190 PART 2 Cardinal Manifestations and Presentation of Diseases

Limbic-predominant aging-related TDP-43 encephalopathy (LATE)

is common after age 70 and has been linked to declining episodic

memory function. Chronic traumatic encephalopathy (CTE), a unique

disease found in individuals with a history of repetitive head impacts

(e.g., professional athletes in collision or fighting sports, military veterans

exposed to multiple blasts), presents with changes in cognition, mood,

behavior, or motor function. Mixed pathology is common, especially in

older individuals. In patients under the age of 65, FTD rivals AD as the

most common cause of dementia. Chronic intoxications, including those

resulting from alcohol and prescription drugs, are an important and often

treatable cause of dementia. Other disorders listed in Table 29-1 are

uncommon but important because many are reversible. The classification of dementing illnesses into reversible and irreversible disorders is a

useful approach to differential diagnosis. When effective treatments for

the neurodegenerative conditions emerge, this dichotomy will become

obsolete.

In a study of 1000 persons attending a memory disorders clinic,

19% had a potentially reversible cause of the cognitive impairment

and 23% had a potentially reversible concomitant condition that may

have contributed to the patient’s impairment. The three most common

potentially reversible diagnoses were depression, normal pressure

hydrocephalus (NPH), and alcohol dependence; medication side

effects are also common and should be considered in every patient

(Table 29-1).

The term rapidly progressive dementia (RPD) is applied to illnesses

that progress from initial symptom onset to dementia within a year

or less; confusional states related to toxic/metabolic conditions are

excluded. Although the prion proteinopathy Creutzfeldt-Jakob disease

(CJD) (Chap. 438) is the classic cause of a rapidly progressive dementia, especially when associated with myoclonus, more often cases of

RPD are due to AD or another neurodegenerative disorder, or to an

autoimmune encephalitis.

Subtle cumulative decline in episodic memory is a common part of

aging. This frustrating experience, often the source of jokes and humor,

has historically been referred to as benign forgetfulness of the elderly.

Benign means that it is not so progressive or serious that it impairs

successful and productive daily functioning, although the distinction

between benign and significant memory loss can be subtle. At age 85,

the average person is able to learn and recall approximately one-half

of the items (e.g., words on a list) that he or she could at age 18. The

term subjective cognitive decline describes individuals who experience

a subjective decline from their cognitive baseline but perform within

normal limits for their age and educational attainment on formal neuropsychological testing. Mild cognitive impairment (MCI) is defined as

a decline in cognition that is confirmed on objective cognitive testing

but does not disrupt normal daily activities. MCI can be further subcategorized based on the presenting complaints and deficits (e.g., amnestic MCI, executive MCI). Factors that predict progression from MCI to

an AD dementia include a prominent memory deficit, family history

of dementia, presence of an apolipoprotein ε4 (Apo ε4) allele, small

hippocampal volumes, an AD-like signature of cortical atrophy, low

cerebrospinal fluid Aβ and elevated tau, or evidence of brain amyloid

and tau deposition on positron emission tomography (PET) imaging.

The major degenerative dementias include AD, DLB, FTD and

related disorders, HD, and prion diseases, including CJD. All are

associated with the abnormal aggregation of a specific protein: Aβ42

and tau in AD; α-synuclein in DLB; tau, TAR DNA-binding protein

of 43 kDa (TDP-43), or the FET family of proteins (fused in sarcoma

[FUS], Ewing sarcoma [EWS], and TBP-associated factor 15 [TAF15])

in FTD; huntingtin in HD; and misfolded prion protein (PrPsc) in CJD

(Table 29-2).

The risk of developing dementia in late-life is associated with exposures and lifestyle factors that can operate across the life span. Modifiable risk factors include low education, hearing loss, traumatic brain

injury, hypertension, diabetes mellitus, obesity, heavy alcohol use,

smoking, depression, physical inactivity, and air pollution. Improved

management of midlife vascular risk factors has been credited with

a decreasing incidence of dementia observed in North America and

Western Europe.

TABLE 29-1 Differential Diagnosis of Dementia

Most Common Causes of Dementia

Alzheimer’s disease Alcoholisma

Vascular dementia PDD/LBD spectrum

Multi-infarct Drug/medication intoxicationa’

 Diffuse white matter disease

(Binswanger’s)

Limbic-predominant age-related

TDP-43 encephalopathy

Less Common Causes of Dementia

Vitamin deficiencies

 Thiamine (B1

): Wernicke’s

encephalopathya

 B12 (subacute combined

degeneration)a

Nicotinic acid (pellagra)a

Endocrine and other organ failure

Hypothyroidisma

 Adrenal insufficiency and Cushing’s

syndromea

Hypo- and hyperparathyroidisma

Renal failurea

Liver failurea

Pulmonary failurea

Chronic infections

HIV

Neurosyphilisa

 Papovavirus (JC virus) (progressive

multifocal leukoencephalopathy)

