153

An Overview of Primary Dementias as

Clinicopathological Entities
Arash Salardini, MD1

1 Department of Neurology, Yale School of Medicine, New Haven, Address for correspondence Arash Salardini, MD, Department of
Connecticut Neurology, Yale School of Medicine, New Haven, CT 06510
(e-mail: Arash.Salardini@yale.edu).
Semin Neurol 2019;39:153–166.

Abstract Dementia is a state of cognitive dysfunction which leads to functional decline. It is a

syndrome caused by several medical and neurological causes, but most cases of
dementia are due to “primary dementias.” Primary dementias are neurological diseases
whose manifestations are predominantly cognitive. Most primary dementias are
caused by neurodegenerative proteinopathies where an accumulation of misfolded
proteins leads to neuronal loss, neuroinflammation and glial reaction. Each proteino-

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Keywords
► primary dementia
► clinicopathological
► Alzheimer’s disease
► vascular dementia
► Lewy body disease
► frontotemporal
dementias
► prion disease
pathy is characterized by the type of protein implicated in its pathophysiology.
Neurodegenerative dementias include the most prevalent cause of dementia—Alzhei-
mer’s disease—as well as Lewy body dementia, Parkinson’s disease dementia, fronto-
temporal dementias, and prion diseases. Vascular dementia, especially small vessel
disease, though not a neurodegenerative condition, is often grouped together with
primary dementias. Each type of proteinopathy, characterized by the location and
nature of misfolded protein accumulation, may correspond to a particular clinical
phenotype. The correspondence between pathologies and clinical phenotypes is not
exclusive, and there is a large degree of overlap. Although in the research setting the
clinicopathological construct is on the wane, in the clinic it is the most practical way of
approaching primary dementias. In this article, we introduce the clinicopathological
construct, the understanding of which will form the basis of the other articles in this
volume.

Among adult neurological disorders, dementia has the high-
est economic cost, and is only second to cerebrovascular
disease as a cause of death.1 Alzheimer’s pathology and
vascular disease, alone or in combination, account for the
vast majority of dementia cases worldwide (70–80%).2 The
remainder are made up of Lewy body disease (5%)3 and a
large number of pathologies with low prevalence. Genetic
forms of primary dementias comprise a very small portion of
cases. Sporadic onset primary dementias are likely due to
complex interactions between an array of genetic suscept-
ibilities and the environment. Of all the known risks for
sporadic dementia, age, an unmodifiable risk factor, dwarves
all others including APOE4 status and vascular risk factors.4
Therefore, as life expectancy increases around the world the
prevalence of dementia will continue to rise.
Sadly, there are no disease-modifying medications avail-
able for the treatment of Alzheimer’s disease (AD) and most
other primary dementias. However, this should not bias the
practitioner toward fatalism. Many common diseases such as
chronic obstructive pulmonary disease and sickle cell ane-
mia lack a disease-modifying treatment, yet they are
expertly and unapologetically managed by the relevant
specialties. Most dementias are manageable by addressing
symptoms and maximizing daily function. These strategies
delay the onset of dementia; in other words, for a given
burden of pathology a patient is enabled to function at a
higher level if he or she is given the tools and is medically
optimized.
The “optimization/harm minimization” approach is
superficially similar to the practice of dementia care going

Issue Theme Dementia; Guest Editor, Copyright © 2019 by Thieme Medical DOI https://doi.org/
Arash Salardini, MD Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0039-1683445.
New York, NY 10001, USA. ISSN 0271-8235.
Tel: +1(212) 584-4662.
154 An Overview of Primary Dementias as Clinicopathological Entities
back decades. The difference is that contemporary neurol-
ogists, geriatricians, and psychiatrists are much better at
diagnosis, symptomatic treatment, and case management
than their erstwhile predecessors. Giant strides have been
made in our understanding of the pathophysiology, natural
history, biomarker biology, and neuropsychology of pri-
mary dementias. Neurologists whose training affords them
familiarity with neurobiology, neuroanatomy, and neuroi-
maging have especially benefitted from the entry of
sophisticated testing modalities into the clinic. Parallel
to advances in neuroscience, there is significant progress
in models of care, functional assessment, nonpharmacolo-
gical interventions, and symptom management. In these,
geriatricians and geriatric psychiatrists will continue
to excel.
Although most interventions required for severe demen-
tia are agnostic vis-à-vis pathological diagnosis, patients in
the earlier stages of the disease require diagnosis and dis-
ease-specific interventions. Neurologists are more likely to
be in charge of care early in the course of dementia. It is
therefore important for all neurologists to have a working
knowledge of different dementia-causing pathologies and
their clinical phenotype, i.e., primary dementias as clinico-
pathological entities. This paper intends to introduce and
expand on this idea.
Definitions
• Dementia is a syndrome of functional and cognitive
decline regardless of pathophysiology. For example, an
individual may be said to have dementia due to late-stage
multiple sclerosis.5
• The term dementia can also be used to refer to a specific
category of neurological disease in which cognitive
decline is the main feature of organic brain disease. AD
is an example of such a disease. The term “primary
dementia” is a more precise term for the category of
disease which presents cognitively.
• Mild cognitive impairment (MCI) is a state of cognitive
decline where independent functioning is relatively pre-
served. MCI is synonymous with prodromal dementia.6
• Rapidly progressive dementias (RPDs) are defined as
dementias which progress from normal cognition to
severe dementia in less than 2 years. The definition of
RPDs is unofficial.7
• A biomarker, for our purposes, is a biological measure-
ment which helps distinguish between several conditions
which may have similar presentations.8
• Cognitive domains: Similar cognitive abilities are grouped
together into “cognitive domains.” This is useful clinically
because members of a cognitive domain share anatomical
substrates and have similar pathological vulnerabilities.
Cognitive domains include memory, perceptual motor,
social cognition, complex attention, executive function
and language domains. Some definitions of dementia
require the involvement of more than one cognitive
domain.9
Seminars in Neurology Vol. 39 No. 2/2019
Salardini
General Considerations
Dementia
A diagnosis of dementia requires two conditions: chronic
cognitive decline and subsequent functional decline in daily
life.5 Differing diagnostic criteria vary mostly in how cognitive
decline is defined, for example, what neuropsychological cut-
off to use, or how many and which cognitive domains need to
be involved. The basic principles remain the same and may be
expressed as follows:
• Presence of cognitive decline:
– Cognitive concern: The patient or their spouse reports
decline in cognitive abilities or work performance. The
patient may alternatively be referred after the primary
physician raises concern about cognition on history or
cognitive screening.
– Objective demonstration of cognitive decline: The gold
standard for cognitive testing is neuropsychological
examination. Cognitive performance is expressed in
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terms of standard deviation (SD) from the mean per-
formance of previously tested cohorts of cognitively
normal individuals. The score is normalized for age and
level of education. Performances which are 1, 1.5, or 2
SD below the mean represent borderline, minor, or
major cognitive decline, respectively.10
• There is chronic functional decline:
– Cognitive changes interfere with independent living. The
activities of daily living are divided into two sets of tasks:
basic activities of daily living (BADL) which refer to basic
self-care tasks such as bathing, feeding, toileting, and
dressing, and instrumental activities of daily living
(IADL) which are more complex tasks such as managing
finances, medication management, managing transpor-
tation, shopping, and meal preparation, as well as house
chores. A loss of function may be exemplified by an
inability to perform IADLs. In later stages of dementia
BADLs are also affected (►Table 1).11,12
• The decline in cognition not explained in terms of delirium or
psychiatric illness: delirium and psychiatric illnesses can be
associated with significant cognitive symptoms. These
Table 1 Activities of daily living (ADL), instrumental activities of
daily living (IADL), and advanced activities of daily living (AADL)
ADL IADL AADL
Dressing Shopping Vocational skills
Bathing Preparing food Vocation
knowledge
Toileting Housework Hobby-related
mastery
Continence Laundry Music
Transferring Use transportation Art
Eating Medication compliance, etc.
handling finances
 An Overview of Primary Dementias as Clinicopathological Entities Salardini 155

