Continuum Disfunciones Memoria 2021

REVIEW ARTICLE

Memory Dysfunction
C O N T I N UU M A UD I O By Roberto Fernandez-Romero, MD, MPH, PhD; D. Malcolm Spica, PhD
I NT E R V I E W A V AI L A B L E
ONLINE
ABSTRACT
PURPOSE OF THE REVIEW: This
article provides a practical overview of the
diagnostic process for patients with memory dysfunction through
exploration of the anatomic, physiologic, and psychological aspects of
human memory.
RECENT FINDINGS: As updated methods become available to neurologists, the

ability to accurately identify and treat patients with memory disorders
evolves. An appreciation of current concepts in the anatomic, physiologic,
and psychological aspects of memory, combined with a rational
application of everyday tools (such as clinical examination, bedside
testing, standardized cognitive screening, and formal neuropsychological
examination), allows the clinician to identify possible etiologies and track
longitudinal changes in functional memory status. Recent findings
regarding the interactions of limbic, anterior temporal, primary sensory,
parietal, and dorsal prefrontal structures shed new light on the putative
classifications of procedural and declarative memory and their
subfunctions.
SUMMARY: An understanding of memory profiles pertaining to registration,

encoding, consolidation, storage, and retrieval, as well as methods to
assess those functions, facilitates the clinician’s identification of
CITE AS: underlying pathology and affected cerebral territories. The memory profile
CONTINUUM (MINNEAP MINN)
2021;27(6, BEHAVIORAL NEUROLOGY
must be appreciated in the context of the entire individual, including
AND PSYCHIATRY):1562–1585. possible confounds of comorbid conditions, psychiatric disorders, and
normal healthy aging.
Address correspondence to
Dr Fernandez-Romero, The
University of Tennessee
Medical Center, Brain and Spine
Institute, 1932 Alcoa Hwy, Ste INTRODUCTION
L
C-150, Knoxville, TN 37920,
RFernandez@UTMCK.edu.
earning and memory are the most critical processes by which humans
gather information from the world around us and incorporate that
RELATIONSHIP DISCLOSURE: information into the knowledge that allows us to comprehend and adapt
Dr Fernandez-Romero has
received research/grant to our environment. Learning is the process of acquiring information,
support from The University and memory is the process of encoding, storing, and retrieving
of Tennessee Medical Center.
that information.
Dr Spica reports no disclosure.
Some consider memory the most critical of all higher-order cognitive
UNLABELED USE OF functions, with the understanding that it is never fully independent from other
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
domains. Erick Kandel, for example, famously stated, “We are who we are
Drs Fernandez-Romero and because of what we learn and what we remember.”1 While the extent of
Spica report no disclosures. preserved memory function in determining who we are may be debatable and
© 2021 American Academy acquired memory impairments will not necessarily strip individuals of their
of Neurology. sense of self or personality, the importance of memory in its broadest sense
1562 DECEMBER 2021
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

should not be underestimated. Thus, it is no coincidence that no other KEY POINTS
cognitive domain has been as broadly studied as memory. It is also the
● Working memory retains
reason why the public so often equates deficits in other domains with a information for seconds or
“memory problem.” minutes, usually while that
This article reviews the different types of memory, with an emphasis on information is relevant to an
episodic memory because of its clinical significance, and the anatomic structures ongoing task.
critical for different memory functions. Recommendations for the assessment of
● Long-term memory is
patients with memory problems, including the use of neuropsychological testing divided into episodic and
as an important diagnostic tool, are presented. Specific conditions affecting semantic. Episodic memory
memory functions are briefly discussed, with an emphasis on patterns of is characterized by the what,
memory loss observed in each condition. The overall goal is to provide the where, and when of a
particular episode that is
clinician with useful and updated information for the assessment and diagnosis being stored and available
of patients presenting with disorders of memory. for later retrieval. Semantic
memory involves the
CLASSIFICATION OF MEMORY retrieval of facts that may be
obtained over a period of
Memory can be divided into explicit (conscious) and implicit (unconscious) time and are not associated
memory.2 Explicit memory refers to information that is acquired through with a specific life episode.
conscious experience and awareness and later consciously retrieved. Implicit
memory refers to information such as skills that, once learned, are done mostly ● The Papez circuit is
crucially involved in the
automatically. Repetition priming is also linked to skill learning and refers to the
processing and transfer of
fact that repeated exposure to a stimulus will make learning it easier, even if the information for long-term
individual is not consciously attempting to learn that particular task or storage. Bilateral lesions to
information. any of its components can
cause significant episodic
Explicit memory is further divided into long-term and working (short-term)
memory deficits and
memory. Working memory retains information for seconds or minutes, usually predominantly anterograde
while that information is relevant to an ongoing task. An everyday example amnesia. Injury to the
might be looking up a phone number that has not been memorized. The numbers hippocampus will also result
are recalled only for the amount of time necessary to make the call. Once the task in temporally graded
retrograde amnesia, where
is completed, that information is no longer relevant and discarded. If the phone information acquired
number is relevant for future use, it can be stored in long-term memory, usually recently before the lesion
through a process of repetition or practice that leads to encoding and will be lost, but more
consolidation. remote memories will
remain intact.
Long-term memory is further divided into episodic and semantic memory.
Episodic memory is characterized by the what, where, and when of a particular ● The basolateral limbic
episode that is being stored and available for later retrieval. An example would be system is primarily involved
recalling the last visit with a doctor, when it happened, where it took place, and with the processing of
emotions, but it also plays a
what was discussed during that visit.
role in the assignment of
Semantic memory involves the retrieval of facts that may be obtained over a emotional value to
period of time and are not associated with a specific life episode. An example is experiences, which can
knowing that Vienna is the capital of Austria. One usually does not know or modulate their
consolidation. Bilateral
remember when, where, or how that information was acquired. Knowing the
injury to the basolateral
meaning of words and what a tool is used for are other examples of semantic limbic structures can result
memory. It should also be noted that these different types of memory may in varying degrees of
converge. For example, a neurologist may have an episodic memory of their first memory dysfunction, often
neurology rotation where a mentor taught how to use a reflex hammer. Over associated with other
behavioral symptoms such
time, the neurologist acquires semantic memory regarding the different ways as hypersexuality,
to use the hammer and what to look for when checking reflexes. The technique hyperorality, and
improves with time as the neurologist develops the procedural memory that hyperphagia (Kluver-Bucy
allows the neurologist to apply it automatically, without necessarily thinking syndrome).
about it.
CONTINUUMJOURNAL.COM 1563

MEMORY DYSFUNCTION
ANATOMY
The neuroanatomy of memory involves a complex group of networks and
interactions of multiple brain regions, some of which are selective to specific
types of memory. This specificity of neural substrates can be of great utility for
clinical diagnosis based on localization.
Episodic Memory
Primary sensory cortices and association areas receive and process information
from sensory systems, whereas frontal regions modulate motivation, attention,
and working memory that are necessary for encoding.3 The Papez circuit
(FIGURE 3-1) is crucially involved in the processing and transfer of information
for long-term storage.4 Highly processed information from multiple cortical
regions is conveyed to the hippocampus. This information enters through four
medial temporal cortical areas: the lateral entorhinal cortex, medial entorhinal
cortex, perirhinal cortex, and parahippocampal cortex. The dentate gyrus and
CA3 regions of the hippocampus integrate preprocessed sensory information,
which is then sent from CA1 back to the perirhinal cortex, entorhinal cortex, and
neocortex through projections to the subiculum for further consolidation into
long-term memory, which is thought to be stored in cortical regions involved in
FIGURE 3-1
The anatomy of episodic memory. A, Critical structures include the hippocampal formation,
the amygdala, paralimbic cortices (piriform cortex, entorhinal cortex, the parahippocampal
cortex on the medial surface of the temporal lobe, and the cingulate cortex), medial and
anterior nuclei of the thalamus and the mammillary bodies, the basal forebrain, and the
ventral striatum. The Papez circuit, which plays a critical role in the processing and transfer
of information for long storage, comprises the hippocampal formation, fornix, mammillary
bodies, mammillothalamic tract, anterior thalamic nucleus, cingulum, and entorhinal cortex.
B, Schematic of the medial temporal lobe memory system.
Panel B modified with permission from Squire LR, Wixted JT, Annu Rev Neurosci.2 © 2011 Annual Reviews.
1564 DECEMBER 2021