Tuberculosis, fungal, and protozoala

Whipple’s diseasea

Head trauma and diffuse brain damage

Chronic traumatic encephalopathy

Chronic subdural hematomaa

Postanoxia

Postencephalitis

Normal-pressure hydrocephalusa

Intracranial hypotension

Neoplastic

Primary brain tumora

Metastatic brain tumora

Autoimmune (paraneoplastic)

encephalitisa

Toxic disorders

 Drug, medication, and narcotic

poisoninga

Heavy metal intoxicationa

Organic toxins

Psychiatric

Depression (pseudodementia)a

Schizophreniaa

Conversion disordera

Degenerative disorders

Huntington’s disease

Multisystem atrophy

Hereditary ataxias (some forms)

 Frontotemporal lobar degeneration

spectrum

Multiple sclerosis

 Adult Down’s syndrome with

Alzheimer’s disease

 ALS-parkinsonism-dementia

complex of Guam

 Prion (Creutzfeldt-Jakob and

Gerstmann-Sträussler-Scheinker

diseases)

Miscellaneous

Sarcoidosisa

Vasculitisa

CADASIL, etc.

Acute intermittent porphyriaa

Recurrent nonconvulsive seizuresa

Additional conditions in children or

adolescents

 Pantothenate kinase–associated

neurodegeneration

Subacute sclerosing panencephalitis

 Metabolic disorders (e.g.,

Wilson’s and Leigh’s diseases,

leukodystrophies, lipid storage

diseases, mitochondrial mutations)

a

Potentially reversible dementia.

Abbreviations: ALS, amyotrophic lateral sclerosis; CADASIL, cerebral autosomal

dominant arteriopathy with subcortical infarcts and leukoencephalopathy;

LBD, Lewy body disease; PDD, Parkinson’s disease dementia.

The many causes of dementia are listed in Table 29-1. The frequency

of each condition depends on the age group under study, access of the

group to medical care, country of origin, and perhaps racial or ethnic

background. AD is the most common cause of dementia in Western

countries, accounting for more than half of all patients. Vascular disease is the second most frequent cause for dementia and is particularly

common in elderly patients or populations with limited access to medical care, where vascular risk factors are undertreated. Often, vascular

brain injury is mixed with neurodegenerative disorders, particularly

AD, making it difficult, even for the neuropathologist, to estimate the

contribution of cerebrovascular disease to the cognitive disorder in

an individual patient. Dementias associated with Parkinson’s disease

(PD) are common and may develop years after onset of a parkinsonian disorder, as seen with PD-related dementia (PDD), or they can

occur concurrently with or preceding the motor syndrome, as in DLB.

191 Dementia CHAPTER 29

TABLE 29-2 The Molecular Basis for Degenerative Dementia

DEMENTIA MOLECULAR BASIS CAUSAL GENES (CHROMOSOME) SUSCEPTIBILITY GENES PATHOLOGIC FINDINGS

AD Aβ/tau APP (21), PS-1 (14), PS-2 (1) (<2% carry these

mutations, most often in PS-1)

Apo ε4 (19) Amyloid plaques, neurofibrillary tangles,

and neuropil threads

FTD Tau MAPT exon and intron mutations (17) (about 10%

of familial cases)

H1 MAPT haplotype Tau neuronal and glial inclusions varying

in morphology and distribution

TDP-43 GRN (10% of familial cases), C9ORF72 (20%–30%

of familial cases), rare VCP, very rare TARDBP,

TBK1, TIA1

TDP-43 neuronal and glial inclusions

varying in morphology and distribution

FET Very rare FUS FET neuronal and glial inclusions varying

in morphology and distribution

DLB α-Synuclein Very rare SNCA (4) Unknown α-Synuclein neuronal inclusions (Lewy

bodies)

CJD PrPSC PRNP (20) (up to 15% of patients carry these

dominant mutations)

Codon 129 homozygosity for

methionine or valine

PrPSC deposition, panlaminar spongiosis

Abbreviations: AD, Alzheimer’s disease; CJD, Creutzfeldt-Jakob disease; DLB, dementia with Lewy bodies; FET, FUS/EWS/TAF-15; FTD, frontotemporal dementia.

APPROACH TO THE PATIENT

Dementias

Three major issues should be kept at the forefront: (1) What is the

clinical diagnosis? (2) What component of the dementia syndrome

is treatable or reversible? (3) Can the physician help to alleviate the

burden on caregivers? A broad overview of the approach to dementia is shown in Table 29-3. The major degenerative dementias can

usually be distinguished by the initial symptoms; neuropsychological, neuropsychiatric, and neurologic findings; and neuroimaging

features (Table 29-4).