causes should be ruled out before a diagnosis of dementia is
made.5
Mild Cognitive Impairment
The current definition of MCI, based on Petersen’s criteria,
has two parts: (1) cognitive decline in excess of that which is
expected for age and (2) relative preservation of function as
evidenced by the ability to perform most IADLs. MCI was
originally conceived as a functional stage of dementia. Over
time, researchers observed that although most individuals
with MCI progressed to dementia, there were smaller groups
of individuals who were either stable clinically or reverted
back to normal cognition after a time. For a time, MCI was
reconceived not as an early stage of dementia, but instead a
risk state for future incidence of dementias. Certain pheno-
types of MCI such as ones that mostly affected episodic
memory appeared to have an even higher risk of conversion
to Alzheimer’s dementia.13
With the advent of reliable biomarkers, this view has been
superseded by a more biological conception where cognitive
Clinically, MCI is divided into amnestic and nonamnestic
types depending on whether episodic memory is involved or
not. Another distinction is made between single-domain and
multidomain MCIs, referring to the number of cognitive
domains affected. By far the most common cause of amnestic
single-domain MCI is AD. Rapid forgetting which characterizes
amnestic disorders is associated with hippocampal dysfunc-
tion.15 A rare alternative diagnosis is “age-related hippocampal
sclerosis,” which is a new clinicopathological entity that pre-
sents much like AD but lacks the characteristic pathological
changes. It occurs in the very elderly patients and is associated
with TDP-43, a protein that is more commonly seen in fronto-
temporal dementias.16 Amnestic multidomain MCI can be
caused by AD, small vessel disease, and some frontotemporal
dementias. Nonamnestic MCI can frequently be due to Lewy
body disease, frontotemporal dementia, and atypical AD.13
Primary Dementias
Primary dementias are a group of diseases whose principle
manifestation is cognitive decline. Most but not all primary

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impairment is one risk factor amongst several other biomar-
kers which can be used to predict the likelihood of an
individual’s progression to dementia. The concept is most
fully developed with regard to AD, for which there are widely
available biomarkers. For example, an individual with minor
cognitive deficits, positive cerebral amyloid angiopathy, and
evidence of mesial temporal atrophy on magnetic resonance
imaging (MRI) is at a very high risk of progressing to
Alzheimer’s dementia (see ►Fig. 1), whereas a person who
has cognitive impairment without any biomarkers is at a
much lower risk of progression to Alzheimer’s dementia. This
approach, for the moment, falls short of diagnosing progres-
sion to dementias other than AD, because reliable biomar-
kers are not available for other primary dementias. This will
change in the near future.14
dementias are neurodegenerative proteinopathies. In pro-
teinopathies certain misfolded proteins form toxic inclusions
and lead to neurodegeneration, glial reaction, and neuroin-
flammation.17 Primary dementias include AD, frontotem-
poral dementia, and prion diseases. Parkinson’s disease
dementia (PDD) and Lewy body dementia (LBD) are protei-
nopathies which present with significant extrapyramidal
motor symptoms; however, because they are also common
causes of dementia, they are included with primary demen-
tias. Vascular dementia is not a proteinopathy, but it is
the second most common cause of dementia in the elderly
population and is also included in this category.2
The present model of primary dementia is as clinico-
pathological entity. These conditions are defined by three
factors: clinical presentation, severity of cognitive-related

Fig. 1 MRIs of a patient with mild cognitive problems who is at high risk of progression to dementia. (A) A FLAIR coronal section just anterior to
the pons. The arrow directs the eye to the salient locale. The choroid fissure and the inferior horn of the lateral ventricle are enlarged. The
hippocampus shows significant loss of height. This is a sign of advanced mesial temporal atrophy. (B) An SWI transverse slice through the corona
radiata showing multiple punctate hemorrhages consistent with amyloid angiopathy. FLAIR, fluid attenuation inversion recovery; SWI,
susceptibility-weighted imaging.

