

✓ Some cross-sectional studies have found a relationship between amyloid burden and decreased episodic memory performance, but
other failed to find such relation
✓ Longitudinal testing (questionnaires that collected subjective memory reports)→ greater subjective memory complaints were
associated with higher amyloid burden even in the absence of memory dysfunction
✓ (Few longitudinal amyloid–cognition studies to date) some studies have demonstrated that initial amyloid burden is predictive of
decline in episodic memory (other failed)
✓ Initial amyloid status is predictive of future progression to MCI and dementia

OTHER COGNITIVE DOMAINS_________________Inconsistent!

✓ Some longitudinal studies have found a correlation between initial amyloid burden and subsequent decline in non-memory domains

COGNITIVE AND BEHAVIOURAL PROFILE OF ALZHEIMER’S DISEASE.

Main categories of genetic risks of Alzheimer’s disease:

❖ Rare autosomal dominant inherited mutations typically occurring before age 65 (early-onset Alzheimer’s disease).
❖ The APOE-4 (located on chromosome 19) genetic polymorphism that incurs an increased risk for lateonset Alzheimer’s disease.
❖ Unknown genetic contributions associated with a family history of AD.

RELATIONSHIP BETWEEN GENES AND PATHOLOGY

❖ APOE4 alleles may code for over production of beta-amyloid which then clump together to form plaques.
❖ This occurs initially in medial temporal lobe memory structures.
❖ Before spreading to other cortical areas.

Alzheimer’s disease Genes and the environment Gatz M, Reynolds CA, Fratiglioni L, Johansson B, Mortimer JA, Berg S, Fiske A, Pedersen NL Arch
Gen Psychiatry.
 THE CLINICAL INTERVIEW

A detailed clinical interview with the patient and a collateral informant, possibly separately (so that they feel free to speak honestly about their
concerns) + information about the current cognitive difficulties experienced by the patient.

Importance of the first symptoms: DOMAIN?

- Memory loss (and sometimes language disturbance such as difficulty in retrieving words)→ AD
- Predominant symptoms language and executive dysfunction (such as disinhibition)→ possibility of a fronto-temporal dementia
- Attention, cognitive slowing, executive and visuospatial disturbance, psychiatric disturbances such as visual hallucinations, and REM
behavior sleep disorders→ Lewy body disease

Importance of the first symptoms: ONSET?

- A sudden onset of cognitive symptoms (often in vascular or other non-AD neurological disorders)
- A slowly progressive course with a gradual worsening of symptoms such as is typically seen in AD.

In clinical interview it’s also examined the premorbid function of the patient (also education, socioeducational level…), the
extent to which observed deficits interfere with social or occupational function, levels of anxiety and depression and finally
medications.

The optimal neuropsychological battery assesses:

(1) Learning and retentive memory,

(2) Executive function,
(3) Language,
(4) Visuospatial skills
(5) Attention and processing speed
NEUROPSYCHOLOGICAL ASSESSMENT
The optimal neuropsychological battery assesses

1. Learning and retentive memory,

2. Executive function,
3. Language,
4. Visuospatial skills
5. Attention and processing speed

e.g., italian batteries: esame neuropsicologico breve (enb 2)

MEMORY DOMAIN→ Multiple indices of memory function:

- Learning curve
- Recognition/recollection
- Effects of proactive and retroactive interference
- Use of semantic cues

California VLT→ 16 items representing four semantic categories five

trials to learn the tobe-remembered targets second list of 16 items is
then administered (proactive and retroactive interference) use of
semantic cues to facilitate recall delayed free and cued recall after a 20-min period as well a recognition memory test

Hopkins VLT→ 12 items Three trials to learn the tobe-remembered targets.

Benton Visual Retention Test (BVRT) The individual examined is shown 10 designs, one at a
time, and asked to reproduce each one as exactly as possible on plain paper from memory.
Investigate visual memory.