the initial processing of the sensory information. FIGURE 3-1B shows a schematic KEY POINTS
of anatomic structures and connections involved in these processes.
● Encoding and
Retrieval of long-term memory is initially dependent on the hippocampal consolidation is the set of
formation but becomes gradually independent of the hippocampus over time. processes that leads to the
Thus, in addition to anterograde amnesia, injury to the hippocampus will result establishment of long-term
in temporally graded retrograde amnesia, where information acquired recently memory. Consolidation
requires the reprocessing of
before the lesion will be lost, but more remote memories will remain intact.
acquired information over
Bilateral lesions to any of the components of the Papez circuit can cause time and is transiently
significant episodic memory deficits and predominantly anterograde amnesia, susceptible to amnestic
most notably due to injury to the hippocampal formation and the anterior and agents, such as interfering
stimuli or distractors.
medial nuclei of the thalamus.5 The basolateral limbic system is primarily
involved with the processing of emotions, but it also plays a role in the ● Consolidation over hours
assignment of emotional value to experiences, which can modulate their and days is thought to
consolidation.6 Because encoding of memory can be modulated by the emotional involve sleep. A period of
content associated with those memories, bilateral injury to the basolateral limbic sleep in the hours after the
encoding of new information
structures can also result in varying degrees of memory dysfunction, often has been shown to prevent
associated with other behavioral symptoms such as hypersexuality, hyperorality, rapid forgetting of the newly
and hyperphagia that may be present as part of the Kluver-Bucy syndrome. acquired material.
Injury to medial diencephalic structures, including mammillary bodies, the Slow-wave sleep, in
particular, may play a critical
medial dorsal nucleus of the thalamus, and the medial pulvinar can lead to role in supporting systems
significant anterograde memory deficits (Wernicke-Korsakoff Syndrome).7 This consolidation.
can be caused by thiamine deficiency, such as can be seen in people with alcohol
use disorder or individuals who are otherwise malnourished (eg, after gastric ● Lesions in the prefrontal
cortex may affect free recall
bypass surgery).8 Other injuries to these structures may result from stroke or
with preservation of cued or
space-occupying lesions.9 recognition memory.
Retrograde amnesia that
Working Memory equally affects recent and
Working memory is primarily an attention-mediated process. Lesion studies in remote events is most
commonly seen in functional
animal models and functional studies in humans have demonstrated that amnesias. The more
dorsolateral and ventrolateral prefrontal cortex, as well as parietal cortices, are all common form, wherein the
implicated in working memory.10 most recent events are also
the hardest to recall, is seen
in patients with pathology
Semantic Memory affecting medial temporal
Semantic memory retrieval is thought to depend on triggering mechanisms that lobes such as Alzheimer
originate in prefrontal and anterior-temporal regions. For more recent memories, disease and medial
retrieval appears to also depend on limbic structures.11 diencephalic lesions.
● Memory cannot be fully

Procedural Memory evaluated in isolation from
Memory for complex motor skills that are enacted automatically is dependent on other cognitive domains.
a network of cortical areas that include the supplementary motor cortex, parietal The type of memory deficits
reported in the clinical
lobes, basal ganglia, and cerebellum.12
history and observed during
evaluation and testing
MEMORY PROCESSES should be interpreted in the
The processing of information that ranges from working memory to the context of other deficits.
encoding, consolidation, and long-term storage of memories for future retrieval
● One should focus on the
involves multiple anatomic and physiologic substrates that are clinically relevant. first memory symptom
experienced by the patient
Encoding, Consolidation, and Storage or observed by family and
Encoding and consolidation is the set of processes that leads to the establishment determine how it has
progressed over time.
of long-term memory. Many anatomic and biological substrates for these

MEMORY DYSFUNCTION
complex processes have been identified, but mechanisms remain an active area
of research. Consolidation requires the reprocessing of acquired information over
periods of time ranging from seconds, minutes, and days to months and even
years. It is also transiently susceptible to amnestic agents, such as interfering
stimuli or distractors.13
At the molecular level, consolidation relies on activation of signaling cascades
that lead to posttranslational modifications and modulation of gene expression,
ultimately resulting in synaptic changes.14 Synaptic consolidation is thought to
occur at the beginning of the consolidation process and last for a few hours. At
the end of this process, the newly formed memory is relatively resistant to
distracting stimuli. Systems consolidation is the time-dependent reorganization
of long-term memory over distributed brain systems, in a process that may last
days, months, and years.
Anatomically, the first seconds of systems consolidation rely on the activity of
the hippocampus, striatum, and cerebellum. Over time, the role of the hippocampus
appears to wane but may still play a role in binding separate episodic elements into a
cohesive memory.13 As time progresses over minutes to hours, other neocortical
regions become engaged in a process of hippocampal-neocortical crosstalk. Cortical
areas involved in this process include the ventral-medial prefrontal cortex and the
lateral occipital cortex. Further consolidation over hours and days is thought to
involve sleep. A period of sleep in the hours after the encoding of new information
has been shown to prevent rapid forgetting of the newly acquired material. Slow-
wave sleep, in particular, may play a critical role in supporting systems
consolidation. The role of rapid eye movement (REM) sleep is still unclear.15
Storage of Information
Evidence suggests that storage of memory takes place across the association cortices.
The limbic system plays an important role in binding information during the process
of storage and is again engaged during retrieval in a time-dependent manner.16
Retrieval
Lesions in the prefrontal cortex may affect free recall with preservation of cued
or recognition memory. As an example, in brief standardized screening tests,
TABLE 3-1 Memory Processes and Their Anatomic Correlates
Memory process Definition Anatomic correlates
Registration Initial input of sensory information (visual, Sensory organs, primary sensory cortex,
auditory) association cortex
Working memory Information that is maintained for seconds Parietal and dorsal prefrontal cortex
to a few minutes
Encoding and consolidation Process of incorporating information into Association cortex and limbic system
longer-term storage
Long-term storage Information that is retained for minutes to years Association cortex and prefrontal cortex
Retrieval Recollection and recognition of previously Prefrontal and anterior temporal cortex,
acquired information limbic system
1566 DECEMBER 2021