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156 An Overview of Primary Dementias as Clinicopathological Entities
Fig. 2 A conceptual model of proteinopathies, where risk factors lead to an accumulation of misfolded proteins, causing neurodegeneration
which manifests as cognitive decline. AD, Alzheimer’s disease; FTD, frontotemporal dementias; LBD, Lewy body dementia; MSA, multi-system
atrophy; PDD, Parkinson disease dementia.
disability, and neuropathological diagnosis based on histo-
pathology and characteristic changes (►Fig. 2). For example,
an individual with severe cognitive problems and a presen-
tation typical for AD would be considered to have probable
AD. The presence of Alzheimer biomarkers strengthens the
probability of a correct diagnosis.18 A newer research frame-
work by National Institute of Aging–Alzheimer’s Association
(NIA-AA) does away with the clinical and neuropathological
parameters. This biological framework classifies AD accord-
ing to biomarker status. This model will standardize demen-
tia research and in the future, may lead to a model where
interactions between different biomarkers and pathologies,
like vascular and Alzheimer’s pathologies, are taken into
account. The biological framework is meant for research
only at this stage and is not for the moment a practical
approach to primary dementias in the clinic.19 In this article,
our conception of primary dementia is based on the clin-
icopathological model.
Rapidly Progressive Dementias
RPDs are conditions which progress from normal cognition
to dementia in 1 to 2 years. As a category, the term was first
used for prion diseases and their differential diagnoses. RPDs
often have features other than cognitive decline such as
behavioral problems, pyramidal or extrapyramidal symp-
toms, electroencephalogram (EEG) changes, and myoclonus.
Crudely, we can categorize RPDs into prion diseases, atypical
presentation of other primary dementias, autoimmune dis-
eases including autoimmune encephalitis, and secondary
encephalopathies (including toxic metabolic encephalopa-
thy). The relative frequency of these conditions depends on
the setting. In tertiary referral centers, prion diseases may
predominate. In a community setting, secondary encepha-
lopathies are more likely to be worked up as RPD.7
Primary dementias which present as RPDs are more likely
to be young onset and often have long tract signs, white
matter changes, myoclonus, and behavioral changes.20 For
Seminars in Neurology Vol. 39 No. 2/2019
Salardini
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Alzheimer-related RPDs, the presence of amyloid pathology
in cerebrospinal fluid (CSF) or on positron-emission tomo-
graphy (PET) imaging can help establish the diagnosis,
especially in the younger patients. For Lewy body disease,
a careful history, evidence of neuroleptic sensitivity, and in
some cases dopamine transporter imaging will help. For
others, especially frontotemporal dementia, many other
causes need to be ruled out before a diagnosis is made.21
Secondary encephalopathies represent some rarer causes
of delirium. Vascular causes include inflammatory cerebral
amyloid angiopathy, primary central nervous system angiitis,
or Behçet disease. Diffuse neoplasms and infections such as
human immunodeficiency virus, herpes encephalitis, syphilis,
Whipple’s disease, and Lyme disease may also present as RPDs.
Some other causes include gastrointestinal-related patholo-
gies such as celiac disease and vitamin malabsorption (e.g.,
Wernicke’s encephalopathy). Finally, difficult-to-detect tem-
poral lobe epilepsies and nonconvulsive seizures, especially
with status epilepticus, can mimic RPDs.22
Different Types of Primary Dementias
We can classify primary dementias according to their neu-
ropathological phenotype, neuropsychological presentation,
and by their clinical features (►Table 2):
• Neuropathological phenotype: Proteinopathies are charac-
terized by different misfolded protein aggregates:
– AD is a double proteinopathy with pathology related to
both amyloid β and hyperphosphorylated tau.
– Tau is also implicated in several other pathologies,
including Pick’s disease (or FTLD-tau), corticobasal
degeneration (CBD), and progressive supranuclear
palsy (PSP).
– Frontotemporal lobar degeneration (FTLD) is seen in
relations to TDP-43 (FTLD-TDP) and FUS (FTLD-FUS),
and in addition to tau (FTLD-tau or Pick’s disease).
 An Overview of Primary Dementias as Clinicopathological Entities Salardini 157

Table 2 Common primary dementias: risk factors, characteristic lesion, and common clinical phenotypes

Risk factors Characteristic lesions Presenting cog. syndrome

AD Age, vascular risk factors, TBI,
low education, genetics
VD Age, vascular RF (HTN, DM, high
cholesterol, smoking, etc.), genetics
FTD Environmental factors, genetics
PDD TBI, family history of PD,
environmental pesticides
LBD Family history of PD, susceptibility
genes (APOE4), low education,
vascular risk factors, depression and
anxiety. Protective: smoking, history
of cancer.
PSP Not well understood
Amyloid plaque (Abeta42), fibrillary
tangles (Ptau)
WMH, microhemorrhages, lacunes,
EPVS
Tau (Pick’s disease, FTDP-17), TDP-43
(various types including ALS-FTLD),
FUS
α-Synuclein predominantly in
subcortical structures.
Synuclein predominantly in cortical
area, high degree of coexistence of
amyloid pathology
Tufted astrocytes, tau and
neurodegeneration in brainstem and
basal ganglia
Amnestic, logopenic variant,
posterior cortical atrophy
Large vessel: highly variable;
small vessel: subcortical cognitive
impairment
Language variant: nfPPA (mostly tau),
SD (mostly TDP), lvPPA (AD > FTLD);
behavioral variant: TDP or tau
Subcortical dementia
Hallucinations, fluctuation in
cognition and level of alertness,
Parkinsonism, visuospatial problems
Slow vertical saccade, gait instability,
Parkinsonism