LANGUAGE DOMAIN

Boston Naming Test BNT → contains 60 line

drawings graded in difficulty It evaluates semantic
lexicon Short form – 15 items.

Letter Fluency→ a more orthographic memory task that requires retrieval from phonological stores and is sensitive to frontal
lobe dysfunction
- reading sample,
- writing sample,
- repetition of phrases
Receptive language→ simple and more complex commands or performing the Token Test.

EXECUTIVE FUNCTIONS DOMAIN

- Wisconsin Card Sorting Test: provides an excellent measure of concept formation, perseverations, and the ability to
shift cognitive sets.
- Trail Making Test – B (A-B)
- Tower Of London
VISUOSPATIAL DISTURBANCES AND CONSTRUCTIONAL PRAXIS
Block Design Subtest of the Wechsler Adult Intelligence Scale The test-taker uses hand movements to
rearrange blocks that have various color patterns on different sides to match a pattern. The items in a block
design test can be scored both by accuracy in matching the pattern and by speed in completing each item.

CLINICAL PEARLS

1. The hallmark features of Alzheimer’s disease (AD) are deficits in delayed recall and rate of
forgetting.
2. List learning tests are optimal for assessment of AD
3. It is desirable to assess memory for verbal as well as nonverbal information (i.e., immediate and delayed
visual reproduction).
4. The AD patient may on occasion present with primary impairments in executive dysfunction, language, or
visuospatial function. Therefore, it is important to assess these domains.
5. A clinical diagnosis of AD is greatly strengthened by evidence of medial temporal lobe atrophy on MR, AB42
in the cerebrospinal fluid, abnormal beta amyloid imaging on PET imaging, or hypometabolism in temporal
and parietal cortices.
6. Differential diagnosis (lewy body, fronto-temporal dementia)
7. Serial testing is recommended
8. Denial of symptoms is commonly observed in AD, yet some early AD patients are aware of changes, which
may lead to significant levels of depression and anxiety

A new treatment, “Solanezumab”, appears to stop the degenerative disease in its tracks.

• The trial followed 1,322 people with mild Alzheimer’s patients

• The patients were allocated to either:
– An immediate start condition where they received the active treatment (“solanezumab”) from the start of the trial
OR
– A delayed start condition, where they received placebo for 28 days prior to the active treatment

PATIENT
CHARACTERISTICS

MAIN FINDINGS
Solanezumab is an
antibody which works by
binding to the amyloid
plaques which cause
Alzheimer’s disease and
clearing them from the
brain.
 FRONTOTEMPORALDEMENTIA AND LEWYBODY DEMENTIA
It is equally as common as Alzheimer’s disease in individuals under the age of 65. Age of onset is typically in the presenium(< 65),
though onset ranges considerably from the 30s to 90s and duration of FTD ranges from 8 to 11 years.

FRONTOTEMPORAL DEMENTIA
THREE PHENOTYPES:

1. Behaviouralvariant (BvFTD)
2. Semantic variant of primary progressive aphasia(svPPA)
Aphasic variants
3. Non fluent variant of primary progressive aphasia (nfPPA)

A male bias in bvFTD and svPPA

SEMANTIC VARIANT OF PRIMARY PROGRESSIVE APHASIA (svPPA) - loss of word knowledge (e.g., semantic structure of
language) → 15%
Selective degeneration of the left anterior temporallobe leads to a disorder of semantic knowledge, slowly decimating the
intricate classification and naming systems that we first develop as children to understand the world.

NON FLUENT VARIANT OF PRIMARY PROGRESSIVE APHASIA (nfPPA) -early disturbances in motor speech output and loss
of syntax (e.g., grammatical structure of language) → 10%
Increasingly difficult to speak yet can still recall the meanings of individual words. The defining feature is the impairment of
grammar. nfvPPA patients (60%) have abnormal accumulations of tau protein in the brain that are distinct from the type of tau
protein that accumulates in Alzheimer’s disease.