patients are asked to repeat a list of words until they are able to do so without KEY POINTS
errors. When asked about those words later, they may not readily recall (free
● If information is readily
recall), but this may improve when given categories (cued) or shown a list that recalled with cuing, it may
includes the word (recognition). This memory pattern of improving with cueing be indicative of problems
or recognition suggests a retrieval deficit. Retrograde amnesia that equally affects with retrieval, with possibly
recent and remote events is most commonly seen in functional amnesias preserved encoding and
consolidation, and may
(discussed further in this article). The more common form of retrieval problems
indicate relative sparing of
is seen in patients with pathology affecting medial temporal lobes such as the limbic system.
Alzheimer disease and medial diencephalic lesions (bithalamic infarctions or
Korsakoff syndrome) in which the most recent events are the hardest to recall. ● Because memory
Although most often retrograde amnesia is accompanied by anterograde problems rarely occur in
isolation, establishing a
amnesia, the two can be dissociated both clinically and anatomically. Injury to timeline of both progression
prefrontal and anterior temporal regions, as well as the underlying uncinate and development of other
fasciculus, can lead to retrograde amnesia, with bilateral lesions causing a more cognitive and neurologic
severe syndrome.3 symptoms can greatly aid in
establishing a diagnosis. As
TABLE 3-1 shows a list of memory processes, their definition, and anatomic
diseases progress, different
structures known to play a role in each particular process. conditions begin to overlap
from a clinical perspective,
APPROACH TO THE PATIENT WITH MEMORY DISORDERS but those same conditions
may greatly differ in both
Memory cannot be fully evaluated in isolation from other cognitive domains. The onset and progression.
type of memory deficits reported in the clinical history and observed during
evaluation and testing should be interpreted in the context of other deficits.17 For ● Working memory can be
example, memory deficits that present along with visuospatial and language assessed by having the
patient perform mental
impairments may be indicative of Alzheimer disease, whereas similar amnestic
arithmetic or digit span.
deficits, along with executive dysfunction and a history of vascular risk factors, Frontal lobes, parietal
may suggest vascular dementia. lobes, and subcortical
It is also important to obtain cues during the history of deficits at different structures are involved in
stages of memory processing (ie, registration, working memory, encoding. and working memory.
retrieval) as previously described. Like any other neurologic assessment, ● Episodic memory can be
anatomic localization plays a critical role in the diagnostic process. evaluated by asking the
patient about recent
Clinical History autobiographic events or
recent news. Visual memory
History is one of the most crucial parts of the evaluation of a patient with can be evaluated by hiding
memory symptoms. One should focus on the first change from baseline (ie, first objects in the room while
symptom) experienced by the patient or observed by family and determine how the patient is observing and
it has progressed over time. Patients with memory disorders are often poor later asking the patient to
recall where the items are.
historians; thus, having other sources of history is critical.
Copying a complex figure
When focusing on memory symptoms, it is important to establish what the and redrawing or
patient and family mean by “memory,” what kinds of information is the patient recognizing after a latency
forgetting, and over what period of time. Common concerns are the patient’s period is another way to test
visual memory. Conditions
inability to recall recent conversations and events or repeating themselves within
affecting structures in
a short period of time, all typically indicative of deficits in episodic memory. If medial temporal lobes and
information is readily recalled with cuing, it may be indicative of problems with the Papez circuit can show
retrieval, with possibly preserved encoding and consolidation, and may indicate deficits in these tests.
relative sparing of the limbic system.
● Semantic memory is
Because memory problems rarely occur in isolation, establishing a timeline of evaluated by assessing the
both progression and development of other cognitive and neurologic symptoms patient’s fund of knowledge
can greatly aid in establishing a diagnosis. As diseases progress, different and should be tailored to the
conditions begin to overlap from a clinical perspective, but those same conditions patient’s cultural and
educational background.
may greatly differ in both onset and progression. As an example, a patient who

MEMORY DYSFUNCTION
has dementia with Lewy bodies (DLB) may initially present with difficulties with
working memory and REM behavior disorder, followed by the onset of visual
hallucinations and parkinsonism. By comparison, a patient with Alzheimer
disease may begin with deficits in episodic memory and visuospatial function,
followed over time by word-finding difficulty and eventually hallucinations in
more advanced stages of disease. Although current symptoms and even cognitive
test scores may overlap in both of these cases during initial clinical evaluation, the
onset and course of symptoms clearly differentiate the two. Likewise, the
timeline of symptom onset and progression will need to be established. Sudden
onset may suggest a vascular etiology or even an infectious process versus the
more typical insidious and gradually progressive nature of
neurodegenerative disorders.
Beyond purely cognitive symptoms, it is also important to inquire about
neuropsychiatric symptoms including apathy, disinhibition, depression,
hallucinations, and delusions. Behavioral symptoms can accompany affective
disorders, behavioral variant frontotemporal dementia (FTD), or DLB, among
others.18 Motor symptoms and signs such as tremor, gait abnormalities, ataxia, or
weakness, as well as sensory deficits such as loss of taste, vision, or hearing, or
somatosensory disturbances, should also be documented and carefully
considered in the context of the neurologic examination.
Establishing the current functional status is also important. Asking a caregiver
to complete a review questionnaire of activities of daily living can aid in that
determination. Functionality with daily activities can differentiate between mild
cognitive impairment and dementia, and an assessment of the time course over
which the patient lost independence with activities of daily living provides
insights about progression. This information can help in staging and also guide
management, prognosis, and support.
Other important aspects to consider are the presence of comorbid conditions,
history of head trauma, exposure to toxins, current and past recreational drug
use, and current medications that may affect cognition (eg, benzodiazepines,
opioids, and anticholinergics). A significant history of one or more vascular risk
factors that may include diabetes, hypertension, and hyperlipidemia almost
invariably accompanies vascular dementia. History of traumatic brain injury or
repeated concussion is associated with chronic traumatic encephalopathy19 and
may increase the risk of Alzheimer disease.20
Knowing the level of education can help contextualize the deficits. Patients
with higher levels of education or high premorbid intelligence may have
significant cognitive reserve and may perform better on screens, despite having
underlying pathology.21 A positive family history of neurodegenerative disorders
such as Alzheimer disease or FTD should also be considered a risk factor.22
Neurologic Examination
Patients with memory impairments often have normal neurologic examinations
(besides their findings on cognitive testing), but focal findings can be very
informative. For neurogenerative conditions, focal findings may be absent at first
but develop later as disease progresses. Ocular motor abnormalities may
accompany multiple neurodegenerative disorders such as corticobasal syndrome
(CBS) and posterior cortical atrophy (oculomotor apraxia), progressive
supranuclear palsy (vertical gaze deficits), and Wernicke-Korsakoff syndrome
(ophthalmoplegia or nystagmus). Asymmetric upper motor neuron findings can
1568 DECEMBER 2021