HISTORY

The history should concentrate on the onset, duration, and tempo

of progression. An acute or subacute onset of confusion may be due

to delirium (Chap. 27) and should trigger a search for intoxication, infection, or metabolic derangement. An elderly person with

slowly progressive memory loss over several years is likely to suffer

from AD. Nearly 75% of patients with AD begin with memory

symptoms, but other early symptoms include anxiety or depression

as well as difficulty managing money, driving, shopping, following instructions, finding words, or navigating. Personality change,

disinhibition, and weight gain or compulsive eating suggest FTD,

not AD. FTD is also suggested by prominent apathy, compulsivity,

loss of empathy for others, or progressive loss of speech fluency or

single-word comprehension with relative sparing of memory and

visuospatial abilities. The diagnosis of DLB is suggested by early

visual hallucinations; parkinsonism; proneness to delirium or sensitivity to psychoactive medications; rapid eye movement (REM)

behavior disorder (RBD; dramatic, sometimes violent, limb movements during dreaming [Chap. 31]); or Capgras syndrome, the

delusion that a familiar person has been replaced by an impostor.

A history of stroke with irregular stepwise progression suggests

vascular dementia. Vascular dementia is also commonly seen in the

setting of hypertension, atrial fibrillation, peripheral vascular disease, smoking, and diabetes. In patients suffering from cerebrovascular disease, it can be difficult to determine whether the dementia

is due to AD, vascular disease, or a mixture of the two because

many of the risk factors for vascular dementia, including diabetes,

high cholesterol, elevated homocysteine, and low exercise, are also

risk factors for AD. Moreover, many patients with a major vascular

contribution to their dementia lack a history of stepwise decline.

Rapid progression with motor rigidity and myoclonus suggests CJD

(Chap. 438). Seizures may indicate strokes or neoplasm but also

occur in AD, particularly early-age-of-onset AD. Gait disturbance

is common in vascular dementia, PD/DLB, or NPH. A history of

high-risk sexual behaviors or intravenous drug use should trigger a

search for central nervous system (CNS) infection, especially HIV or

syphilis. A history of recurrent head trauma could indicate chronic

subdural hematoma, CTE, intracranial hypotension, or NPH. Subacute onset of severe amnesia and psychosis with mesial temporal

T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities

on MRI should raise concern for autoimmune (paraneoplastic)

encephalitis, sometimes in long-term smokers or other patients at

risk for cancer. The spectrum of autoimmune etiologies producing

TABLE 29-3 Evaluation of the Patient with Dementia

ROUTINE EVALUATION OPTIONAL FOCUSED TESTS

OCCASIONALLY

HELPFUL TESTS

History Psychometric testing EEG

Physical examination Chest x-ray Parathyroid function

Laboratory tests Lumbar puncture Adrenal function

Thyroid function (TSH) Liver function Urine heavy metals

Vitamin B12 Renal function RBC sedimentation rate

Complete blood count Urine toxin screen Angiogram

Electrolytes HIV Brain biopsy

CT/MRI Apolipoprotein E SPECT

RPR or VDRL PET

Autoantibodies

Diagnostic Categories

REVERSIBLE CAUSES

IRREVERSIBLE/

DEGENERATIVE

DEMENTIAS

PSYCHIATRIC

DISORDERS

Examples Examples Depression

Hypothyroidism Alzheimer’s Schizophrenia

Thiamine deficiency Frontotemporal dementia Conversion reaction

Vitamin B12 deficiency Huntington’s

 Normal pressure

hydrocephalus

 Dementia with Lewy

bodies

Subdural hematoma Vascular

Chronic infection Leukoencephalopathies

Brain tumor Parkinson’s

Drug intoxication

 Autoimmune

encephalopathy

Associated Treatable Conditions

Depression Agitation

Seizures Caregiver “burnout”

Insomnia Drug side effects

Abbreviations: CT, computed tomography; EEG, electroencephalogram; MRI,

magnetic resonance imaging; PET, positron emission tomography; RBC, red blood

cell; RPR, rapid plasma reagin (test); SPECT, single-photon emission computed

tomography; TSH, thyroid-stimulating hormone; VDRL, venereal disease research

laboratory (test for syphilis).