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CBD Not well understood Achromatic ballooned neurons, Asymmetrical apraxia, asymmetrical
4R tau mostly, astrocytic plaques, dystonia or myoclonus, and
parietal and temporal atrophy Parkinsonism

Abbreviations: AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis; CBD, corticobasal degeneration; EPVS, enlarge perivascular space; FTD,
frontotemporal dementias; LBD, Lewy body dementia; lvPPA, logopenic variant primary progressive aphasia; nfPPA, nonfluent primary progressive
aphasia; PD, Parkinson’s disease dementia; PSP, progressive supranuclear palsy; Ptau, phosphorylated tau; SD, semantic dementia; TBI, traumatic
brain injury; VD, vascular dementia; WMH, white matter hyperintensity.
Note: Both PSP and CBD are types of FTD.

– α-Synuclein is associated with PDD and LBD, and the – Moderate dementia stage when the patient starts
two may be considered as parts of the spectrum of the requiring help with their BADLs.
same disease. – Severe stage when the patient is completely dependent.25
– In vascular dementia, several pathological findings often
coexist, including large vessel atherosclerosis, small ves-
sel arteriosclerosis, and cerebral amyloid angiopathy.18
Several other clinical terms are used in the diagnosis of
• Neuropsychological presentation: Each neurodegenerative primary dementias, such as early onset (<65 years) versus
disease has a predilection for a particular part of the brain late onset (>65 years) and familial versus sporadic. Familial
and for certain brain networks. The spread of pathology in and early onset primary dementias are less common than
the early stages of disease is mostly along the connections late onset sporadic disease.
of one or few of these brain networks. For example,
pathology in AD begins in the mesial temporal area but Alzheimer’s Disease
spreads to parts of the parietal lobe which are also part of
• Neuropathology: AD is the most common form of primary
a network called the default mode network.23 As a result,
dementia. AD is characterized by the presence of amyloid
each primary dementia has several typical presentations
β plaques, neurofibrillary tangles (NFTs), neurodegenera-
relating to the brain networks it favors. In time, pathology
tion, synaptic loss, and neuroinflammation. The accumu-
spreads to the rest of the brain and the clinical picture
lation of amyloid and tau precedes the onset of symptoms
becomes less distinct.24
by many years. The presence of amyloid is required for a
• Clinical features: A patient’s functional status has great
pathological diagnosis of AD; however, the distribution of
practical significance in the clinical management of pri-
NFT more closely correlates with cognitive symptoms.26
mary dementias. Functional status is expressed in terms
• Clinical phenotypes: Four clinical presentations are com-
of clearly defined disease stages:
– Prodromal stage in which there is no discernable mon in AD27 (►Fig. 3):
– Amnestic or typical AD: By far the most common one is
cognitive decline.
– MCI stage in which cognition can be demonstrated to the amnestic presentation, also called “typical AD.” In
this presentation, problems with episodic memory
have declined but the subject continues to function
predominate and changes to the mesial temporal
independently.
– Mild dementia stage in which an individual requires area occur early. Other domains may also be affected,
most commonly visuospatial cognition as exemplified
help with their IADLs.

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158 An Overview of Primary Dementias as Clinicopathological Entities Salardini

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Fig. 3 A 57-year-old woman with MOCA 8/30 and severe short-term memory deficits. (A) Parasagittal MRI image showing widespread cortical
atrophy especially in the parietal region. (B) This is a graph of pTau vs. ATI (amyloid tau index) which shows very low amyloid and very high pTau
unambiguously consistent with a diagnosis of Alzheimer’s disease. (C) The panel shows the average L and R hippocampal volume as a percentage
of intracranial volume. The parallel lines drawn are age norms expressed in terms of percentage, assuming a normal distribution. Our patient is in
the bottom 5% of her peers. This is consistent with a diagnosis of Alzheimer’s disease.

by an inability to navigate. When more than one
domain is involved, the presentation is a multidomain
amnestic presentation.
– Visual variant or posterior cortical atrophy: A visual
variant of AD called posterior cortical atrophy affects
visual areas of the brain. In these patients, visual
perception is compromised in the absence of any
ophthalmological problems. An inability to recognize
objects or faces or an inability to judge the relative
position of objects in space may occur, with relative
preservation of episodic memory.
– Language variant or logopenic dementia: A language
variant of AD affects the brain’s phonemic lexicon, lead-
ing to impaired naming, hesitation in speech, and
changes to spelling. Memory deficits and anxiety often
coexist.
– Executive variant or frontal AD: Executive variant of AD
presents with executive dysfunction and behavioral
symptoms. It is relatively rare and is frequently mis-
diagnosed as frontotemporal dementia. It is sometimes
called frontal variant of AD but this is a misnomer
because the frontal lobes are not necessarily involved
in the executive variant of AD.
• Genetics and other risk factors: A minority of individuals
with AD have a familial form of the disease which is
transmitted in an autosomal dominant fashion. The genes
involved, APP, PSEN1, and PSEN2, code for proteins which
are involved in amyloid metabolism and can be tested in
the clinic using available commercial laboratories. Famil-
ial forms of AD form a much greater proportion of early
onset AD compared with later onset forms.28 Most AD is
sporadic. The main risk factor for sporadic AD, as with all
primary dementias, is advanced age. Several other risk
factors such as low education, cardiovascular risk factors,
APOE4 genotype, and head injuries have been demon-
strated for sporadic AD.29 Genome-wide association stu-
dies have uncovered several susceptibility genes which
are relatively rare and have small effects on overall risk.
Models which use these genes in addition to APOE4 to
predict future risk of dementia have been promising.30
• Biomarkers: Compared with other primary dementias, the
greatest advances have been made in the field of AD. The
most tangible result has been the development of several
biomarkers which can be used to diagnose AD in vivo. The
current research framework proposed by NIA-AA uses
biomarker status as a way of classifying AD. It identifies
three biomarkers: amyloid (A), tau (T), and neurodegen-
eration (N)19,31 (see ►Table 3).
– Amyloid positivity may be gauged either by CSF analy-
sis or by PET imaging using amyloid directed radioli-
gands: florbetapir, florbetaben, and flutemetamol.
These ligands do not require onsite cyclotron synthesis,
which means amyloid PET scans can now be performed