be present in vascular disease but also in focal variants of Alzheimer disease and KEY POINTS
CBS. Weakness, muscle wasting, and fasciculations in a patient with suspected
● The Montreal Cognitive
FTD should raise concern for motor neuron disease (FTD-amyotrophic lateral Assessment (MoCA) allows
sclerosis). Parkinsonism is common in DLB, CBS, FTD, and vascular dementia discrimination of encoding,
and invariably present with Parkinson disease dementia. Patients with storage, and retrieval
visuospatial variants of Alzheimer disease, DLB, and CBS may show asymmetric deficits through its use of
repeated presentation of
apraxia. Gait should also be evaluated for evidence of apraxia, ataxia, or
memory targets and
parkinsonism. Proprioceptive sensory loss should raise concern for nutritional cued-recall conditions.
deficiencies. Frontal release signs are also common in neurodegenerative Intact cued recall or
dementias. Palmomental and snout reflexes can be present in more advanced recognition in the context of
poor free recall points to
cases of most dementias but may also be present with aging. By contrast, grasp
retrieval deficits.
reflex is invariably pathologic and indicative of frontal lobe disfunction. It is
usually present in FTD and can also be seen in advanced Alzheimer disease and ● Standardized cognitive
vascular dementia. screens provide a rapid
assessment of the patient’s
cognitive function but may
BEDSIDE EVALUATION OF MEMORY not be sufficient to support
Assessment of cognitive function encompasses several domains and should start a diagnosis. Because of their
with an evaluation of the level of consciousness and observation of the patient’s relative brevity, cognitive
behavior. Details about the patient’s cognitive status can be obtained during screens are of important
practical use in clinical
casual conversation (ie, level of alertness and awareness, insight, thought process, settings and, if repeated at
language fluency), and further assessment can be accomplished by means of follow-up visits, may
qualitative evaluations and standardized screening tests. This section focuses on provide some measure of
bedside strategies for assessing memory and further discusses a selection of brief cognitive decline. Although
the total score is informative
cognitive screens and more comprehensive neuropsychological testing.
regarding normative data, it
is the pattern of deficits that
Working Memory is often most useful when
Working memory can be assessed by having the patient perform mental considering a differential
diagnosis.
arithmetic or digit span. Frontal lobes, parietal lobes, and subcortical structures
are involved in working memory. Consequently, patients with conditions such as ● The initial diagnostic
vascular dementia, Parkinson disease dementia, DLB,23 and FTD may have workup for memory
prominent deficits in these tests. dysfunction includes
laboratory tests, imaging
studies, and more
Episodic Memory comprehensive
Episodic memory can be evaluated by asking the patient about recent neuropsychological testing
autobiographic events (what they had for dinner, where they spent vacation to further assess the pattern
last summer) or recent news events and is based on the assumption that the and extent of cognitive
deficits and possibly
patient has previously acquired the information that is being asked. Verbal establish a baseline for
memory can be further tested by giving a list of words or a story to recall that tracking disease
the patient is later asked about. Cues can be provided (eg, categories or lists to progression.
choose from) to help differentiate encoding from retrieval deficits. Asking if the
● In cases in which the
patient recalls the examiner’s name is another simple way to assess verbal
cause of a memory disorder
memory. Visual memory can be evaluated by hiding objects in the room while remains uncertain, more
the patient is observing and later asking the patient to recall where the items are. specialized diagnostic
Copying a complex figure and redrawing or recognizing after a latency period is studies can be obtained.
another way to test visual memory. Conditions affecting structures in medial These may include
fludeoxyglucose positron
temporal lobes and the Papez circuit can show deficits in these tests. The emission tomography
amnestic presentation of Alzheimer disease, limbic-predominant age-related (FDG-PET), amyloid PET, and
transactive response DNA-binding protein 43 (TDP-43) encephalopathy (LATE) CSF studies.
(CASE 3-1), posterior circulation stroke (CASE 3-2), and Korsakoff syndrome
are prime examples of conditions that affect episodic memory. Visuospatial

MEMORY DYSFUNCTION
memory can be affected by involvement of occipitoparietal networks; the focal,

posterior-predominant variant of Alzheimer disease, known as posterior cortical
atrophy, and DLB are examples.
Semantic Memory
Semantic memory is evaluated by assessing the patient’s fund of knowledge and
should be tailored to the patient’s cultural and educational background. One can
present a series of pictures of famous personalities (eg, former presidents) and
ask the names, similarities, and differences among them. Testing category
CASE 3-1 An 85-year-old woman presented with a 5-year history of difficulties

with recollection of recent events and rapid forgetting of
conversations. She was a retired nurse. At the time of her first
evaluation, the patient was fully independent with all activities of daily
living, was able to manage the household finances, and was driving
without difficulty. During that initial examination, the patient was
alert, fully oriented, and socially appropriate. Her speech was fluent
with no word-finding difficulty on casual conversation or
confrontation naming. General neurologic examination was
unremarkable. Brief standardized cognitive testing showed deficits in
delayed recall of verbal information that partially improved with
cueing (Montreal Cognitive Assessment [MoCA]24 total score 25/30;
the patient recalled 2/5 with category cuing and an additional item
with multiple-choice cuing). MRI was notable only for mild
hippocampal atrophy (FIGURES 3-2A and 3-2B). A diagnosis of amnestic
mild cognitive impairment was made.
The patient was subsequently lost to follow-up but returned 4 years
later with a concern of further decline in episodic memory. She was
still independent with all activities of daily living but had given up
management of finances because she was forgetting to make
payments. She retained her ability to navigate in familiar environments
and reported no deficits in language or changes in behavior. On casual
conversation during the examination, the patient was fluent and
cogent but often repeated herself. She was oriented to self, place,
situation, and year but not to date, day, or month. She was not able to
provide details about recent news events. General neurologic
examination remained normal. MoCA showed deficits of delayed
recall, this time without cued improvement and now accompanied by
deficits in orientation (MoCA score of 22/30). Comprehensive
neuropsychological evaluation showed severe and selective deficits in
episodic memory for both visual and verbal material (Dementia Rating
Scale, Second Edition [DRS-2]25 memory index less than 1%) with
preserved function in all other domains and was still consistent with a
diagnosis of amnestic mild cognitive
1570 DECEMBER 2021

fluency and asking the meaning of words are also used in the context of assessing
semantic knowledge. Semantic dementia,18 which causes focal degeneration of
anterior temporal lobes, is the most well-known example of selective impairment
in this domain.
COGNITIVE SCREENING MEASURES

Some of the most routinely used in-office screening measures of cognitive
functioning for patients with memory symptoms are the Mini-Mental State
Examination (MMSE),26 the Saint Louis University Mental Status (SLUMS),27
impairment. Repeat MRI

(FIGURES 3-2C and 3-2D) showed
clear progression of
hippocampal atrophy, with
relatively preserved volumes
elsewhere. CSF analysis of
Alzheimer disease biomarkers
reported levels of amyloid-b
42, total tau, phospho-tau,
and amyloid-to-tau index
that were not consistent
with Alzheimer disease.
Six months after her last
visit, the patient died of
natural causes. Following
her wishes, a brain autopsy
was conducted and showed
FIGURE 3-2
changes in bilateral Imaging of the patient in CASE 3-1. A, Initial coronal
hippocampi and adjacent T1-weighted MRI showing mild hippocampal
limbic structures consistent volume loss. B, Axial fluid-attenuated inversion
with neuropathologic recovery (FLAIR) MRI showing only mild
generalized volume loss with particular
limbic-predominant preservation of parietal lobes. Repeat coronal
age-related transactive T1-weighted (C) and axial FLAIR (D) MRI 5 years
response DNA-binding after symptom onset shows severe atrophy of
protein 43 (TDP-43) bilateral hippocampi (C, arrow), with no
significant change in other cortical areas (D).
encephalopathy (LATE).
Alzheimer disease is highly prevalent in older adults with severe episodic COMMENT
memory deficits. However, lack of involvement of other cognitive domains
(eg, visuospatial and language), very gradual progression, and focal atrophy
that does not clearly progress to other brain regions should raise the
possibility of non–Alzheimer disease pathology. Biomarkers can be of
assistance in these cases and may help guide prognosis and management.