BEHAVIOURALVARIANT (BVFTD)
It is most common and accounts for approximately 70% of the clinical expression of the disease. It presents profound and early
changes in personality and behavior.

Earliest Signs of bvFTD→ subtle personality and behavioral changes that become increasingly pronounced as time goes on:

Dramatic changes and consequences: partners and families no longer

recognize their loved one. Impulsive decisions or actions, including such
behaviors as shoplifting, driving recklessly, or physically assaulting
others. Violate social norms by making inappropriate sexual comments.
Emotionally cold and self-centered.
Diagnostic Criteria for bvFTD
Patients must meet at least three of the six following criteria:
(1) early behavioral disinhibition,
(2) early apathy/inertia,
(3) early loss of sympathy or empathy,
(4) early perseverative, stereotyped or compulsive behaviors,
(5) hyperoralityor dietary changes,
(6) a neuropsychological profile suggesting deficits on tasks of executive function with relative sparing of memory and
visuospatialfunction.

Moreover:

o Exhibit significant functional decline

o Show evidence of frontal and/or temporal atrophy on structural MRI or CT, or hypometabolismon positron emission
tomography (PET).

Exclusion criteria for bvFTD

A. Pattern of deficits is better accounted for by other nondegenerative nervous system or medical disorders
B. Behavioral disturbance is better accounted for by a psychiatric diagnosis, e.g., depression, bipolar disorder, schizophrenia,
pre-existing personality disorder
C. Biomarkers strongly indicative of Alzheimer’s disease or other neurodegenerative process (e.g., genetic mutations, extensive
PIB finding, CSF markers)

→ Criteria A and B must both be answered negatively for any bvFTD diagnosis. Criterion C can be positive for possible bvFTDbut
must be negative for probable bvFTD.

NEUROANATOMY AND PATHOLOGY OF bvFTD

The hallmark symptoms of bvFTD strongly reflect initial areas of neurodegeneration, primarily in paralimbic structures:

- Anterior cingulate cortex,

- Frontoinsular region, Social behaviour awareness of the self-decoding the emotional salience
- Dorsal anterior insula, in order to make the appropriate action
- Lateral orbitofrontal cortex
BvFTDis caused by abnormal aggregation of protein in the brain, that leads to frontotemporal lobar degeneration (FTLD).

Two most common proteins: TAU and TDP-43→ They aggregate and accumulate in the cytoplasm of neurons and glial cells and
are associated with neuronal death and atrophy.

GENETIC
30–40% of all cases appear to be genetic in nature with rates of autosomal dominant pattern of inheritance ranging from 10% to
30%. Genetic mutations known to cause familial FTD have been found on three different chromosomes (three, nine, seventeen)
The greatest proportion of familial cases comes from individuals who have mutations on two independent, but extremely close
locations on chromosome 17.

DIFFERENTIAL DIAGNOSIS

Neurodegenerative→ - Progressive supranuclearpalsy - Corticobasalsyndrome - Amyotrophic lateral sclerosis - Alzheimer’s

disease - Semantic variant primary - progressive aphasia - Huntington’s disease - Lewybody dementia

Psychiatric disorders→ Bipolar disorder - Major depression - FTD phenocopy [bvFTDhave been characterized as
“nonprogressive” or “bvFTD phenocopies” due to the presence of a behavioral disturbance in the context of lack of notable
atrophy on imaging or cognitive decline over time]- Psychopathy
→ Of the patients with bvFTD, 51% of patients had received a prior diagnosis of a psychiatric disorder

Neurologic disorders

Cerebrovascular accident

Traumatic

NEUROPSYCHOLOGICAL PROFILE
MEMORY

Compared to patients with AD who exhibit severe verbal and visuospatialepisodic memory deficits, patients with bvFTD
demonstrate a relative preservation in their episodic memory.
bvFTD patients tend to retain information over delays, while AD patients exhibit more rapid forgetting.
(Sometimes attenuated learning with a disorganized or inefficient approach)

LANGUAGE

Individuals with bvFTD do not experience the same types of changes in language that accompany PPA variants of FTD.
Intact semantic and syntactical knowledge ______However_____ Speech and language may reflect notable changes: reductions
in spontaneous speech; decreased verbal output (can potentially progress to complete mutism).