192 PART 2 Cardinal Manifestations and Presentation of Diseases

TABLE 29-4 Clinical Differentiation of the Major Dementias

DISEASE FIRST SYMPTOM MENTAL STATUS NEUROPSYCHIATRY NEUROLOGY IMAGING

AD Memory loss Episodic memory loss Irritability, anxiety,

depression

Initially normal Entorhinal cortex and

hippocampal atrophy

FTD Apathy, poor judgment/

insight, speech/language,

hyperorality

Frontal/executive and/or

language; spares drawing

Apathy, disinhibition,

overeating, compulsivity

May have vertical gaze palsy,

axial rigidity, dystonia, alien

hand, or MND

Frontal, insular, and/or

temporal atrophy; usually

spares posterior parietal lobe

DLB Visual hallucinations, REM

sleep behavior disorder,

delirium, Capgras syndrome,

parkinsonism

Drawing and frontal/

executive, spares

memory, delirium-prone

Visual hallucinations,

depression, sleep

disorder, delusions

Parkinsonism Posterior parietal atrophy,

hippocampi larger than in AD

CJD Dementia, mood, anxiety,

movement disorders

Variable, frontal/

executive, focal cortical,

memory

Depression, anxiety,

psychosis in some

Myoclonus, rigidity,

parkinsonism

Cortical ribboning and

basal ganglia or thalamus

hyperintensity on diffusion/

FLAIR MRI

Vascular Often but not always sudden,

variable, apathy, falls, focal

weakness

Frontal/executive,

cognitive slowing, can

spare memory

Apathy, delusions, anxiety Usually motor slowing,

spasticity, can be normal

Cortical and/or subcortical

infarctions, confluent white

matter disease

Abbreviations: AD, Alzheimer’s disease; CBD, cortical basal degeneration; CJD, Creutzfeldt-Jakob disease; DLB, dementia with Lewy bodies; FLAIR, fluid-attenuated

inversion recovery; FTD, frontotemporal dementia; MND, motor neuron disease; MRI, magnetic resonance imaging; REM, rapid eye movement.

RPD has rapidly expanded, and includes antibodies targeting

leucine-rich glioma-inactivated 1 (LGI1; faciobrachial dystonic

seizures); contactin-associated protein-like 2 (Caspr2; insomnia, ataxia, myotonia); N-methyl-d-aspartate (NMDA)-receptor

(psychosis, insomnia, dyskinesias); and α-amino-3-hydroxy-5-

methylisoxazole-4-propionic acid (AMPA)-receptor (limbic encephalitis with relapses), among others (Chap. 94). Alcohol abuse creates

risk for malnutrition and thiamine deficiency. Veganism, bowel

irradiation, an autoimmune diathesis, a remote history of gastric

surgery, and chronic therapy with histamine H2-receptor antagonists for dyspepsia or gastroesophageal reflux predispose to B12

deficiency. Certain occupations, such as working in a battery or

chemical factory, might indicate heavy metal intoxication. Careful

review of medication intake, especially for sedatives and analgesics,

may raise the issue of chronic drug intoxication. An autosomal

dominant family history is found in HD and in familial forms of

AD, FTD, DLB, or prion disorders. A history of mood disorder, the

recent death of a loved one, or depressive signs such as insomnia

or weight loss, raise the possibility of depression-related cognitive

impairment.

PHYSICAL AND NEUROLOGIC EXAMINATION

A thorough general and neurologic examination is essential to

identify signs of nervous system involvement and search for clues

suggesting a systemic disease that might be responsible for the cognitive disorder. Typical AD spares motor systems until late in the

course. In contrast, patients with FTD often develop axial rigidity,

supranuclear gaze palsy, or a motor neuron disease reminiscent of

amyotrophic lateral sclerosis (ALS). In DLB, the initial symptoms

may include a parkinsonian syndrome (resting tremor, cogwheel

rigidity, bradykinesia, festinating gait), but DLB often starts with

visual hallucinations or cognitive impairment, and symptoms referable to the lower brainstem (RBD, gastrointestinal, or autonomic

problems) may arise years or even decades before parkinsonism

or dementia. Corticobasal syndrome (CBS) features asymmetric

akinesia and rigidity, dystonia, myoclonus, alien limb phenomena,

pyramidal signs, and prefrontal deficits such as nonfluent aphasia

with or without motor speech impairment, executive dysfunction,

apraxia, or a behavioral disorder. Progressive supranuclear palsy

(PSP) is associated with unexplained falls, axial rigidity, dysphagia,

and vertical gaze deficits. CJD is suggested by the presence of diffuse rigidity, an akinetic mute state, and prominent, often startlesensitive, myoclonus.

Hemiparesis or other focal neurologic deficits suggest vascular dementia or brain tumor. Dementia with a myelopathy and

peripheral neuropathy suggests vitamin B12 deficiency. Peripheral

neuropathy could also indicate another vitamin deficiency, heavy

metal intoxication, thyroid dysfunction, Lyme disease, or vasculitis.

Dry cool skin, hair loss, and bradycardia suggest hypothyroidism.

Fluctuating confusion associated with repetitive stereotyped movements may indicate ongoing limbic, temporal, or frontal seizures.