MEMORY DYSFUNCTION
and the Montreal Cognitive Assessment (MoCA). Each of these three measures
has a wealth of research to support its use in clinical settings, and each provides at
least some aspect of memory assessment (TABLE 3-2).
In contrast to the other screening measures listed, the MoCA isolates problems
with encoding, retention, and retrieval through use of cued-recall memory trials.
The MoCA memory procedure asks the patient to repeat the target words
immediately after they have been presented (similar to the MMSE procedure),
allowing the examiner to perceive on a qualitative level whether the patient is
able to register and encode the material. After a 5-minute delay, the patient is first
asked to recall the items freely and then is provided guided cues for missed items,
first categoric (eg, “it’s a type of flower”) and then multiple choice. If memory
storage proves to be the most affected, mesial temporal (or other Papez circuit
CASE 3-2 A 60-year-old right-handed woman presented with persistent but stable
memory difficulties that first developed 4 years earlier after a posterior
circulation stroke. At presentation, she described difficulties recalling
recent conversations and events, remembering when and how to take
medications, and recalling names of familiar people. She also was
concerned about mild word-finding difficulty and described having
trouble with organization, decision-making, and taking care of finances
and other personal affairs. She did not endorse visuospatial symptoms.
Per the patient and her
brother, cognitive symptoms
had a rather abrupt onset but
remained relatively stable
with only mild declines in
attention span and executive
function. She also reported a
history of residual right-sided
weakness from the stroke
that resolved over time. She
had 14 years of education and
had a history of multiple
cardiovascular risk factors.
She worked in retail but
resigned because of her
cognitive difficulties. Review
of past records confirmed a
FIGURE 3-3
history of sudden-onset right Imaging of the patient in CASE 3-2. Acute ischemic
hemiparesis and trouble with left hippocampal lesion (arrows) is evidenced by
memory at the time of her restricted diffusion on axial diffusion-weighted
stroke 4 years ago. Imaging MRI (A) and signal change on axial fluid-attenuated
inversion recovery (FLAIR) MRI (B). Coronal
studies at that time had
postcontrast T1-weighted MRI of the original scan
confirmed the presence of a shows normal hippocampal volume (C). Coronal
left posterior cerebral artery T1-weighted MRI 4 years after stroke shows left
territory stroke (FIGURE 3-3). hippocampal atrophy (D) (arrow).
1572 DECEMBER 2021

structures) pathology is suspected, as seen in Alzheimer dementia. The pathology
may be in widespread, distributed networks if the difficulties are found in initial
encoding or subsequent retrieval. For example, memory that improves with
cueing, combined with signs of impaired working memory and slow processing
speed (and other cardinal clinical features on presentation), would raise suspicion
of an α-synucleinopathy (eg, Parkinson disease dementia or DLB).
As with any other cognitive screen, the intent of these tests is to provide rapid
assessment of the patient’s cognitive function, but on its own may not be sufficient
to support a diagnosis unless the entirety of the clinical picture and diagnostic
evaluation is deemed by the clinician to be sufficiently supportive of a specific
diagnosis. Because of the relative brevity of screens, they are of important practical
use in busy clinical settings and, if repeated at follow-up visits, may provide some
At the time of her memory evaluation, the patient was alert, fully
oriented, and able to answer questions appropriately and follow all
commands. Her speech had normal pace, prosody, articulation, and
content and no word-finding difficulty or paraphasic errors during casual
conversation or anomia on a 30-item confrontation naming test. When
shown pictures of three famous presidents, she was able to name all of
them and identified similarities and differences, including historical facts.
Her responses were vague when she was recalling recent news events.
General neurologic examination was remarkable only for right-sided
hyperreflexia with a right Babinski sign. Montreal Cognitive Assessment
(MoCA) showed deficits in trail-making, attention, abstraction, and
delayed recall that did not improve with cuing (total score, 17/30).
Neuropsychological evaluation revealed weaknesses in processing
speed, verbal memory, new learning, and visual analysis, with relative
strengths in semantic fluency and confrontation naming. Her Dementia
Rating Scale, Second Edition (DRS-2) score of 118/144 ranked in the mild
dementia range. Repeat MRI showed white matter changes suggestive of
moderate macroangiopathic changes, as well as areas of gliosis in the left
posterior cerebral artery territory, including atrophy of the left mesial
temporal lobe and hippocampus. A diagnosis of vascular dementia was
made based on history, examination findings, pattern of cognitive test
results, and supporting imaging.
This case highlights the onset and course of vascular lesions involving COMMENT
mesial temporal lobes. In this case, the patient had a sudden onset of
deficits in anterograde memory that persisted over time without clear
progression. Because it was unilateral, her deficits were not as profound.
The presence of extensive small vessel disease likely contributed to
deficits in other domains (eg, processing speed), and occipital involvement
may have affected her performance in visual analysis.

MEMORY DYSFUNCTION
measure of cognitive decline. It is also important to remember that, although the

total score is informative regarding normative data, it is the pattern of deficits that
is often most useful when considering a differential diagnosis. TABLE 3-3 shows a
list of common memory symptoms with possible associated anatomic and
pathologic correlates, as well as relevant findings on cognitive screens.
DIAGNOSTIC WORKUP
The initial diagnostic workup includes laboratory tests, imaging studies, and
more comprehensive neuropsychological testing to further assess the pattern and
extent of cognitive deficits and possibly establish a baseline for tracking disease
progression (see the following section). Basic bloodwork may include complete
blood cell count; renal, liver, and thyroid function tests; and vitamin B12 and
folate levels. Depending on the level of suspicion, inflammatory (eg,
sedimentation rate) or infection (eg, syphilis serology) markers can be obtained.
Basic structural brain imaging (preferably MRI, although CT can suffice) should
be part of the initial workup and are intended to assess for patterns of focal
atrophy (eg, medial temporal lobe structures in Alzheimer disease, hippocampal
sclerosis, or LATE), evidence of cerebrovascular pathology (eg,
microangiopathic changes, lacunar infarcts, or susceptibility artifacts suggestive
TABLE 3-2 Examples of Cognitive Screening Measures
Measure Functions assessed Memory assessment features
Mini-Mental State Episodic memory, Registration: repetition of 3 words immediately after presented
Examination (MMSE) working memory,
Semantic memory: confrontation naming of a wristwatch and
confrontation naming,
pencil
orientation, verbal
comprehension, Working memory: serial 7 subtraction; follow 3-step command
visuoconstruction,
Episodic memory: recall of 3 words after a brief delay
verbal repetition,
linguistic expression Cued retrieval: none
Saint Louis University Episodic memory, Registration: none

Mental Status (SLUMS) working memory,
Semantic memory: identification of a triangle among 3 geometric
orientation, mental
shapes; name animals in 60 seconds
computation, semantic
fluency, semantic Working memory: digit span task; arithmetic task
memory
Episodic memory: recall of 5 words after a 2-minute delay; four
questions requiring recall of content from a 64-word paragraph
Cued retrieval: none
Montreal Cognitive Episodic memory, Registration: repetition of 5 words immediately after presented
Assessment (MoCA) working memory,
Semantic memory: identification of 3 animals in visual stimuli;
visuoconstruction,
name words beginning with a specified letter in 60 seconds
orientation,
confrontation naming, Working memory: digit span task; serial 7 subtraction
verbal repetition,
Episodic memory: recall of 5 words after a 5-minute delay
phonemic fluency,
executive functioning, Cued retrieval: category clues for 5 words; multiple-choice cues
cued retrieval, abstract for 5 words
reasoning, attention
1574 DECEMBER 2021

of microhemorrhages in cerebral amyloid angiopathy), abnormal ventricular
enlargement as seen in normal pressure hydrocephalus, or space-occupying
lesions, among other entities. In cases in which the diagnosis remains uncertain,
more specialized diagnostic studies can be obtained. These may include
fludeoxyglucose positron emission tomography (FDG-PET), amyloid PET, and
CSF studies, the last of which can be obtained to assess for markers of infection,
inflammation, paraneoplastic antibodies, or biomarkers of Alzheimer disease as
the case may indicate. FDG-PET can be used to assess for patterns of
hypometabolism (decreased FDG uptake) that may provide supporting evidence
for focal neurodegeneration, such as parietotemporal hypometabolism in
Alzheimer disease, asymmetric frontotemporal hypometabolism in FTD, or
occipitoparietal hypometabolism with preservation of the posterior cingulum in
DLB. Amyloid PET28 has been approved for determination of amyloid burden in
Common Memory Symptoms TABLE 3-3
Memory
Patient report Neuroanatomy Example conditions type Screening results
Misplaces objects, Medial temporal Alzheimer disease, Episodic Mini-Mental State Examination
cannot recall having (more left if verbal, dementia with Lewy memory (MMSE): intact registration with
conversation, cannot more right if visual), bodies (DLB), hypoxic poor recall of 3 words
recall details of Papez circuit brain injury,
Montreal Cognitive Assessment
recent meaningful encephalitis,
(MoCA): poor delayed recall
events hippocampal sclerosis,
of 5 words
limbic-predominant
age-related transactive Saint Louis University Mental Status
response DNA-binding (SLUMS): poor recall of 5 words,
protein 43 (TDP-43) poor recognition of narrative stimuli
encephalopathy (LATE)
Can no longer Supplementary Parkinson disease, Procedural MMSE: mis-sequence 3-step