VISUOSPATIAL

Visuoconstruction and visual perceptual skills are better preserved in patients with bvFTD relative to AD.
Difficulties can arise for bvFTDpatients when the task relies heavily on top-down control of spatial processing.

ATTENTION/EXECUTIVE FUNCTIONS

CONFLICTING RESULTS AMONG THE STUDIES!!! Probably because it depends on the stage of disease: Neurodegeneration begins
in the ventromedial aspect of the frontal lobe and moves dorsolaterally with disease progression to see executive deficits
manifest until later in the disease. It appears that “traditional” clinical measures of executive function are notparticularly
sensitive earlyin the disease process.

- Executive functions impaired in later stages

ONSET
Has the onset been slow and insidious, or abrupt and explicit?
Behavioral variant FTD is an insidious disease that may begin many years before changes become obvious. because the age of
onset of bvFTD tends to be in the late 50s, the personality and behavior changes are often misinterpreted as “mid-life” troubles.

FAMILY HISTORY
Approximately 30–40% of all individuals with bvFTD have a strong family history of the disease. If a history reveals family
members who exhibited significant changes in personality and social behavior after the fifth decade or who had symptoms of
motor disorder (e.g., ALS, PSP, CBS), these are potential clues that the individual may have a genetic form of the disease.

CLINICAL ASSESSMENT OF bvFTD

• Cognitive Assessment

• Neuroimaging→ Structural MRI is best for reviewing degenerations Atrophy is often asymmetric (right > left) and,
in the early middle stages, confined to the medial frontal and anterior temporal lobes.
PET scans may also reveal hypometabolismof the frontal and temporal lobes. PET imaging that utilizes Pittsburg
Compound B (PIB), a radioligandwhich binds to amyloid in the brain, has been shown to be negative in bvFTD

• Behavioral Observations→ a brief behavior-rating scale where patients are rated on a scale ranging from none,
mild, moderate, and severe on the following observable behaviors: agitation, stimulus boundedness, perseverations,
decreased initiation, motor stereotypies, distractibility, lack of social/emotional engagement, impulsivity, socially
inappropriate behavior, and impaired or fluctuating levels of attention.

• Informant-Based Measures → regarding social and emotional deficits experienced by the patient. Information
whichwas not gleaned on interview.

• Neuropsychiatric Inventory (NPI) → is a screening measure that is administered to the patient’s informant by the
clinician and is a well-validated measure of neuropsychiatric symptoms common in neurodegenerative disease. -
assess the frequency and severity of 12 different neuropsychiatric behaviors that may occur in the context of
dementia (e.g., anxiety, apathy, disinhibition, aberrant motor behavior).

• Revised Self-Monitoring Scale → 13-item questionnaire

measures an individual’s sensitivity and responsiveness
to social cues

• Interpersonal Reactivity Index The empathic concern (EC) and perspective taking (PT) subscales of the IRI were
designed to evaluate an individual’s ability to empathize with others.