In the elderly, hearing impairment or visual loss may produce

confusion and disorientation misinterpreted as dementia. Profound

bilateral sensorineural hearing loss in a younger patient with short

stature or myopathy, however, should raise concern for a mitochondrial disorder.

COGNITIVE AND NEUROPSYCHIATRIC EXAMINATION

Brief screening tools such as the Mini-Mental State Examination

(MMSE), the Montreal Cognitive Assessment (MOCA), the Tablet

Based Cognitive Assessment Tool, and Cognistat can be used to

capture dementia and follow progression. None of these tests is

highly sensitive to early-stage dementia or reliably discriminates

between dementia syndromes. The MMSE is a 30-point test of cognitive function, with each correct answer being scored as 1 point.

It includes tests of: orientation (e.g., identify season/date/month/

year/floor/hospital/town/state/country); registration (e.g., name

and restate 3 objects); recall (e.g., remember the same three objects

5 minutes later); and language (e.g., name pencil and watch; repeat

“no ifs ands or buts”; follow a 3-step command; obey a written command; and write a sentence and copy a design). In most patients

with MCI and some with clinically apparent AD, bedside screening

tests may be normal, and a more challenging and comprehensive

set of neuropsychological tests will be required. When the etiology

for the dementia syndrome remains in doubt, a specially tailored

evaluation should be performed that includes tasks of working and

episodic memory, executive function, language, and visuospatial

and perceptual abilities. In AD, the early deficits involve episodic

memory, category generation (“name as many animals as you can in

1 minute”), and visuoconstructive ability. Usually deficits in verbal

or visual episodic memory are the first neuropsychological abnormalities detected, and tasks that require the patient to recall a long

list of words or a series of pictures after a predetermined delay will

demonstrate deficits in most patients. In FTD, the earliest deficits

on cognitive testing involve executive control or language (speech

or naming) functions, but some patients lack either finding despite

profound social-emotional deficits. PDD or DLB patients have

more severe deficits in executive and visuospatial function but do

better on episodic memory tasks than patients with AD. Patients

with vascular dementia often demonstrate a mixture of executive

and visuospatial deficits, with prominent psychomotor slowing. In

delirium, the most prominent deficits involve attention, working

193 Dementia CHAPTER 29

memory, and executive function, making the assessment of other

cognitive domains challenging and often uninformative.

A functional assessment should also be performed to help the

physician determine the day-to-day impact of the disorder on the

patient’s memory, community affairs, hobbies, judgment, dressing,

and eating. Knowledge of the patient’s functional abilities will help

the clinician and the family to organize a therapeutic approach.

Neuropsychiatric assessment is important for diagnosis, prognosis, and treatment. In the early stages of AD, mild depressive

features, social withdrawal, and irritability or anxiety are the most

prominent psychiatric changes, but patients often maintain core

social graces into the middle or late stages, when delusions, agitation, and sleep disturbance may emerge. In FTD, dramatic personality change with apathy, overeating, compulsions, disinhibition,

and loss of empathy are early and common. DLB is associated with

visual hallucinations, delusions related to person or place identity,

RBD, and excessive daytime sleepiness. Dramatic fluctuations occur

not only in cognition but also in arousal. Vascular dementia can

present with psychiatric symptoms such as depression, anxiety,

delusions, disinhibition, or apathy.

LABORATORY TESTS

The choice of laboratory tests in the evaluation of dementia is

complex and should be tailored to the individual patient. The

physician must take measures to avoid missing a reversible or

treatable cause, yet no single treatable etiology is common; thus a

screen must use multiple tests, each of which has a low yield. Cost/

benefit ratios are difficult to assess, and many laboratory screening

algorithms for dementia discourage multiple tests. Nevertheless,

even a test with only a 1–2% positive rate is worth undertaking if

the alternative is missing a treatable cause of dementia. Table 29-3

lists most screening tests for dementia. The American Academy

of Neurology recommends the routine measurement of a complete blood count; electrolytes; glucose; renal, liver, and thyroid

functions; a vitamin B12 level; and a structural neuroimaging study

(MRI or CT).

Neuroimaging studies, especially MRI, help to rule out primary

and metastatic neoplasms, locate areas of infarction or inflammation, detect subdural hematomas, and suggest NPH or diffuse

white matter disease. They also help to establish a regional pattern

of atrophy. Support for the diagnosis of AD includes hippocampal

atrophy in addition to posterior-predominant cortical atrophy

(Fig. 29-1). Focal frontal, insular, and/or anterior temporal atrophy suggests FTD (Chap. 432). DLB often features less prominent

atrophy, with greater involvement of the amygdala than the hippocampus. In CJD, magnetic resonance (MR) diffusion-weighted

imaging reveals restricted diffusion within the cortical ribbon and/

or basal ganglia in most patients. Extensive multifocal white matter

abnormalities suggest a vascular etiology (Fig. 29-2). Communicating hydrocephalus with vertex effacement (crowding of dorsal

convexity gyri/sulci), gaping Sylvian fissures despite minimal cortical atrophy, and additional features shown in Fig. 29-3 suggest