operate television motor region, basal Huntington disease, memory command
remote, cannot ganglia, cerebellum cerebellar injury or
MoCA: not assessed
recall sequenced degeneration
steps for household SLUMS: not assessed
appliances
Can no longer Bilateral prefrontal Traumatic brain injury, Working MMSE: recall of 3-step command,
complete simple cortices, neurotoxin exposure, memory/ registration of 3 words, serial
calculations for subcortical regions, cerebrovascular insults, attentional subtraction by 7s
purchases, cannot association cortex frontotemporal lobar control
MoCA: repetition of 5 words, Trail
retain phone number degeneration, DLB
Making Test, digit repetition, serial
long enough to dial
subtraction by 7s, letter vigilance
SLUMS: mental calculation
problems; digit repetition
Difficulty recalling Anterior temporal Semantic dementia, Semantic MMSE: object naming, sentence
the meaning of lobes, inferior Alzheimer disease memory reading
words, difficulty temporal lobes
MoCA: animal naming, letter
naming objects, not
fluency
recalling what
objects are used for SLUMS: animal naming, identify
triangle

MEMORY DYSFUNCTION
patients with suspected Alzheimer disease and has high sensitivity and
specificity.29 Likewise, CSF levels of amyloid-b 42, total tau, and phospho-tau
can be used to determine the probability of Alzheimer disease pathology.30
However, these tests are still costly and may not be covered by insurance.
A Tau-PET agent has been recently approved for use in Alzheimer disease while
research in other conditions is ongoing.31 Likewise, blood biomarkers of
Alzheimer disease are in advanced stages of development.32
EEG can be helpful when epilepsy is suspected, and recent evidence has
supported its diagnostic utility in DLB.33 Given the role of sleep in memory
consolidation, a formal evaluation with polysomnography is recommended if
sleep disorders are suspected. If genetic predisposition is a concern (eg, familial
Alzheimer disease, FTD-amyotrophic lateral sclerosis) genetic counseling and
testing can be considered. As with any other neurologic disorder, diagnostic tests
performed in patients with memory dysfunction should always be interpreted in
the context of history, examination findings, and cognitive test results.
FORMAL NEUROPSYCHOLOGICAL EXAMINATIONS

Neuropsychologists administer batteries of well-validated tests assessing
multiple neurocognitive domains (TABLE 3-4) via standardized procedures under
controlled conditions to ensure the resultant data are valid and interpretively
useful (TABLE 3-534-38). By conducting precise measurements of the patient’s
functioning in each domain, the results reveal configurations of strengths and
weaknesses, forming a neuropsychological “fingerprint” (FIGURE 3-4). In
addition to testing the cognitive domains of interest, formal assessment of the
patient’s psychological status during the testing session is necessary to provide
context in which the resultant examination data may be interpreted, as some
behavioral health conditions have the ability to mimic the cognitive profiles of
neurologic conditions, such as in pseudodementia.
The results from neuropsychological examinations can aid in diagnosis, help
establish baseline status as well as longitudinal rate of change, assess treatment
response, and inform clinical decisions regarding mental capacities, fitness for
work, etc. Patients with more advanced illness may not be candidates for
TABLE 3-4 Neurocognitive Domains
◆ Intelligence
◆ Executive control
◆ Somatosensory functioning
◆ Visuospatial analysis
◆ Learning
◆ Attention/concentration
◆ Language (expressive and receptive)
◆ Motor speed
◆ Memory (linguistic and nonlinguistic)
◆ Psychological/mood status
1576 DECEMBER 2021

neuropsychological testing, as minimal levels of attention, receptive language,
and task persistence are required.
Serial Neurocognitive Testing

The study of human memory functioning over time, and cognition in general, is a
study of curves. Just as memory abilities in neurodegenerative conditions decline
over time, so follows the memory abilities of the healthy normal older patient.
However, the decline noted in any condition tends not to be unitary in character,
as disease processes exhibit differential degradation of functions across
neuropsychological domains. This adds dimensionality to envisioning functional
decline, with multidimensional shapes of the functional curves accommodating
pertinent domains.
Each examination is a “snapshot” of functioning at a particular point in time;
conducting an examination (taking the snapshot) at a different point along the
disease progression thus alters the resultant neuropsychological profile
(FIGURE 3-5). These patterns can be observed through serial neuropsychological
examinations, serial screenings (such as the MMSE, MoCA, or SLUMS), and
qualitative patient observations over multiple patient contacts.
OVERVIEW OF SELECTIVE DISORDERS AFFECTING MEMORY

Memory dysfunction is never global and is rarely selective for one type of memory
(episodic, semantic, working memory, or procedural) or memory process
(encoding, consolidation, storage, or retrieval) and seldom occurs in isolation from
other cognitive domains. This last section presents brief descriptions of selected
disorders that cause memory dysfunction. It also reviews memory changes that
occur with normal aging and those that are associated with functional neurologic
disorders and affective disorders, as they can often present a diagnostic challenge.
Commonly Used Neuropsychological Measures of Memory TABLE 3-5
Repeated trials Immediate Delayed Recognition

Test name learning recall recall trial
Verbal/linguistic
Hopkins Verbal Learning Test-Revised34 X X X X
California Verbal Learning Test, Third Edition35 X X X X
Wechsler Memory Scale, Fourth Edition (WMS-IV) X X X

Logical Memory Subtest36
Dementia Rating Scale, Second Edition (DRS-2)25 X X
Visual/pictorial
Brief Visuospatial Memory Test-Revised37 X X X X

38
Rey-Osterrieth Complex Figure Test X X X
WMS-IV Visual Reproduction Subtest36 X X X
DRS-225 X

MEMORY DYSFUNCTION
FIGURE 3-4
Example of a domain-specific cognitive profile.
Alzheimer Disease
Alzheimer disease is the most common age-related neurodegenerative dementia.
The amnestic phenotype is the most common presentation and is characterized
by deficits in anterograde episodic memory, with variable impairments in
semantic and working memory. Deficits in other domains may precede memory
impairment in many cases and invariably develop over the course of the disease.
Hallmark pathologic findings are the deposition of extracellular amyloid-β 42
plaques and intracellular hyperphosphorylated tau tangles. Typically, pathologic
changes and neurodegeneration follow a predictable pattern, with changes
FIGURE 3-5
Temporal effects on cognitive profiles in progressive condition. A cognitive evaluation takes
a “snap-shot” of patient abilities in a specific point in time. The pattern of findings may
change significantly as the condition progresses over time.
1578 DECEMBER 2021