• Interpersonal Reactivity Index

CLINICAL PEARLS

✓ FTD is first and foremost a disease that disrupts behavior and social function.
✓ Compared to AD, patients with bvFTDtend to have little insight into their condition and are more flat,
perseverative, inappropriate, and emotionally dysregulated.
✓ BvFTD is often misdiagnosed as late-onset psychiatric disease or early onset AD.
✓ The presence of executive dysfunction in the absence of other major cognitive impairments is not specific to
bvFTD
 LEWYBODY DEMENTIA
LBD is an umbrella term that includes two clinical diagnoses: “dementia with Lewy bodies”
(DLB) and “Parkinson’s disease dementia” (PDD). These disorders share a common
biological disease process but have differing primary symptoms in the early stage. Its
name comes from the underlying biological disease process, the accumulation of
Lewy bodies in brain cells. These are abnormal clumps, named after the doctor
who first identified them, of a protein called: alpha-synuclein. The central
characteristic of DLB is a progressive loss of cognitive function that significantly
interferes with everyday life (dementia). Compared to patients with AD, those with DLB tend to have more severe
problems with visual processing as well as executive function. Memory, while impaired, is relatively intact in
comparison to AD.
Other core features of DLB:

- Unpredictable changes in cognition and attention (fluctuations)

- Impairments in motor function typical of Parkinson’s disease (parkinsonism)
- Visual hallucinations
- Rapid eye movement (REM) sleep behavior disorder (in which a person physically acts out his or her dreams)
- Problems with automated, more basic body functions like blood pressure, temperature regulation and digestion and
urinary control

Prevalence
Recent estimates suggest that DLB is responsible for 4 to 16% of cases of dementia seen in the clinic, but probably higher.
It’s ifficult to diagnose→ the only way to diagnose DLB definitively is by identifying Lewybodies in a patient’s brain tissue after
death.

The biology of DLB

DLB is associated with protein misfolding. Alpha-synucleinis a type of protein present in everyone’s brain. • The normal function
of alpha-synucleinin nerve cells is not yet fully understood.

➔ regulation of the release of chemical messengers (neurotransmitters) from nerve cell processes.

• Alpha-synucleinis produced in cells as a string of amino acid building blocks. These must then fold into a specific three-
dimensional shape in order to function properly.
• Genetic mutations or cellular stressors can cause alpha-synucleinmolecules to fold into abnormal shapes and stick to one
another.
• These sticky protein aggregates build up inside cells like hairs caught in a drain, eventually forming the round clumps called
Lewybodies

Mechanisms of Disease Progression

It is theorized that the spread of alpha-synuclein pathology through the brain proceeds like dominoes falling.
Misfolded alpha-synuclein molecules provoke nearby normal alpha-synuclein molecules into adopting their
abnormal configuration and sticking to them.

Brain Regions and Processes Affected

- Lewy bodies typically develop first in the olfactory bulb and in neurons that send cell processes to the heart, gut, and
other internal organs
- They also appear in the brain in certain regions important for thought and emotion, and other regions involved in
movement and sleep.
- The build-up of alpha-synuclein inside neurons interferes with their ability to generate electrical signals and release
neurotransmitters, such as dopamine and acetylcholine.
- Abnormal alpha-synuclein deposits also provoke inflammatory responses in the brain, which further worsens brain
function
- Fluorodeoxyglucosepositron emission tomography (FDG-PET), which measures regional use of glucose throughout the
brain, is useful.
- The brains of people with DLB may show decreased metabolism in the occipital lobe of the cortex, where visual
information is processed.
- FDG-PET scans have good sensitivity and specificity for detecting DLB.
 VASCULAR DEMENTIA
Vascular cognitive impairment
The risk of cerebrovascular disease increases as individuals age: 70% of individuals over the age of 70 exhibiting evidence of
vascular lesions on MRI. Vascular cognitive impairment (VCI): introduced to describe all forms of cognitive impairment caused by
cerebrovascular disease.
The type of impairment associated with VCI can be variable depending on the location and amount of damaged tissue

- Small vessel ischemic disease VCI-no dementia (VCIND)

- Stroke in a large vassel→ vascular dementia (VaD) or post-stroke dementia

The most common types of dementia among older adults after AD

• About one-third of individuals will develop dementia within 1 year after a stroke
• Mixed dementia between VCI and AD is common and argued by some to share neuropathogenic mechanisms

Majority of lesions are subcortical→ cortical lesions account for less than 15% of the total number of strokes. Patterns of abrupt
onset and stepwise decline in function are less common than a slow and progressive disease course.