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 An Overview of Primary Dementias as Clinicopathological Entities Salardini 159

Table 3 Different diagnoses made in relationship to common Similar to amyloid PET, tau PET has the added advan-
Alzheimer’s biomarkers tage of showing the topographic distribution of NFTs.
This is even more important in the case of tau because
Amyloid β
Amyloid βþ tau localization and regional distribution correlates
Low Ptau Normal cognition Probable Alzheimer’s well with clinical symptoms.34
disease – Neurodegeneration: The third proposed biomarker,
High Ptau Rare non-Alzheimer’s Alzheimer’s disease “neurodegeneration,” is a less specific biomarker. It is
tauopathies represented by any biomarker which documents neu-
Abbreviation: Ptau, phosphorylated tau.
ronal damage. Measures of atrophy on MRI35 and
hypometabolism on fluorodeoxyglucose-positron
emission tomography (FDG-PET) are the most common
in most nuclear medicine sites. Sadly, insurance does
methods for ascertaining neurodegeneration. Hippo-
not cover the costs, so amyloid PET does not have
campal atrophy can be measured using automated
widespread use outside of research and tertiary set-
computer algorithms. It can also be visually rated by
tings. CSF studies are widely available and significantly
clinicians. FDG-PET uses radioactive glucose to find
cheaper. A positive amyloid biomarker is represented
areas of reduced metabolism, which corresponds to
by low levels of amyloid β 42 in the CSF. The ratio of
neuronal dysfunction and loss. Total tau (as opposed to
amyloid β 42 to amyloid 40 may be used instead, when
phosphorylated tau) measured in the CSF is also a
available, to increase diagnostic specificity.32 CSF sam-
measure of “neurodegeneration”36 (see ►Fig. 4).
pling has the advantage of being available to measure
• Treatments: Presently, no disease-modifying medications

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other biomarkers such as phosphorylated tau. PET
scans, on the other hand, demonstrate amyloid dis-
tribution in addition to overall levels.33
– Hyperphosphorylated tau: CSF is also used for measure-
ment of hyperphosphorylated tau. A raised level repre-
sents pathology. Tau PET ligands are in advanced stages
of development but are not yet clinically available.
exist for the treatment of AD, but several strategies have
been advanced including immunotherapy directed
against amyloid, inhibition of amyloid synthesis, and
immunotherapy against extracellular tau. Of these, mono-
clonal antibodies against amyloid seem to show the
greatest promise. Pharmacological interventions for

Fig. 4 These are reconstructed FDG-PET images of three patients with atypical presentation of Alzheimer’s disease. The darker areas are areas of
hypometabolism when compared with age-matched normal controls. Each column represents a single patient, with left hemisphere on top. PCA
images show significant posterior parietooccipital and occipitotemporal hypometabolism. Executive variant AD shows frontal and tempor-
oparietal hypometabolism on the right. This is not a typical pattern compared with the literature. lvPPA shows mainly left sided temporoparietal
hypometabolism. AD, Alzheimer’s disease; FDG-PET, fluorodeoxyglucose-positron emission tomography; lvPPA, logopenic variant primary
progressive aphasia; PCA, posterior cortical atrophy.