NPH. Single-photon emission computed tomography (SPECT) and

fluoro-deoxyglucose PET scanning show temporal-parietal hypoperfusion or hypometabolism in AD and frontotemporal deficits in

FTD, but abnormalities in these patterns can be detected with MRI

alone in many patients. Recently, amyloid- and tau-PET imaging

have shown promise for the diagnosis of AD. There are currently

62 y.o. HC 60 y.o. AD

A B C D

FIGURE 29-1 Alzheimer’s disease (AD). Axial T1-weighted magnetic resonance images of a healthy 62-year-old (A, B) and a 60-year-old with AD (C, D). Note the

diffuse atrophy, plus temporal lobe volume loss, in the patient with AD. Aβ positron emission tomography (PET) with [11C]PIB (B and D) reveals extensive radiotracer

retention in neocortex bilaterally in AD, consistent with the known distribution of amyloid plaques. HC, healthy control. (Source: Gil Rabinovici, University of California,

San Francisco and William Jagust, University of California, Berkeley.)

FIGURE 29-2 Diffuse white matter disease. Axial fluid-attenuated inversion

recovery (FLAIR) magnetic resonance image through the lateral ventricles reveals

multiple areas of hyperintensity (arrows) involving the periventricular white matter

as well as the corona radiata and striatum. Although seen in some individuals with

normal cognition, this appearance is more pronounced in patients with dementia of

a vascular etiology.

194 PART 2 Cardinal Manifestations and Presentation of Diseases

FIGURE 29-3 Normal pressure hydrocephalus. A. Sagittal T1-weighted MRI

demonstrates dilation of the lateral ventricle and stretching of the corpus callosum

(arrows), depression of the floor of the third ventricle (single arrowhead), and

enlargement of the aqueduct (double arrowheads). Note the diffuse dilation of the

lateral, third, and fourth ventricles with a patent aqueduct, typical of communicating

hydrocephalus. B. Axial T2-weighted MRIs demonstrate dilation of the lateral

ventricles. This patient underwent successful ventriculoperitoneal shunting.

three amyloid PET ligands (F18-florbetapir, F18-florbetaben,

F18-flutametamol) and one tau PET ligand (F18-flortaucipir)

approved by the US Food and Drug Administration for clinical use.

Amyloid PET ligands bind to diffuse and neuritic amyloid plaques,

as well as to vascular amyloid deposits (prominent in cerebral amyloid angiopathy), while tau PET ligands bind to the paired helical

filaments of tau characteristic of neurofibrillary tangles in AD

(Chap. 431). Because amyloid plaques are also commonly found in

cognitively normal older persons (~25% of individuals at age 65),

the main clinical value of amyloid imaging is to exclude AD as the

likely cause of dementia in patients who have negative scans. The

spread of tau is more tightly linked to cognitive state (Chap. 431),

and thus may be more useful than amyloid imaging for “ruling in”

AD, as well as for disease staging. Once disease-modifying therapies

become available, CSF or molecular PET biomarkers will likely be

used to identify treatment candidates. In the meantime, the prognostic value of detecting brain amyloid in an asymptomatic elder

to assess preclinical disease and risk of future cognitive decline

remains a topic of vigorous investigation.

Lumbar puncture need not be done routinely in the evaluation of

dementia, but it is indicated when CNS infection or inflammation

are credible diagnostic possibilities. Cerebrospinal fluid (CSF) levels

of Aβ42 and tau proteins show differing patterns with the various

dementias, and the presence of low Aβ42 (or a low Aβ42/Aβ40 ratio),

mild-moderately elevated CSF total tau, and elevated CSF phosphorylated tau (at residues 181 or 217) is highly suggestive of AD.

Novel fully automated CSF Aβ and tau assays perform comparably

to amyloid and tau PET respectively, though, as with PET, their

routine use in the diagnosis of dementia is debated. Blood-based

biomarkers for AD show promise as a less invasive screening tool

but remain under development (Chap. 431). Formal psychometric

testing helps to document the severity of cognitive disturbance,

suggests psychogenic causes, and provides a more formal method

for following the disease course. Electroencephalogram (EEG) is

not routinely used but can help to suggest CJD (repetitive bursts

of diffuse high-amplitude sharp waves, or “periodic complexes”)

or an underlying nonconvulsive seizure disorder (epileptiform discharges). Brain biopsy (including meninges) is not advised except

to diagnose vasculitis, neoplasms, or unusual infections when the

diagnosis is uncertain. Systemic disorders with CNS manifestations, such as sarcoidosis, can often be confirmed through biopsy

of lymph node or solid organ rather than brain. MR angiography

should be considered when cerebral vasculitis or cerebral venous

thrombosis is a possible cause of the dementia.