Common stroke sites and corresponding clinical features:

1. Anterior cerebral artery→ Paraplegia, incontinence, abulia,

executive dysfunction, personality changes.
2. Middle cerebral artery→ Hemiplegia, aphasia, homonymous
hemianopia, hemianesthesia contralateral.
3. Posterior cerebral artery→ Homonymous hemianopia, alexia
with or without agraphia, visual agnosias, color anomia, Balint syndrome, prosopagnosia.
Balint syndrome: [uncommon]
- inability to perceive the visual field as a whole (simultagnosia),
- difficulty in fixating and controlling the eye movements (oculomotor apraxia),
- inability to move the hand to a specific object by using vision (optic ataxia)

Corbetta et al., 2015

BEYOND the lesion-symptom maps

▪ Studied a large prospective sample of first-time stroke

patients with heterogeneous lesions at 1–2 weeks poststroke.
▪ Measured behavior over multiple domains and lesion
anatomy with structural MRI
▪ Multivariate methods estimated the percentage of
behavioral variance explained by structural damage

A few clusters of behavioral deficits spanning multiple functions

explained neurological impairment.

Common behavioral clusters

Behavioral deficits were strongly correlated within each domain (e.g., motor, language, attention, and memory) with one or a
few factors accounting for the majority of variability, and across domains.
In the language domain:
• A single factor accounted for 76% of impairment variability across tests of expression, auditory comprehension, and
reading, both at the single-word and sentence level.
• A pz with language dysfunction, e.g., in reading, will nevertheless show some impairment across all language functions, as
compared to patients without any impairment in that domain.
• Classic aphasia syndromes (e.g., Broca, Wernicke, or Alexia) account for more modest amounts of variance (20%–30%)
than overall impairments in language.
• Common language impairment mapped to multiple nodes of a distributed language network, which included not only
classic perisylvian regions, but also left caudate, thalamus, fusiform gyrus, and right inferior frontal. Both dorsal and
ventral white matter were involved.

In the attention domain:

 • Three factors related to:
• deficits of lateralized spatial attention (both perceptual and motor)
• sustained attention/general performance
• attention shifting/re-orienting
• Most neglect patients have multiple concurrent deficits
• Attention biases were most strongly localized to the right dorsal periventricular
white matter near/at the superior longitudinal fasciculus

In the memory domain:

• A strong correlation among multiple processes (long-term, short-term, and working memory), and between spatial and
verbal memory
• Verbal memory: left hemisphere damage distribution
• Spatial memory: bilateral distribution of damage that included both cortical and subcortical tissue.

VASCULAR COGNITIVE IMPAIRMENT: NO DEMENTIA

Vascular lesions evident on MRI that cause impairment too mild to impact activities of daily living.

On MRI:

• Lacunes (i.e., small cerebrospinal filled cavities in the white matter)

• Subcortical hyperintensities (areas of bright white on neuroimaging that represent vascular-related damage).

These “silent” infarcts may not be truly silent: normal age-related cognitive decline. VCIND may be a prodromal stage for VaD
(half of the VCIND cases progressed to dementia over a 5-year period of time). Modifiable risk factors, such as hypertension,
may play an important role in determining the progression of VCIND to VaD.

About cognitive profile, VCIND patients display poor performance on tests of :

• Cognitive flexibility and verbal retrieval
• Learning
• Psychomotor speed
• May increase the incidence of depression
 VASCULAR DEMENTIA
VaD is the result of extensive white matter lesions and lacunar
infarcts due to small vessel disease, the result of one or more
strokes to the main cerebral arteries, or some combination of
the two. Executive function, learning, and delayed memory,
with intact recognition memory are the most consistently
impaired domains of function in VaD.

