Harrison's Neurology in Clinical Medicine, 4e

CHAPTER 21: DEMENTIA

William W. Seeley; Bruce L. Miller

INTRODUCTION

Dementia, a syndrome with many causes, affects >5 million people in the United States and results in a total annual health care cost between $157 and $215 billion. Dementia is defined as an acquired deterioration in cognitive abilities that impairs the successful performance of activities of daily living. Episodic memory, the ability to recall events specific in time and place, is the cognitive function most commonly lost; 10% of persons age >70 years and 20–40% of individuals age >85 years have clinically identifiable memory loss. In addition to memory, dementia may erode other mental faculties, including language, visuospatial, praxis, calculation, judgment, and problem-solving abilities. Neuropsychiatric and social deficits also arise in many dementia syndromes, manifesting as depression, apathy, anxiety, hallucinations, delusions, agitation, insomnia, sleep disturbances, compulsions, or disinhibition. The clinical course may be slowly progressive, as in Alzheimer’s disease (AD); static, as in anoxic encephalopathy; or may fluctuate from day to day or minute to minute, as in dementia with Lewy bodies. Most patients with AD, the most prevalent form of dementia, begin with episodic memory impairment, although in other dementias, such as frontotemporal dementia, memory loss is not typically a presenting feature. Focal cerebral disorders are discussed in Chap. 22 and illustrated in a video library in Chap. 23; the pathogenesis of AD and related disorders is discussed in Chap. 35.

FUNCTIONAL ANATOMY OF THE DEMENTIAS

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Dementia syndromes result from the disruption of specific large-scale neuronal networks; the location and severity of synaptic and neuronal loss combine to produce the clinical features (Chap. 22). Behavior, mood, and attention are modulated by ascending noradrenergic, serotonergic, and dopaminergic pathways, whereas cholinergic signaling is critical for attention and memory functions. The dementias differ in the relative neurotransmitter deficit profiles; accordingly, accurate diagnosis guides effective pharmacologic therapy.

AD begins in the entorhinal region of the medial temporal lobe, spreads to the hippocampus, and then moves to lateral and posterior temporal and parietal neocortex, eventually causing a more widespread degeneration. Vascular dementia is associated with focal damage in a variable patchwork of cortical and subcortical regions or white matter tracts that disconnect nodes within distributed networks. In keeping with its anatomy, AD typically presents with episodic memory loss accompanied later by aphasia or navigational problems. In contrast, dementias that begin in frontal or subcortical regions, such as frontotemporal dementia (FTD) or Huntington’s disease (HD), are less likely to begin with memory problems and more likely to present with difficulties with judgment, mood, executive control, movement, and behavior.

Lesions of frontal-striatal¹ pathways produce specific and predictable effects on behavior. The dorsolateral prefrontal cortex has connections with a central band of the caudate nucleus. Lesions of either the caudate or dorsolateral prefrontal cortex, or their connecting white matter pathways, may result in executive dysfunction, manifesting as poor organization and planning, decreased cognitive flexibility, and impaired working memory. The lateral orbital frontal cortex connects with the ventromedial caudate, and lesions of this system cause impulsiveness, distractibility, and disinhibition. The anterior cingulate cortex and adjacent medial prefrontal cortex project to the nucleus accumbens, and interruption of this system produces apathy, poverty of speech, emotional blunting, or even akinetic mutism. All corticostriatal systems also include topographically organized projections through the globus pallidus and thalamus, and damage to these nodes can likewise reproduce the clinical syndrome of cortical or striatal injury.

THE CAUSES OF DEMENTIA

The single strongest risk factor for dementia is increasing age. The prevalence of disabling memory loss increases with each decade over age 50 and is usually associated with the microscopic changes of AD at autopsy. Yet some centenarians have intact memory function and no evidence of clinically significant dementia. Whether dementia is an inevitable consequence of normal human aging remains controversial.

The many causes of dementia are listed in Table 21-1. 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 considered 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, 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) (Chap. 36) are common and may develop years after onset of a parkinsonian disorder, as seen with PD-related dementia (PDD), or can occur concurrently with or preceding the motor syndrome, as in dementia with Lewy bodies (DLB). 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 21-1 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.