developing first in medial temporal lobes (entorhinal cortex) and subsequently KEY POINTS
spreading to other areas within temporal, parietal, and eventually frontal lobes.
● Diagnostic tests
Common imaging findings include progressive generalized atrophy that is more performed in patients with
prominent in the hippocampus, entorhinal cortex, and parietal lobes. FDG-PET memory dysfunction should
may show hypometabolism of medial temporal lobes, parietal lobes, and always be interpreted in the
posterior cingulum, but frontal hypometabolism may be present with disease context of history,
examination findings, and
progression and occipital hypometabolism can be seen in posterior cortical
cognitive test results.
atrophy.29 Amyloid PET shows increased radiotracer uptake, and CSF biomarker
studies show decreased levels of amyloid-b 42, with elevated levels of total tau ● Neuropsychological
and phospho-tau.30 testing consists of batteries
of well-validated tests
assessing multiple
Dementia With Lewy Bodies neurocognitive domains and
DLB is characterized by a combination of several core features that include produces configurations of
fluctuating cognition, with pronounced variations in the level of alertness and strengths and weaknesses
attention, recurrent and well-formed visual hallucinations, REM sleep behavior that form a
neuropsychological
disorder, and parkinsonism. Patients usually have prominent deficits in “fingerprint” for the patient.
attention, executive function, and visuospatial function, with less pronounced
abnormalities in memory retrieval. Consequently, cognitive tests may show ● Neuropsychologists
deficits in working memory, encoding, and retrieval that improve with cuing. consider the patient’s
effort, validity, and
When overlapping with Alzheimer disease, patients may have a more rapid
emotional status when
decline and more pronounced episodic memory deficits. Parkinson disease interpreting examination
dementia may have a similar cognitive profile but with more pronounced data.
parkinsonism that precedes the onset of cognitive symptoms by a year or more.
Pathologically, DLB is characterized by the presence of Lewy bodies, which are ● Each neuropsychological
evaluation is a “snapshot” of
intraneuronal aggregates of α-synuclein. MRI may show loss of posterior cortical functioning at a particular
volume, and FDG-PET can reveal occipitoparietal hypometabolism with point in time; conducting
preserved uptake in the posterior cingulum (cingulate island sign). EEG may an examination at a
show posterior slow-wave activity with periodic fluctuations in the pre-alpha/ different point along the
disease progression alters
theta range.39 the resultant
neuropsychological profile.
Semantic Dementia
Semantic dementia, also known as semantic variant primary progressive aphasia, ● Memory dysfunction is
never global, rarely
is characterized clinically by fluent aphasia that starts with anomia and single-
selective for one type of
word comprehension deficits, later progressing to globally impaired knowledge memory (episodic,
of objects (what they are, what they do, where they are found). Semantic deficits semantic, working memory,
in other modalities beyond language are also present (visual, tactile, and or procedural) or memory
process (encoding,
olfactory). The impairment of semantic knowledge is related to the asymmetric
consolidation, storage, or
but bilateral involvement of anterior temporal lobes (temporal pole), which can retrieval), and seldom
be readily seen in structural imaging. Asymmetric anterior-temporal occurs in isolation from
hypometabolism is observed in FDG-PET. Episodic memory, visuospatial other cognitive domains.
function, and orientation are usually preserved. The right-sided variant may
have more prominent behavioral changes and difficulties with facial
recognition.40
Limbic-Predominant Age-Related Transactive Response DNA-binding

Protein 43 Encephalopathy
Late-onset hippocampal sclerosis has long been recognized as a cause of selective
memory decline in older patients.41 More recently, a proteinopathy characterized
by abnormal deposition of TDP-43 in limbic structures has been described as a
unique clinical and pathologic entity.42 This condition appears to be highly

MEMORY DYSFUNCTION
prevalent in patients older than 80 years of age who develop memory deficits that
mimic the amnestic presentation of Alzheimer disease but often without
significant involvement of other cognitive domains. As disease progresses,
hippocampal sclerosis becomes more pronounced and other cognitive domains
become affected, but the rate of cognitive decline in pure LATE cases may be
slower compared with Alzheimer disease (CASE 3-1). The incidence of this
condition appears to increase with extreme old age, whereas the incidence of
Alzheimer disease tends to decrease in that same age group. Neuropsychological
testing may show major deficits in delayed word list recall, with preserved verbal
fluency. Imaging studies show rather disproportionally atrophic hippocampi. As
the disease progresses, atrophy extends to frontal, anterior temporal, and insular
cortices, in a distribution that follows the TDP-43 pathology. No biomarkers are
currently available for this condition.
Cerebrovascular Syndromes
Strokes in anterior and middle cerebral artery territories can cause diverse
cognitive syndromes but often include deficits in working memory and retrieval.
Posterior cerebral artery occlusions may cause injury to the hippocampus and
other medial temporal lobe structures, leading to anterograde amnesia (CASE 3-2).
Thalamic infarction is associated with diencephalic amnesia,43 which mimics
bilateral medial temporal lobe pathology. Ischemic lesions caused by small vessel
disease can cause lacunar strokes or white matter ischemic changes (Binswanger
disease).44 Cognitive impairments are related to interruption of frontal cortical
circuits and disruption of cholinergic pathways. Consequently, memory deficits
TABLE 3-6 Cognitive Function and Aging
Course with normal aging Cognitive function Behavioral example
Decline Free recall (no-cue) Remembering items on a shopping list
Source of memory Recalling where or in what circumstances a fact was learned
Prospective memory Remembering to take a medication before going to bed
Processing speed Time to complete tasks, reaction times
Attention Divided, selective, and sustained attention
Executive function Abstraction, mental flexibility, and concept formation decline after
age 70; response inhibition
Stable Recognition memory Retrieving memory when given a cue (eg, recalling details of a story
when asked yes/no questions)
Temporal order Recalling the sequence of events
Procedural memory How to tie a shoelace, ride a bike
Language Overall intact with aging; vocabulary may improve; some decline
in confrontational naming and word search; sporadic
word-finding difficulty
Visual analysis Navigation, orientation, and depth perception tend to remain intact
1580 DECEMBER 2021

are related to inattention with retrieval deficits that are worse with free recall but KEY POINTS
improve with cuing and recognition.
● Alzheimer disease is the
most common age-related
Transient Global Amnesia neurodegenerative
Transient global amnesia (TGA) is commonly seen in patients 50 to 70 years old and dementia. The amnestic
is characterized by the sudden onset of anterograde amnesia, often with a limited phenotype is the most
common presentation and is
retrograde component, lasting for up to 24 hours and in the absence of other
characterized by deficits in
neurologic signs or symptoms. Patients present with acute inability to incorporate anterograde episodic
new memory, repeatedly asking the same questions within minutes, and are unable memory, with variable
to recall what they are told. They may also look anxious and confused, but cognitive impairments in semantic and
working memory. Deficits in
processes other than acquisition of new memory are preserved. Eventually, the
other domains may precede
patient experiences complete resolution with full recovery of their ability to memory impairment and
incorporate new memory, but amnesia for a period of time preceding the onset of invariably develop over the
symptoms through the duration of the episode will invariably persist.5 Clinical course of the disease.
investigations are usually unrevealing. In some cases, MRI may show hippocampal
● Dementia with Lewy
signal changes in diffusion-weighted imaging and fluid-attenuated inversion bodies is characterized by a
recovery (FLAIR) sequences that tend to be most apparent in the first 48 hours.45 combination of several core
The differential diagnosis includes posterior circulation stroke, focal seizures or features that include
postictal state, posttraumatic amnesia, hypoglycemia, and psychogenic amnesia. If fluctuating cognition,
recurrent and well-formed
the patient has a history of seizures or recent head trauma, presents with visual hallucinations, rapid
concomitant neurologic or systemic symptoms, or has focal findings on neurologic eye movement (REM) sleep
examination, conditions other than TGA should be considered and additional behavior disorder, and
tests pursued accordingly. The pathophysiology of TGA has not been established, parkinsonism. Cognitive
tests may show deficits in
but proposed mechanisms include venous congestion, arterial ischemia,
working memory, encoding,
and migraine. and retrieval that improve
with cuing.
Forgetfulness in Normal Aging
Cognitive aging is a well-known phenomenon and a common source of concern ● Limbic-predominant
age-related transactive
leading to referrals. Aging is associated with anatomic changes that include loss response DNA-binding
of volume31,46 that may be more prominent in specific cortical and subcortical protein 43 (TDP-43)
regions.47 Changes in the corpus callosum have also been found in normal aging and encephalopathy (LATE) is
associated with decreases in memory retrieval, efficiency, and processing speed.48 characterized by the
deposition of abnormal
These structural and molecular changes in the aging brain functionally TDP-43 protein in limbic
manifest across multiple cognitive processes. Older individuals are found to structures. It is highly
have diminished ability to lay down new memory traces, retrieve learned prevalent in patients older
material, access semantic information, and use prospective memory.49 than 80 years of age who
develop memory deficits
Salthouse50 reported that normal cognitive aging demonstrates near-linear that mimic the amnestic
declines in memory and reasoning, whereas vocabulary knowledge increases presentation of Alzheimer
until the sixth decade. Typically, memory concerns associated with normal disease but often without
aging will be reported by the patient and not the family, are not associated significant involvement of
other cognitive domains.
with loss of functional capacity, and tend to involve prospective memory.
Neuropsychological testing
In general, cognitive screen test scores that are normal and stable over time may show major deficits in
should be reassuring. Normal brain imaging, showing only age-appropriate delayed word list recall,
changes in volume, will not rule out underlying neurodegenerative pathology with preserved verbal
fluency.
but can provide further reassurances in the context of normal cognitive tests.
If cognitive screen results are abnormal, trending down over time, or
associated with functional decline in activities of daily living, further
evaluation with comprehensive neuropsychological testing and brain imaging
is recommended. TABLE 3-6 shows examples of cognitive functions in the
context of normal aging.