- Executive function: Verbal fluency, inhibition, cognitive

flexibility

- Episodic memory: deficits on tests of list learning and recall,

but recognition may remain intact (particularly if the structures
of the medial temporal lobe are spared of vascular damage.)

- Physical symptoms: extrapyramidal symptoms, bilateral

pyramidal symptoms, positive masseter reflex, imbalance,
incontinence, dysarthria, and dysphagia

- Psychological symptoms: Depression is the most common

behavioral feature associated with stroke. About 20% of
individuals with stroke also exhibit depression

The DSM-IV criteria are based on symptoms similar to AD and

require memory deficits as a prominent feature. This requirement
presents a diagnostic conundrum since core aspects of episodic
memory can remain intact in the context of vascular disease, and
memory impairment may not be the primary feature of the disease.

DSM-V has removed the necessity for memory impairment as one of

the criteria for dementia.

RISK FACTOR
Vascular Risk Factors
• The greatest risk factor associated with VCI is age.
• Additional unmodifiable risk factors for stroke include:
- male sex - low birth weight - atrial fibrillation - race (i.e., African American) - ethnicity (i.e., Latino)
• Susceptibility genetic factors that increase an individuals’ risk of vascular disease, including cerebral autosomal dominant
arteriopathy with subcortical infarcts leukoencephalopathy (CADASIL).

Modifiable risk factors for stroke include:

- Hypertension
- Smoking
- Diabetes mellitus
- Dyslipidemia

Risk factors for dementia after stroke include: - increasing age, - low education, - female sex, - vascular risk factors, - stroke
location, - presence of strokes, and both global and medial temporal atrophy on structural imaging - late life depression.
 VCI DIFFERENTIAL DIAGNOSIS
• Lewy body dementia
• AD→ challenging, sometimes coexist
• Fronto-temporal dementias→ typically
presents with more unique symptoms
than VCI, such as significant aphasia or
personality abnormalities. The age of
onset for VCI is often, but not always,
older than what is typical for
frontotemporal dementia with behavioral
disturbances present before age 65.
• Normal pressure hydrocephalus (NPH)

Typical symptoms of NPH includes urinary urgency (or urinary frequency/ incontinence) and gait disturbance.

CLINICAL EVALUATION

• Clinical Interview and History • Neuropsychological Assessment • Neuroimaging Corroboration

- MOCA vs MMSE → MoCA has greater sensitivity to more subtle cognitive impairment and early AD than the MMSE.
However, the MoCA was not developed specifically for VCI, and it is unclear whether the limited task demands
adequately capture mild to moderate cognitive impairments associated with cerebrovascular disease.
- Evaluating cognitive reserve à CRIq
- Evaluating ADL independence (activity daily living scale, ADLS)→ it is important to communicate to families that while
the patient may be independent today with instrumental activities that facilitate independence (e.g., cooking, driving,
medication, and financial management), this independence is likely to change.
-

For Italian assessment: ESAME NEUROPSICOLOGIC

O BREVE (ENB2).

OXFORD COGNITIVE SCREEN (2015): short screen for

cognitive problems that targets stroke survivors
specifically

MOTRICITY INDEX AND TRUNK CONTROL TEST→ To quantify motricity and weakness of limb segments and trunk.

CLINICAL PEARLS
• The course of decline associated with VCI can be abrupt with stepwise decline or slow, insidious, and progressive, resembling
the course for age-related neurodegenerative diseases, such as AD
• The pattern of neuropsychological deficits associated with vascular burden is heterogeneous and dependent on the location of
the cerebrovascular damage. Executive impairment may be dominant but not universal and not necessary for the diagnosis.
• Integration of structural brain MRI results is critical for the diagnosis of VCI.
• The progression of VCI can be influenced by healthy lifestyle interventions. Early diagnosis is critical!
 PARKINSON DISEASE
PD prevalence:
• 1−2% (>60−65 ys)
• 0.3% general population
• Second most common
neurodegenerative
disorder after Alzheimer’s
disease