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160 An Overview of Primary Dementias as Clinicopathological Entities
symptomatic management of AD are based on the effect of
pathology on several neurotransmitter systems, including
acetylcholine, norepinephrine, and serotonin. Cholines-
terase inhibitors are Food and Drug Administration
approved to manage symptoms of AD, and work by
increasing acetylcholine neurotransmission. Nonpharma-
cological interventions aimed at curtailing excess disabil-
ity consist of patient education, cognitive interventions,
and lifestyle modifications.37
Frontotemporal Lobar Degeneration
• Neuropathology: Frontotemporal dementias are a group of
pathologies with overlapping clinical phenotypes. The
most common protein aggregates in these conditions
include tau, TDP-43, and FUS. The corresponding designa-
tions are FTLD-tau, FTLD-TDP, and FTLD-FUS, respectively.
Tau protein has six isoforms due to alternative splicing of
the gene product of its gene MAPT. These isoforms can be
divided into two groups based on the number of repeat
motifs found in the microtubule-binding domains. There
are three isoforms of tau which have three repeat motifs
(3R tau), and the other three isoforms have four repeat
motifs (4R tau). CBD and PSP are caused by 4R tau. Pick’s
disease is associated with 3R tau. FTLD-FUS is relatively
rare, with FTLD-TDP and FTLD-tau comprising the major-
ity of cases that reach biopsy.38,39
• Clinical phenotype: FTLD has a wide range of neuropsy-
chological presentations, which often overlap, increasing
diagnostic uncertainty in the clinical setting. Common
neuropsychological presentations include40,41:
– Behavioral variants of FTLD (bvFTLD): Patients with
bvFTLD present executive and behavioral deficits.
Loss of social graces, disinhibition, and changes in
personality are the classic signs of bvFTLD. Also com-
mon are apathy and loss of motivation and executive
dysfunction. Psychosis can be seen in on presentation.
New onset psychosis in the elderly is rarely due to
primary psychiatric disease, except for depression with
psychotic features. Extrapyramidal symptoms may be
present in this group. Pathologically, most bvFTLDs are
FTLD-TDP43 and FTLD-tau.42
– Language variants of FTLD or primary progressive apha-
sia (PPA): At presentation, several phenotypes may be
recognized43:
○ Nonfluent PPA (nfPPA) resembles a slowly progressive
Broca’s aphasia with some differences. At the outset,
naming and repetition may be relatively intact. The
patient has problems with sentence formation and
uses telegraphic speech which is noted for its agram-
matism. There is often coexistent apraxia of speech,
which causes the speech to sound flat and aprosodic.
There is often difficulty with pronouncing longer
words. In time, all language functions are affected
and behavioral changes may follow. A high proportion
of nfPPA are FTLD-tau.
○ Semantic variant PPA (svPPA) is characterized by
atrophy of temporal lobes bilaterally. The patient loses
Seminars in Neurology Vol. 39 No. 2/2019
Salardini
semantic information including meaning of words and
may have problems with visual agnosia. Writing and
reading deficits occur early in the disease. svPPA may
be associated with behavioral problems. There is a
high proportion of FTLD-TDP amongst this group.
▪ Richardson syndrome (RS): Steele, Richardson, and
Olszewski first described the clinical feature of
PSP. In this, the patient presents with ocular
motor difficulties, cognitive findings, parkinso-
nian features, and gait instability. Ocular findings
include loss of vertical gaze, problems with
optokinetic reflex, loss of convergence, and
eye-opening apraxia. Presence of an akinetic-
rigid form of parkinsonism is the most frequent
extrapyramidal presentation. Gait is unstable,
and progressively worsening freezing of gait is
common. Cognitively, frontal findings and sub-
cortical deficits are found. These include execu-
tive dysfunction and mood disorders. With the
progression of disease, patients may develop
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compulsive behaviors, palilalia and apraxia of
speech, disinhibition, or apathy. Most cases of
RS are due to the characteristic neuropathology
of PSP. However, other pathologies such as CBD
and Pick’s disease can also present this way.
Conversely, a person with PSP pathology may
present with syndromes which may involve
mostly gait or cognition. Some may mimic idio-
pathic Parkinson’s disease or corticobasal degen-
eration. Most will begin to resemble RS as the
disease progresses.44
– Corticobasal syndrome (CBS): This is a clinical syn-
drome first described in relation to CBD, a 4R tau
pathology which frequently presents with this syn-
drome. CBS is characterized by ideomotor apraxia,
parkinsonism, dystonia, visuospatial defect, myoclo-
nus, and alien hand syndrome. CBS can be caused by
several pathologies including PSP, AD, and FTLD-TDP.
Conversely, CBD may present with RS, nf-PPA, and a
behavioral-spatial syndrome characterized by person-
ality change, executive dysfunction, and visuospatial
defects.30,45
– Frontotemporal lobar degeneration–motor neuron dis-
ease (FTLD-MND): FTLD and MND are commonly seen
together. Most patients with FTLD have MND on elec-
tromyography. Some progress to clinical disease.
Familial forms of this are associated with C9orf72
gene repeat expansion. The disease can be rapidly
progressive, presenting similar to amyotrophic lateral
sclerosis but affecting the bulbar muscles early.46
• Genetics and other risk factors: Several genes implicated in
FTLD are available clinically. A family history of dementia
should prompt referral to a geneticist. The most common
gene mutation in this group is C9orf72 which is due to
hexanucleotide expansion in the noncoding region. It is
most common in families with history of FTLD-MND.
 An Overview of Primary Dementias as Clinicopathological Entities Salardini 161

Along with progranulin, valosin-containing protein, and
TARDBP, C9orf72 is associated with TDP-43 pathology.
Whereas MAPT mutations are associated with tauopathy.
MAPT H1 haplotype is a risk factor for 4R tauopathies.18,40
• Biomarkers: FTLD-specific CSF biomarkers are not pre-
sently available in the clinic. Imaging modalities such as
MRI, FDG-PET, and tau-PET can determine the pattern of
distribution of brain atrophy, hypometabolism, and tau
deposition. These patterns support clinical diagnosis.
Patterns may include bifrontal (bv-FTLD), bilateral tem-
poral poles (sv-PPA), more limited frontal including left
inferior frontal lobe (nf-PPA) and predominantly temporal
(CBD or PCA). Ruling out AD using biomarkers may
improve diagnostic confidence47 (see ►Fig. 5).
• Treatments: Cholinesterase inhibitors are of limited effi-
cacy, and in some instances, may be associated with
adverse behavioral changes. Selective serotonin reuptake
inhibitors are commonly used for reducing affective
symptoms. Otherwise, treatment options are limited to
nonpharmacological and behavioral interventions.40
brain. As a result, the characteristic cognitive deficits
include arousal and visuospatial dysfunction.48,49
• Clinical phenotypes: The two phenotypes are LBD and
PDD. They are both associated with rapid eye movement
(REM) behavior disorder, a sleep disorder which causes
the patient to act out their dreams while still sleeping.
LBD is associated with fluctuations, parkinsonism, visuos-
patial deficits, and hallucinations. Hallucinations, called
peduncular hallucinosis, are classically of children and
animals and are brightly colored. In our clinic, visions of
people standing around while silent and other visual
illusions are common. Visual illusions occur especially
in poor lighting. Most LBD hallucinations are not threa-
tening to the patient. Episodic memory is often affected
less and later than is the case with AD. PDD starts with
motor symptoms, slowness of mentation, and problems
with memory retrieval, and goes on to include visuospa-
tial problems seen in LBD.50
• Genetics and other risk factors: Certain pesticides, vitamin
D, and traumatic brain injury have been implicated in

