William W. Seeley Bruce L. Miller
Dementia, a syndrome with many causes, affects >4 million Americans and results in a total health care cost of >$100 billion annually. It is defined as an acquired deterioration in cognitive abilities that impairs the successful performance of activities of daily living. Memory is the most common cognitive ability lost with dementia; 10% of persons >70 and 20–40% of individuals >85 have clinically identifiable memory loss. In addition to memory, other mental faculties may be affected; these include language, visuospatial ability, calculation, judgment, and problem solving. Neuropsychiatric and social deficits also arise in many dementia syndromes, resulting in depression, apathy, hallucinations, delusions, agitation, insomnia, and disinhibition. The most common forms of dementia are progressive, but some are static and unchanging or fluctuate from day to day or even minute to minute. Most patients with Alzheimer’s disease (AD), the most prevalent form of dementia, begin with memory impairment, although in other dementias, such as frontotemporal dementia, memory loss is not a presenting feature. Focal cerebral disorders are discussed in Chap. 18 and illustrated in a video library in Chap. 19.
FUNCTIONAL ANATOMY OF THE DEMENTIAS
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. 18). Behavior and mood are modulated by 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 pharmacotherapy.
AD begins in the transentorhinal region, 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 random patchwork of cortical and subcortical regions or white matter tracts that disconnect nodes within distributed networks. In keeping with the anatomy, AD typically presents with memory loss accompanied later by aphasia or navigational problems. In contrast, patients with 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 have difficulties with judgment, mood, and behavior.
Lesions of cortical-striatal pathways produce specific effects on behavior. The dorsolateral prefrontal cortex bears connections with a central band of the caudate. Lesions of either node or connecting white matter pathways result in poor organization and planning, decreased cognitive flexibility, and impaired working memory. The lateral orbital frontal cortex connects with the ventrome-dial caudate. Lesions of this system cause impulsiveness, distractibility, and disinhibition. The anterior cingulate cortex projects to the nucleus accumbens, and interruption of these connections produces apathy, poverty of speech, or even akinetic mutism. All corticostriatal systems also include topographically organized projections through the pallidum and thalamus, and damage to these nodes can likewise reproduce the clinical syndrome of corticostriatal damage.
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 29-1. The frequency of each condition depends on the age group under study, the access of the group to medical care, the 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 under-treated. Often, vascular disease is mixed with other 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 related to Parkinson’s disease (PD) are extremely common, and temporally can follow a parkinsonian disorder as seen with PD-related dementia (PDD) or can occur concurrently with or preceding the motor syndrome as with 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 the table 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.
DIFFERENTIAL DIAGNOSIS OF 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. The three most common potentially reversible diagnoses were depression, hydro-cephalus, and alcohol dependence (Table 29-1).
Subtle cumulative decline in episodic memory is a natural 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 the number of items (e.g., words on a list) that he or she could at age 18. A measurable cognitive problem that does not disrupt daily activities is often referred to as mild cognitive impairment (MCI). Factors that predict progression from MCI to AD include a prominent memory deficit, family history of dementia, presence of an apolipoprotein ε4 (Apo ε4) allele, small hippocampal volumes, and AD-like signature of cortical atrophy, low cerebrospinal fluid Aβ and elevated tau or positive amyloid imaging with Pittsburgh Compound-B (PiB), although the latter remains an experimental approach not yet available for routine clinical use.
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 43kDa (TDP-43), or fused in sarcoma (FUS) in FTD; huntingtin in HD; and misfolded prion protein (PrPsc) in CJD (Table 29-2).
THE MOLECULAR BASIS FOR DEGENERATIVE DEMENTIA
APPROACH TO THE
Three major issues should be kept at the forefront: (1) What is the most accurate diagnosis? (2) Is there a treatable or reversible component to the dementia? (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).