ATYPICAL PARKINSONISM

• Multiple system atrophy

(MSA)
• Progressive supranuclear
palsy (PSP)
• Corticobasal
degeneration (CBD)
• Dementia with Lewy
bodies (DLB)

PD is characterized by the degeneration of nerve cells, in several brain regions particularly in

the substantia nigra, due to filamentous inclusions in the form of Lewy Bodies and Lewy
neuritis, whose major component is synuclein (Spillantini & Goedert, 2000).
Motor symptoms that characterize PD patients arise from the loss of nigrostriatal neurons
that use dopamine as neurotransmitter to communicate within the striatal network.

For a probable diagnosis of PD, three of four cardinal symptoms should be observed:

- Resting tremor
- Bradykinesia
- Rigidity
- Postural instability

For at least three years and substantial response to

levodopa therapy should be documented (Gelb et al.,
1999).
 TREMOR
• 80% of patient experience tremor
• Most commonly affects hands and arms
• Can possibly become more severe with strong emotions and stress
• Generally most severe when limb is at rest and improves with movements

BRADYKINESIA, characterized by:

• Usually slow movements
• Slow reaction time
• Decreased of spontaneous movements
• Affects all patients
• INTERFERES WITH DAILY

RIGIDITY, characterized by:

• Stiff muscle tone
• Resistance to movement
• Can possibly decreased range of movement
• Affects all patients
• May contribute to discomfort and pain

POSTURAL INSTABILITY, characterized by:

• Loss of ability to maintain an upright posture
• Developed later in the course of the disease
• Results in fall
• Most disabling motor symptom

GAIT DISTURBANCE, characterized by:

• Abnormal manner of walking
• Lack of arm swing
• Arms flexed at elbow
• Dragging of one leg
• Small shuffling steps (freezing)
• Can contribute to falling

OTHER MOTOR SYMPTOMS

• Dysarthria (speech disorder)
• Difficulty swallowing
• Micrographia (small handwriting)

NON-MOTOR SYMPTOMS IN PD
Recently, it has been recognized that also non-motor symptoms in movement
disorders represent a crucial part of the parkinsonian disorders spectrum
(Chaudhuri, Healy, & Schapira, 2006) Motor deficits.
Among the non-motor symptoms cognitive deficits are probably the most
relevant→ They markedly affect patients’ autonomy, increase caregiver burden
and wield a considerable socioeconomic impact (McCrone et al., 2011; Vossius et
al., 2011).
PD AS A NEUROPSYCHIATRIC DISORDER

✓ DSM-5 encapsulated – Depression, psychosis, cognitive impairment, impulse control disorders, anxiety,
apathy, disorders of sleep and wakefulness
✓ Neural substrate relevant to neuropsychiatry – Brain regions (basal ganglia, prefrontal cortex),
neurotransmitters (dopamine, norepinephrine, serotonin, acetylcholine and glutamate), neural pathways
(cortico-striatal-thalamic circuitry)
✓ Inter- and intra-individual variability allows study- cognitive fluctuation

NEUROTRANSMITTERS PROJECTION LOSS IN PD

1. Dopamine
2. Noradrenaline→ Noradrenergic dysfunction (locus coeruleus) in PD probably underlies the attentional set
shifting deficit, which forms part of the dysexecutive syndrome.
3. Acetylcholine→ Some frontal cholinergic deficit (cortico-striato-thalamic loop/nigrostriatal system) also
compromises early Parkinson’s disease cognition.

Parkinson’s Disease Cognitive Functional Rating Scale (PD-CFRS)

PD-CFRS cut-off score of > 3 for detecting functional impairment in PD-MCI
PD-CFRS cut-off score of > 6 for detecting functional impairment in PDD

Pennsylvania Daily Activities Questionnaire (PDAQ) (Weintraub, D; Brennan et al. 2015)