TABLE 21-1^aDIFFERENTIAL DIAGNOSIS OF DEMENTIA

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TABLE 21-1DIFFERENTIAL DIAGNOSIS OF DEMENTIA

Most Common Causes of Dementia

Alzheimer’s disease

Alcoholism^a

Vascular dementia

PDD/LBD spectrum

Multi-infarct

Drug/medication intoxication^a

Diffuse white matter disease (Binswanger’s)

Less Common Causes of Dementia

Vitamin deficiencies
- Thiamine (B₁): Wernicke’s encephalopathy^a
- B₁₂ (subacute combined degeneration)^a
- Nicotinic acid (pellagra)^a
Endocrine and other organ failure
- Hypothyroidism^a
- Adrenal insufficiency and Cushing’s syndrome^a
- Hypo- and hyperparathyroidism^a
- Renal failure^a
- Liver failure^a
- Pulmonary failure^a
Chronic infections
- HIV
- Neurosyphilis^a
- Papovavirus (JC virus) (progressive multifocal leukoencephalopathy)
- Tuberculosis, fungal, and protozoal^a
- Whipple’s disease^a
Head trauma and diffuse brain damage
- Chronic traumatic encephalopathy
- Chronic subdural hematoma^a
- Postanoxia
- Postencephalitis
- Normal-pressure hydrocephalus^a
Intracranial hypotension
Neoplastic
- Primary brain tumor^a
- Metastatic brain tumor^a
- Paraneoplastic/autoimmune limbic encephalitis^a

Toxic disorders
- Drug, medication, and narcotic poisoning^a
- Heavy metal intoxication^a
- Organic toxins
Psychiatric
- Depression (pseudodementia)^a
- Schizophrenia^a
- Conversion disorder^a
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
- Sarcoidosis^a
- Vasculitis^a
- CADASIL, etc.
- Acute intermittent porphyria^a
- Recurrent nonconvulsive seizures^a
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)

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.

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 21-1).

Subtle cumulative decline in episodic memory is a common part of aging. This frustrating experience, often the source of jokes and humor, is referred to as benign forgetfulness of the elderly. Benign means that it is not so progressive or serious that it impairs reasonably successful and productive daily functioning, although the distinction between benign and more significant memory loss can be difficult to make. 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. A measurable cognitive problem that does not seriously disrupt daily activities is often referred to as mild cognitive impairment (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 deposition on positron emission tomography (PET) imaging.

The major degenerative dementias include AD, DLB, FTD and related disorders, HD, and prion diseases, including Creutzfeldt-Jakob disease (CJD). These disorders are all 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 fused in sarcoma (FUS) in FTD; huntingtin in HD; and misfolded prion protein (PrP^sc) in CJD (Table 21-2).

TABLE 21-2THE MOLECULAR BASIS FOR DEGENERATIVE DEMENTIA

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TABLE 21-2THE MOLECULAR BASIS FOR DEGENERATIVE DEMENTIA

DEMENTIA

MOLECULAR BASIS

CAUSAL GENES (CHROMOSOME)

SUSCEPTIBILITY GENES

PATHOLOGIC FINDINGS

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

TDP-43 neuronal and glial inclusions varying in morphology and distribution

FUS

Very rare FUS

FUS neuronal and glial inclusions varying in morphology and distribution

DLB

α-Synuclein

Very rare SNCA (4)

Unknown

α-Synuclein neuronal inclusions (Lewy bodies)

CJD

PrP^SC

PRNP (20) (up to 15% of patients carry these dominant mutations)

Codon 129 homozygosity for methionine or valine

PrP^SC deposition, panlaminar spongiosis

Abbreviations: AD, Alzheimer’s disease; CJD, Creutzfeldt-Jakob disease; DLB, dementia with Lewy bodies; FTD, frontotemporal dementia.

APPROACH TO PATIENT

APPROACH TO THE PATIENT: Dementias

Three major issues should be kept at the forefront: (1) What is the best fit for a 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 21-3. The major degenerative dementias can usually be distinguished by the initial symptoms; neuropsychological, neuropsychiatric, and neurologic findings; and neuroimaging features (Table 21-4).