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Lewy Body Dementia and Parkinson’s Disease
Dementia
• Neuropathology: Both LBD and PDD are characterized by
the accumulation of α-synuclein in neurons to form Lewy
bodies. These are overlapping clinical syndromes which
are on the spectrum of the same disease. In PDD, Lewy
bodies begin by affecting subcortical structures including
the brainstem, thalamus, and basal ganglia before spread-
ing to the cortex. Subsequently, the deficits seen in PDD
include attentional issues, slowness of mentation, and
executive dysfunction associated with involvement of the
dorsolateral prefrontal cortex. LBD, on the other hand, has
earlier cortical involvement, often coexists with AD or
vascular pathologies, and affects posterior parts of the
Parkinson’s disease, therefore PDD and to a lesser extent
LBD. Some genes associated with genetic forms of Par-
kinson’s disease such as SNCA and LRRK2 are also asso-
ciated with LBD. The gene implicated in Gaucher’s disease,
GBA1, appears in 10% of individuals with Parkinson’s
disease and increases the risk of LBD. Given that there
are other pathologies present in patients with LBD, it is
not surprising that both vascular risk factors and APOE4
are most frequent in individuals with LBD than the
general population.51
• Biomarkers: Loss of dopaminergic neurotransmission can be
demonstrated by a dopamine transport scan or a DAT scan.
When distinguishing LBD from AD, the presence or absence
of amyloid is not useful, because both often have amyloid
pathology. However, the pattern of amyloid deposition is

Fig. 5 MRI images of a patient with nonfluent primary progressive aphasia variant frontotemporal dementia due to progranulin mutation. (A)
Transverse FLAIR slice shows the asymmetrical L > R in this case. (B) Atrophy of the temporal pole is accompanied by the so-called “knife sign”
where the slender temporal tissue resembles a knife. (C) FDG-PET shows hypometabolism in frontotemporal areas L > R. FDG-PET,
fluorodeoxyglucose-positron emission tomography; FLAIR, fluid attenuation inversion recovery; MRI, magnetic resonance imaging.

Seminars in Neurology Vol. 39 No. 2/2019

162 An Overview of Primary Dementias as Clinicopathological Entities
Fig. 6 The patient has Lewy body dementia. (A) The FDG-PET scan shows the presence of occipital hypometabolism. The darker areas
superimposed on the CT represent areas of hypometabolism compared with age-matched controls. (B) DAT-SPECT scan shows a loss of
dopaminergic innervation in the striatum. The superimposed lighter signal is dopamine transporter uptake signal. CT, computed tomography;
DAT-SPECT, dopamine transporter single-photon emission computed tomography; FDG-PET, fluorodeoxyglucose-positron emission
tomography.
different in LBD. A sparing of the posterior cingulate cortex,
the so-called island sign, on amyloid PET is fairly specific to
LBD. Another difference is on FDG-PET, where LBD affects
the occipital lobe, this is spared in AD52 (see ►Fig. 6).
• Treatment: Treatment of cognitive symptoms in LBD and
PDD centers around cholinesterase inhibitors reduces
fluctuations and hallucinations and improves cognition
in general. Judicious treatment of motor symptoms can be
attempted, with the knowledge that cognitive symptoms
may worsen with dopaminergic medications. Depression
and anxiety are common in these diseases and need to be
treated.52
Vascular Dementia
• Neuropathology: Vascular dementia is a general term
applied to dementia caused by vascular pathology. Cog-
nitive impairment can occur after multiple infarcts, a
large infarct, or a strategically placed infarct. These
infarcts can be hemorrhagic or ischemic. The dementia
due to these causes is commonly referred to as poststroke
dementia. Hypoperfusion causing laminar necrosis can
also cause cognitive decline. However, most vascular
dementia is due to chronic cerebral small vessel disease.
This form of vascular dementia progresses insidiously,
causing chronic white matter changes, cortical and sub-
cortical microinfarcts, lacunar infarcts, microbleeds, and
superficial siderosis. The two most common causes of
small vessel disease are arteriosclerosis and cerebral
amyloid angiopathy. In arteriosclerosis, the vessels lose
their elasticity and have lumenal narrowing . Cerebral
amyloid angiopathy is caused by deposition of amyloid in
Seminars in Neurology Vol. 39 No. 2/2019
Salardini
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vessel walls. This damages the vessel wall and increases
the risk of bleeding. These bleeds are in the form of
microhemorrhages and large lobar bleeds. Cerebral amy-
loid angiopathy also has an inflammatory form which
presents as an RPD.53,54
• Clinical phenotypes: The clinical stage of vascular demen-
tia which corresponds with MCI is vascular cognitive
impairment. The clinical phenotype of poststroke demen-
tia is determined by the location and extent of the stroke.
Small vessel disease is more diffuse and affects cognitive
domains, which neurologists have traditionally referred
to as “subcortical.” These include speed of information
processing, complex attention, and some executive func-
tions. Additionally, there is a high rate of problems with
memory retrieval, gait apraxia, urinary urge, and psychia-
tric manifestations. The psychiatric manifestations
include depression, abulia, and apathy.55,56
• Genetics and risk factors: Vascular risk factors such as
hypertension, obesity, hypercholesterolemia, smoking,
and family history are closely linked to the risk of stroke
and therefore poststroke dementia. The risk of dementia
in stroke depends on the location of the strokes as well as
the presence of reduced cognitive reserve (advanced age
and low education, and coexistence of AD pathology).
There is a correlation between small vessel disease and
traditional vascular risk factors, but the link is not as
strong as that seen in large vessel disease. Several genetic
conditions cause small vessel disease, the most common
being cerebral autosomal dominant arteriopathy with
subcortical infarcts and leukoencephalopathy (CADSIL)
in which the patient presents with cognitive deficits in
their 40s and 50s. There is some evidence that nondisease
 An Overview of Primary Dementias as Clinicopathological Entities Salardini 163