MEMORY DYSFUNCTION
Functional and Psychogenic Memory Impairment

Large numbers of patients who present with cognitive problems are ultimately
determined to be free of any underlying neurologic disorder that could reasonably
explain their self-perceived symptoms, as determined by neurologic examination,
cognitive testing, neuroimaging, and neurocognitive assessment. For instance, a
study from 30 Alzheimer disease centers in the United States indicated that 50% of
assessed patients were determined to have normal cognition.51
When poor memory performance is found on examination, confounds such as
medication side effects, sleep deprivation, low effort, and functional causes should
be considered. The clinician should be mindful of false-positive patterns, as causes
of low performance on memory testing may be either pathologic or nonpathologic.
Psychogenic memory dysfunction, caused by emotional rather than
physiologic factors, is described as “functional amnesia.” Such conditions are
often induced by extreme stress, interpersonal conflict, or other nonphysical
factors. For example, somatic symptom disorder involves multiple, current
symptoms that cause distress or interfere in daily life. The symptoms can be
specific (eg, focal pain) or nonspecific (eg, generalized fatigue), but the patient’s
distress is authentic whether or not a medical explanation is evident. It is
important to note that a somatic symptom disorder diagnosis can coexist with
other medical conditions. In the less common dissociative amnesia, patients
demonstrate an inability to recall autobiographic information, commonly of a
traumatic nature. This memory loss is viewed as a psychological defense
mechanism to protect the individual from upsetting memory content.
The distracted patient will also produce poor memory scores. Preoccupation
with pain, agitation, and noncompliance can all interfere with an individual’s
opportunities to submit information into the sensory register for subsequent
memory processing. The effect on standardized testing is similar to general
sedation (ie, low attention and working memory scores). Finally, although
relatively rare, patients who are malingering may attempt to feign memory
impairment for personal gain or avoid responsibility for their actions.
Mood disruption from anxiety and depression interferes with memory
encoding and retrieval. In such cases, patients tend to perform below premorbid
levels for initial recall of target information but then exhibit minimal decay of the
information that was encoded on delayed cued-recognition trials. That is,
whatever they learn, they keep.
Recently, efforts have been made to clarify and operationalize nonpathologic
memory dysfunction,52 including the proposed classifications of cogniform
disorder53 and functional cognitive disorder.54 The diagnostic criteria for
functional cognitive disorder proposed by Ball and colleagues appear particularly
promising, as they include positive signs (such as inconsistency of performance
within a cognitive domain on neuropsychological testing), rather than the
condition being a diagnosis purely of exclusion.
CONCLUSION
The evaluation and diagnosis of patients with memory symptoms require a
well-organized and systematic assessment that is supported by the
understanding of the complex interactions between brain structure, function,
and behavior. Assessment of neurocognitive disorders relies heavily on the
history provided by patients or caregivers. Knowledge of the classification of
1582 DECEMBER 2021

memory types and processes is crucial to obtaining an accurate history. It also KEY POINTS
supports the interpretation of cognitive tests, accurate neuroanatomic
● Ischemic lesions caused
localization, and the formulation of a differential diagnosis and ultimately by small vessel disease can
informs the diagnostic workup. The development of sophisticated diagnostic cause cognitive impairments
tools, including structural and functional imaging, standardized and related to interruption of
comprehensive neuropsychological tests, and molecular and imaging frontal cortical circuits and
disruption of cholinergic
biomarkers, have greatly enhanced our ability to make accurate diagnoses,
pathways. Consequently,
particularly for neurodegenerative disorders that cause memory dysfunction. As memory deficits are related
disease-modifying therapies become available in the future, the use of this body to inattention with retrieval
of knowledge and growing diagnostic arsenal will become even more critical in deficits that are worse with
free recall but improve with
everyday clinical practice.
cuing and recognition.
● Normal aging involves

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REVIEW ARTICLE

RECENT FINDINGS: As updated methods become available to neurologists, the

SUMMARY: An understanding of memory profiles pertaining to registration,

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● Memory cannot be fully

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TABLE 3-1 Memory Processes and Their Anatomic Correlates

Memory process Definition Anatomic correlates

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memory can be affected by involvement of occipitoparietal networks; the focal,

CASE 3-1 An 85-year-old woman presented with a 5-year history of difficulties

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COGNITIVE SCREENING MEASURES

impairment. Repeat MRI

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measure of cognitive decline. It is also important to remember that, although the

TABLE 3-2 Examples of Cognitive Screening Measures

Measure Functions assessed Memory assessment features

Saint Louis University Episodic memory, Registration: none

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Common Memory Symptoms TABLE 3-3

Can no longer Supplementary Parkinson disease, Procedural MMSE: mis-sequence 3-step

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FORMAL NEUROPSYCHOLOGICAL EXAMINATIONS

TABLE 3-4 Neurocognitive Domains

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Serial Neurocognitive Testing

OVERVIEW OF SELECTIVE DISORDERS AFFECTING MEMORY

Commonly Used Neuropsychological Measures of Memory TABLE 3-5

Repeated trials Immediate Delayed Recognition

Hopkins Verbal Learning Test-Revised34 X X X X

California Verbal Learning Test, Third Edition35 X X X X

Wechsler Memory Scale, Fourth Edition (WMS-IV) X X X

Dementia Rating Scale, Second Edition (DRS-2)25 X X

Brief Visuospatial Memory Test-Revised37 X X X X

WMS-IV Visual Reproduction Subtest36 X X X

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Limbic-Predominant Age-Related Transactive Response DNA-binding

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TABLE 3-6 Cognitive Function and Aging

Course with normal aging Cognitive function Behavioral example

Decline Free recall (no-cue) Remembering items on a shopping list

Source of memory Recalling where or in what circumstances a fact was learned

Prospective memory Remembering to take a medication before going to bed

Processing speed Time to complete tasks, reaction times

Attention Divided, selective, and sustained attention