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. 18) and should trigger the 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 difficulty with 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 and by a 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; the loss of skeletal muscle paralysis during dreaming); 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, 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 putative 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. 40). 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, chronic traumatic encephalopathy (a progressive dementia best characterized in contact sport athletes such as boxers and American football players), intracranial hypotension, or NPH. Subacute onset of severe amnesia and psychosis with mesial temporal T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities on magnetic resonance imaging (MRI) should raise concern for paraneoplastic limbic encephalitis, especially in a long-term smoker or other patients at risk for cancer. Related autoimmune conditions, such as voltage-gated potassium channel (VGKC)- or N-methyl-d-aspartate (NMDA)-receptor antibody-mediated encephalopathy, can present with a similar tempo and imaging signature with or without characteristic motor manifestations such as myokymia (anti-VGKC) and faciobrachial dystonic seizures (anti-NMDA). Alcohol abuse creates risk for malnutrition and thiamine deficiency. Veganism, bowel irradiation, an autoimmune diathesis, a remote history of gastric surgery, and chronic antihistamine therapy 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 disorders, the recent death of a loved one, or depressive signs, such as insomnia or weight loss, raise the possibility of depression-related cognitive impairments.

PHYSICAL AND NEUROLOGIC EXAMINATION

A thorough general and neurologic examination is essential to document dementia, to look for other signs of nervous system involvement, and to search for clues suggesting a systemic disease that might be responsible for the cognitive disorder. Typical AD spares motor systems until later in the course. In contrast, FTD patients 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 the new onset of a parkinsonian syndrome (resting tremor, cogwheel rigidity, bradykinesia, festinating gait), but DLB often starts with visual hallucinations or dementia. 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 startle-sensitive 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), and Cognistat can be used to capture dementia and follow progression. None of these tests is highly sensitive to early-stage dementia or 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 in the areas 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 if’s and’s or but’s”; 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) function, but some patients lack either finding despite profound social-emotional deficits. PDD or DLB patients have more severe deficits in visuospatial function but do better on episodic memory tasks than patients with AD. Patients with vascular dementia often demonstrate a mixture of executive control and visuospatial deficits, with prominent psychomotor slowing. In delirium, the most prominent deficits involve attention, working 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, euphoria, 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 21-3 lists most screening tests for dementia. The American Academy of Neurology recommends the routine measurement of a complete blood count, electrolytes, renal and thyroid function, a vitamin B₁₂ level, and a neuroimaging study (computed tomography [CT] or MRI).

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. 21-1). Focal frontal, insular, and/or anterior temporal atrophy suggests FTD (Chap. 35). DLB often features less prominent atrophy, with greater involvement of amygdala than hippocampus. In CJD, magnetic resonance (MR) diffusion-weighted imaging reveals restricted diffusion within the cortical ribbon and basal ganglia in most patients. Extensive white matter abnormalities correlate with a vascular etiology (Fig. 21-2). Communicating hydrocephalus with vertex effacement (crowding of dorsal convexity gyri/sulci), gaping Sylvian fissures despite minimal cortical atrophy, and additional features shown in Fig. 21-3 suggest NPH. Single-photon emission computed tomography (SPECT) and PET scanning show temporal-parietal hypoperfusion or hypometabolism in AD and frontotemporal deficits in FTD, but these changes often reflect atrophy and can therefore be detected with MRI alone in many patients. Recently, amyloid imaging has shown promise for the diagnosis of AD, and Pittsburgh Compound-B (PiB) (not available outside of research settings) and ¹⁸F-AV-45 (florbetapir; approved by the U.S. Food and Drug Administration in 2013) are reliable radioligands for detecting brain amyloid associated with amyloid angiopathy or neuritic plaques of AD (Fig. 21-4). Because these abnormalities can be seen in cognitively normal older persons, however (~25% of individuals at age 65), amyloid imaging may also detect preclinical or incidental AD in patients lacking an AD-like dementia syndrome. Currently, the main clinical value of amyloid imaging is to exclude AD as the likely cause of dementia in patients who have negative scans. Once disease-modifying therapies become available, use of these biomarkers may help to identify treatment candidates before irreversible brain injury has occurred. In the meantime, the significance of detecting brain amyloid in an asymptomatic elder remains a topic of vigorous investigation. Similarly, MRI perfusion and structural/functional connectivity methods are being explored as potential treatment-monitoring strategies.

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 and mildly elevated CSF tau is highly suggestive of AD. The routine use of lumbar puncture in the diagnosis of dementia is debated, but the sensitivity and specificity of AD diagnostic measures are not yet high enough to warrant routine use. Formal psychometric testing helps to document the severity of cognitive disturbance, suggest psychogenic causes, and provide 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, potentially treatable neoplasms, or unusual infections when the diagnosis is uncertain. Systemic disorders with CNS manifestations, such as sarcoidosis, can usually 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.