■ GLOBAL CONSIDERATIONS

Vascular dementia (Chap. 433) is more common in Asia due to the

higher prevalence of intracranial atherosclerosis. Rates of vascular

dementia are also on the rise in developing countries as vascular risk

factors such as hypertension, hypercholesterolemia, and diabetes mellitus become more widespread. CNS infections, HIV (and associated

opportunistic infections), syphilis, cysticercosis, and tuberculosis,

likewise represent major contributors to dementia in the developing

world. Systemic infection with SARS-CoV-2 may, in some individuals, have lasting effects on cognition due to involvement of brain

microvasculature or to immunologically mediated white matter injury

(acute disseminated encephalomyelitis [ADEM]) (Chap. 444). Some

individuals complain of lasting fatigue, changes in mood, and cognitive difficulties, but the long-term prognosis for SARS-CoV-2-related

cognitive impairment remains unknown. Isolated populations have

also contributed to our understanding of neurodegenerative dementia.

Kuru, the cannibalism-associated rapidly progressive dementia seen in

tribal New Guinea, played a role in the discovery of human prion disease. Amyotrophic lateral sclerosis-parkinsonism-dementia complex

of Guam (or, Lytico-bodig disease) is a poly-proteinopathy, often with

tau, TDP-43, and alpha-synuclein aggregation. The root cause of the

disease remains uncertain, but its incidence has declined sharply over

the past 60 years.

TREATMENT

Dementia

The major goals of dementia management are to treat reversible

causes and provide comfort and support to the patient and caregivers. Treatment of underlying causes includes thyroid replacement

for hypothyroidism; vitamin therapy for thiamine or B12 deficiency

or for elevated serum homocysteine; antimicrobials for opportunistic infections or antiretrovirals for HIV; ventricular shunting for

NPH; or surgical, radiation, and/or chemotherapeutic treatment for

CNS neoplasms. Removal of cognition-impairing drugs or medications is essential when appropriate. If the patient’s cognitive complaints stem from a psychiatric disorder, vigorous treatment of the

condition should be tried to eliminate the cognitive complaint or

to confirm that it persists despite adequate resolution of the mood

or anxiety symptoms. Patients with degenerative diseases may also

be depressed or anxious, and those aspects of their condition often

respond to therapy while not necessarily improving cognition.

Antidepressants, such as selective serotonin reuptake inhibitors

(SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs)

(Chap. 452), which feature anxiolytic properties but few cognitive

side effects, provide the mainstay of treatment when necessary.

Anticonvulsants are used to control AD-associated seizures.

Agitation, hallucinations, delusions, and confusion are difficult

to treat. These behavioral problems represent major causes for

nursing home placement and institutionalization. Before treating

these behaviors with medications, the clinician should aggressively

seek out modifiable environmental or metabolic factors. Hunger,

lack of exercise, toothache, constipation, urinary tract or respiratory infection, electrolyte imbalance, and drug toxicity all represent

easily correctable causes that can be remedied without psychoactive drugs. Drugs such as phenothiazines and benzodiazepines

may ameliorate the behavior problems but have untoward side

effects such as sedation, rigidity, or dyskinesia; benzodiazepines

can occasionally produce paradoxical disinhibition. Despite their

unfavorable side effect profile, second-generation antipsychotics

such as quetiapine (starting dose, 12.5–25 mg daily) can be used

for patients with agitation, aggression, and psychosis, although the

risk profile for these compounds is significant, including increased

mortality in patients with dementia. When patients do not respond

to treatment, it is usually a mistake to advance to higher doses or

to use anticholinergic drugs (like diphenhydramine) or sedatives

(such as barbiturates or benzodiazepines). It is important to recognize and treat depression; treatment can begin with a low dose of an

195Aphasia, Memory Loss, and Other Cognitive Disorders CHAPTER 30

SSRI (e.g., escitalopram, starting dose 5 mg daily, target dose 5–10 mg

daily) while monitoring for efficacy and toxicity. Sometimes apathy,

visual hallucinations, depression, and other psychiatric symptoms

respond to cholinesterase inhibitors, especially in DLB, obviating

the need for other more toxic therapies.