causing variations in several genes associated with her-
editary small vessel diseases can be risk factors for
sporadic small-vessel disease.57,58
• Biomarkers: Presently there are no good biomarkers for
vascular dementia due to small vessel disease. Several
lesion types, including lacunar infarcts, perivascular space
enlargements, white matter hyperintensities, microhe-
morrhages, superficial siderosis, and microinfarcts, are
associated with the severity of small vessel disease.
However, they are very poor at predicting cognitive out-
comes. MRI techniques measuring cerebrovascular reac-
tivity (to CO2) and structural connectivity using diffusion
tensor imaging (DTI) are being studied as possible bio-
markers for small vessel disease. Presence of amyloid and
tau, which is common, will worsen the severity of the
dementia59 (see ►Fig. 7).
• Treatment: Treatment is well established for large vessel
disease in the brain and includes antiplatelet therapy or
thrombolysis in the acute setting followed by secondary
prevention to reduce the risk of reoccurrence. Apart from
control of blood pressure, these interventions do not
appear to be as effective in slowing the progression of
small vessel disease.53
Prion Disease
• Neuropathology: Misfolded prions are proteinaceous
infectious particles which cause several devastating neu-
rodegenerative diseases, including Creutzfeldt–Jakob dis-
ease (CJD), fatal familial insomnia (FFI), Gerstmann–
Straussler–Scheinker (GSS) syndrome, kuru, variably pro-
tease-sensitive prionopathy, and variant CJD (vCJD).
Prions are normal parts of neuronal cell surface. Misfolded

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Fig. 7 MRI showing evidence of advance small vessel disease. Panels (A) and (B) (FLAIR coronal and transverse, respectively) show confluent
white matter hyperintensities affecting predominantly the corona radiata. Panel (C) (transverse section SWI) shows the presence of
hypertensive microbleeds in the basal ganglia and thalamus. Panel (D) (transverse section T2) shows the presence of enlarged perivascular
spaces best seen in the putamen. This is an example of état criblé or cribriform state found in classic neurological literature. FLAIR, fluid
attenuation inversion recovery; MRI, magnetic resonance imaging; SWI, susceptibility-weighted imaging.

Seminars in Neurology Vol. 39 No. 2/2019

164 An Overview of Primary Dementias as Clinicopathological Entities
Fig. 8 (A) This shows a DWI image with increased cortical signal suggesting cortical cytotoxic edema or cortical ribboning in a patient suspected
of having CJD. Uncharacteristically there are no basal ganglionic or thalamic changes. (B) This shows a DWI image with increased caudate and
mesial thalamic (hockey stick) increased signal. In this case there is little evidence of cortical ribboning. CJD, Creutzfeldt–Jakob disease; DWI,
diffusion-weighted imaging.
prions replicate and interact with normal prion protein to
cause them to misfold, causing damage and spreading
throughout the brain. The disease progresses over a few
months after its first symptoms, leading to death. Most
prion disease is sporadic, followed by those caused by
genetic and infectious transmission.60
• Clinical phenotypes61:
– CJD: Sporadic CJD (sCJD) is the most common form of
prion disease, and presents with cognitive symptoms,
pyramidal and extrapyramidal motor symptoms, ataxia,
myoclonus, and psychiatric comorbidities. Infrequently
there is a prodrome of psychological or constitutional
symptoms such as anxiety, depression, apathy, sleep
problems, and feeling unwell. The phenotype of the
disease is partially determined by polymorphism at
codon 129 which can either be valine or methionine.
Familial CJD presents very similarly but may have a
slower course.
– vCJD: This is a prion disease which is caused by eating
of contaminated meat from livestock stricken with
bovine spongiform encephalopathy. vCJD progresses
more slowly and can have a psychiatric prodrome.
– Other prion diseases: FFI, now referred to as fatal
insomnia because sporadic forms are also known,
presents with sympathetic hyperarousal with insom-
nia, dysautonomia, cognitive problems, and eventually
death. GSS is a difficult disease to diagnose because of
its prolonged course. It is associated with cerebellar or
extrapyramidal symptoms. There is considerable
variability in the natural history of the disease, but it
is generally slow and may progress over 10 to 20 years.
• Biomarkers: Several classic test findings are described in
prion disease, including periodic sharp-wave complexes
Seminars in Neurology Vol. 39 No. 2/2019
Salardini
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at 1 to 2 Hz. More reliable is the MRI findings especially
the demonstration of diffusion restriction (DWI MRI)
along the cortical ribbon (ribboning), thalamus, and basal
ganglia. CSF testing now relies on 14–3-3 protein and total
tau. When the test is positive, the test is double checked
with CSF real-time quaking-induced conversion (RT-
QuIC) test which is highly sensitive and specific. Brain
biopsy confirms the diagnosis postmortem. vCJD can be
diagnosed, during life, by performing a tonsil biopsy (vCJD
gets into the lymphatic system)62 (see ►Fig. 8).
• Treatment: There is no treatment for CJD. Autopsy of the
brain may be organized with the National Prion Disease
Pathology Surveillance Center situated in Case Western
University.
Conclusion
Primary dementias are predominantly proteinopathies
where misfolded proteins accumulate and lead to neuroin-
flammation, synaptic loss, cell death, and gliosis. The excep-
tion is vascular dementia, which accumulates vascular
lesions. Each clinical-pathological entity is defined by the
type of misfolded protein which causes it, and by its clinical
presentation. Among the primary dementias, AD is the best
characterized with good biomarkers for accurate diagnosis.
Frontotemporal dementia clinical phenotypes, on the other
hand, overlap and do not have the benefit of reliable bio-
markers for confirmation. The diagnostic complexity for the
rest of the conditions falls somewhere between these two
extremes. A knowledge of primary dementias is the basis of
the practice of dementia medicine.
Conflict of Interest
Dr. Salardini has nothing to disclose.
 An Overview of Primary Dementias as Clinicopathological Entities
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