TABLE 21-3

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TABLE 21-3

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

Lab screen for autoantibodies

DIAGNOSTIC CATEGORIES

REVERSIBLE CAUSES

IRREVERSIBLE/DEGENERATIVE DEMENTIAS

PSYCHIATRIC DISORDERS

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).

TABLE 21-4CLINICAL DIFFERENTIATION OF THE MAJOR DEMENTIAS

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TABLE 21-4CLINICAL DIFFERENTIATION OF THE MAJOR DEMENTIAS

DISEASE

FIRST SYMPTOM

MENTAL STATUS

NEUROPSYCHIATRY

NEUROLOGY

IMAGING

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; PSP, progressive supranuclear palsy; REM, rapid eye movement.

FIGURE 21-1

Alzheimer’s disease (AD). Axial T1-weighted magnetic resonance images of a healthy 71-year-old (A) and a 64-year-old with AD (C). Note the reduction in medial temporal lobe volume in the patient with AD. Fluorodeoxyglucose positron emission tomography scans of the same individuals (B and D) demonstrate reduced glucose metabolism in the posterior temporoparietal regions bilaterally in AD, a typical finding in this condition. HC, healthy control. (Images courtesy of Gil Rabinovici, University of California, San Francisco and William Jagust, University of California, Berkeley.)

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FIGURE 21-2

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.

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FIGURE 21-3

Normal-pressure hydrocephalus. A. Sagittal T1-weighted magnetic resonance image (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.

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FIGURE 21-4

Positron emission tomography (PET) images obtained with the amyloid-imaging agent Pittsburgh Compound-B ([¹¹C]PIB) in a normal control (left); three different patients with mild cognitive impairment (MCI; center); and a patient with mild Alzheimer’s disease (AD; right). Some MCI patients have control-like levels of amyloid, some have AD-like levels of amyloid, and some have intermediate levels. (Images courtesy of William Klunk and Chester Mathis, University of Pittsburgh.)

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TREATMENT

TREATMENT: Dementia

The major goals of dementia management are to treat reversible causes and to 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 appropriate surgical, radiation, and/or chemotherapeutic treatment for CNS neoplasms. Removal of cognition-impairing drugs or medications is frequently useful. If the patient’s cognitive complaints stem from a psychiatric disorder, vigorous treatment of this condition should seek to eliminate the cognitive complaint or 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. Antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) (Chap. 60), which feature anxiolytic properties but few cognitive side effects, provide the mainstay of treatment when necessary. Anticonvulsants are used to control seizures. Levetiracetam may be particularly useful, but there have as yet been no randomized trials for treatment of 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, dyskinesia, and occasionally paradoxical disinhibition (benzodiazepines). 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. When patients do not respond to treatment, it is usually a mistake to advance to higher doses or to use anticholinergic drugs or sedatives (such as barbiturates or benzodiazepines). It is important to recognize and treat depression; treatment can begin with a low dose of an 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 the 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). Recent work has focused on developing antibodies against Aβ₄₂ as a treatment for AD. Although the initial randomized controlled trials failed, there was some evidence for efficacy in the mildest patient groups. Therefore, researchers have begun to focus on patients with very mild disease and asymptomatic individuals at risk for AD, such as those who carry autosomal dominantly inherited genetic mutations or healthy elders with CSF or amyloid imaging biomarker evidence supporting presymptomatic AD. Memantine proves useful when treating 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.

A proactive strategy has been shown to reduce the occurrence of delirium in hospitalized patients. This strategy includes frequent orientation, cognitive activities, sleep-enhancement measures, vision and hearing aids, and correction of dehydration.

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 activities such as walking, bowling, dancing, singing, bingo, and golf. Demented patients often object to losing control over familiar tasks such as driving, cooking, and handling finances. Attempts to help or take over 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 in this setting. 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 be of considerable benefit.

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.

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CHAPTER 21: DEMENTIA

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INTRODUCTION

FUNCTIONAL ANATOMY OF THE DEMENTIAS

THE CAUSES OF DEMENTIA

APPROACH TO PATIENT

FIGURE 21-1

FIGURE 21-2

FIGURE 21-3

FIGURE 21-4

TREATMENT

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