Cholinesterase inhibitors are being used to treat AD (donepezil,

rivastigmine, galantamine) and PDD (rivastigmine). Memantine is

useful for some patients with moderate to severe AD; its major benefit relates to decreasing caregiver burden, most likely by decreasing

resistance to dressing and grooming support. In moderate to severe

AD, the combination of memantine and a cholinesterase inhibitor

delayed nursing home placement in several studies, although other

studies have not supported the efficacy of adding memantine to

the regimen. Memantine should be used with great caution, or not

at all, in patients with DLB, due to risk of worsening agitation and

confusion. Therapies targeting the production, aggregation, and

spread of misfolded proteins associated with dementia are under

development. Recently the first drug in this class, the amyloid-beta

targeting monoclonal antibody aducanumab, was approved by the

United States Food & Drug Administration for treatment of Alzheimer’s disease (Chap. 431). Other drugs under development target

disease-associated neuroinflammation metabolic changes, synaptic

loss, and neurotransmitter changes.

Proactive approaches reduce the occurrence of delirium in hospitalized patients. Frequent orientation, cognitive activities, sleepenhancement measures, vision and hearing aids, and correction of

dehydration are all valuable in decreasing the likelihood of delirium.

Nondrug behavior therapy has an important place in dementia

management. The primary goals are to make the patient’s life comfortable, uncomplicated, and safe. Preparing lists, schedules, calendars, and labels can be helpful in the early stages. It is also useful

to stress familiar routines, walks, and simple physical exercises. For

many demented patients, memory for events is worse than their

ability to carry out routine activities, and they may still be able

to take part in their favorite hobbies, sports, and social activities.

Demented patients often object to losing control over familiar

tasks such as driving, cooking, and handling finances. Attempts to

help may be greeted with complaints, depression, or anger. Hostile

responses on the part of the caregiver are counterproductive and

sometimes even harmful. Reassurance, distraction, and calm positive statements are more productive when resistance is present.

Eventually, tasks such as finances and driving must be assumed by

others, and the patient will conform and adjust. Safety is an important issue that includes not only driving but controlling the kitchen,

bathroom, and sleeping area environments, as well as stairways.

These areas need to be monitored, supervised, and made as safe as

possible. A move to a retirement complex, assisted-living center,

or nursing home can initially increase confusion and agitation.

Repeated reassurance, reorientation, and careful introduction to the

new personnel will help to smooth the process. Providing activities

that are known to be enjoyable to the patient can also help.

The clinician must pay special attention to frustration and

depression among family members and caregivers. Caregiver guilt

and burnout are common. Family members often feel overwhelmed

and helpless and may vent their frustrations on the patient, each

other, and health care providers. Caregivers should be encouraged

to take advantage of day-care facilities and respite services. Education and counseling about dementia are important. Local and

national support groups, such as the Alzheimer’s Association (www.

alz.org), can provide considerable help.

■ FURTHER READING

Barton C et al: Non-pharmacological management of behavioral

symptoms in frontotemporal and other dementias. Curr Neurol Neurosci Rep 16:14, 2016.

Griem J et al: Psychologic/functional forms of memory disorder.

Handb Clin Neurol 139:407, 2017.

Wesley SF, Ferguson D: Autoimmune encephalitides and rapidly

progressive dementias. Semin Neurol 39:283, 2019.

The cerebral cortex of the human brain contains ~20 billion neurons

spread over an area of 2.5 m2

. The primary sensory and motor areas

constitute 10% of the cerebral cortex. The rest is subsumed by modalityselective, heteromodal, paralimbic, and limbic areas collectively known

as the association cortex (Fig. 30-1). The association cortex mediates

the integrative processes that subserve cognition, emotion, and comportment. A systematic testing of these mental functions is necessary

for the effective clinical assessment of the association cortex and

its diseases. According to current thinking, there are no centers for

“hearing words,” “perceiving space,” or “storing memories.” Cognitive

30 Aphasia, Memory Loss,

and Other Cognitive

Disorders

M.-Marsel Mesulam

FIGURE 30-1 Lateral (top) and medial (bottom) views of the cerebral hemispheres.

The numbers refer to the Brodmann cytoarchitectonic designations. Area 17

corresponds to the primary visual cortex, 41–42 to the primary auditory cortex, 1–3

to the primary somatosensory cortex, and 4 to the primary motor cortex. The rest of

the cerebral cortex contains association areas. AG, angular gyrus; B, Broca’s area;

CC, corpus callosum; CG, cingulate gyrus; DLPFC, dorsolateral prefrontal cortex; FEF,

frontal eye fields (premotor cortex); FG, fusiform gyrus; IPL, inferior parietal lobule;

ITG, inferior temporal gyrus; LG, lingual gyrus; MPFC, medial prefrontal cortex; MTG,

middle temporal gyrus; OFC, orbitofrontal cortex; PHG, parahippocampal gyrus;

PPC, posterior parietal cortex; PSC, peristriate cortex; SC, striate cortex; SMG,

supramarginal gyrus; SPL, superior parietal lobule; STG, superior temporal gyrus;

STS, superior temporal sulcus; TP, temporopolar cortex; W, Wernicke’s area.