EVALUATION OF THE PATIENT WITH DEMENTIA
CLINICAL DIFFERENTIATION OF THE MAJOR DEMENTIAS
HISTORY The history should concentrate on the onset, duration, and tempo of progression. An acute or subacute onset of confusion may represent delirium 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. A personality change, disinhibition, and weight gain or compulsive eating suggest FTD, not AD. FTD is also suggested by prominent apathy, compulsivity, or progressive loss of speech fluency or word comprehension, and by a relative sparing of memory or visuospatial abilities. The diagnosis of DLB is suggested by early visual hallucinations; parkinsonism; brittle proneness to delirium or sensitivity to psychoactive medications; 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 as many of the risk factors for vascular dementia, including diabetes, high cholesterol, elevated homocysteine, and low exercise, are also risk factors for AD. Rapid progression with motor rigidity and myoclonus suggests CJD. 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 normal-pressure hydrocephalus (NPH). A prior history of high-risk sexual behaviors or intravenous drug use should trigger a search for central nervous system (CNS) infection, especially for HIV or syphilis. A history of recurrent head trauma could indicate chronic subdural hematoma, dementia pugilistica, or NPH. Subacute onset of severe amnesia and psychosis with mesial temporal T2 hyperintensities on MRI should raise concern for paraneoplastic limbic encephalitis, especially in a long-term smoker or other patients at risk for cancer. Related nonparaneo-plastic autoimmune conditions can present with a similar tempo and imaging signature. Alcoholism creates risk for malnutrition and thiamine deficiency. Veganism, bowel irradiation, an autoimmune diathesis, or a remote history of gastric surgery can result in B12deficiency. 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. The recent death of a loved one, or depressive signs such as insomnia or weight loss, raises 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 does not affect 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 often starts with visual hallucinations or dementia. Symptoms referable to the lower brainstem (RBD, gastrointestinal or autonomic problems) may arise years before parkinsonism or dementia. Corticobasal syndrome (CBS) features asymmetric akinesia and rigidity, dystonia, myoclonus, alien limb phenomena, and pyramidal or cortical sensory deficits. Associated cognitive features include 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. Hearing impairment or visual loss may produce confusion and disorientation misinterpreted as dementia. Such sensory deficits are common in the elderly but can be a manifestation of mitochondrial disorders.
COGNITIVE AND NEUROPSYCHIATRIC EXAMINATION Brief screening tools such as the minimental status examination (MMSE) help to confirm the presence of cognitive impairment and to follow the progression of dementia (Table 29-5). The MMSE, a simple 30-point test of cognitive function, contains tests of orientation, working memory (e.g., spell world backwards), episodic memory (orientation and 3-word recall), language comprehension, naming, and figure copying. In most patients with MCI and some with clinically apparent AD, the MMSE may be normal and a more rigorous 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 one 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 or language (speech or naming) function. 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 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.
THE MINI-MENTAL STATUS EXAMINATION
A functional assessment should also be performed. The physician should 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 day-to-day function 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 skills into the middle or late stages, when delusions, agitation, and sleep disturbance may emerge. In FTD, dramatic personality change featuring 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 primary arousal, such that caregivers may seek emergency room evaluation for suspected stroke. 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. The physician must take measures to avoid missing a reversible or treatable cause, yet no single treatable etiology is common; thus, a screen must employ 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 probably 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 thyroid function, a vitamin B12 level, and a neuroimaging study (CT or MRI).
Neuroimaging studies help to rule out primary and metastatic neoplasms, locate areas of infarction, 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. Focal frontal and/or anterior temporal atrophy suggests FTD. DLB often features less prominent atrophy, with greater involvement of amygdala than hippocampus. In CJD, MR diffusion-weighted imaging reveals abnormalities in the cortical ribbon and basal ganglia in the majority of patients. Extensive white matter abnormalities correlate with a vascular etiology for dementia. The role of functional-metabolic imaging in the diagnosis of dementia is still under study, although the Federal Drug Administration has approved the use of positron emission tomography (PET) in dementia differential diagnosis. 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) and 18F-AV-45 appear to be reliable radioligands for detecting brain amyloid associated with amyloid angiopathy or neuritic plaques (Fig. 29-1). Because these abnormalities can be seen in cognitively normal older persons, however, amyloid imaging may detect preclinical or incidental AD in patients lacking an AD-like dementia syndrome. Once powerful disease-modifying therapies become available, use of these biomarkers may help to identify treatment candidates before irreversible brain injury has occurred. In the meantime, however, the significance of detecting brain amyloid in an asymptomatic elder remains a topic of vigorous investigation. Similarly, MRI perfusion and functional connectivity methods are being explored as potential treatment-monitoring strategies.
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 mild AD patient (right). Some MCI patients have control-like levels of amyloid, some have AD-like levels of amyloid, and some have intermediate levels. AD, Alzheimer’s disease; MCI, mild cognitive impairment; PET, positron emission tomography.
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 tau protein and Aβ42 show differing patterns with the various dementias; however, the sensitivity and specificity of these measures are not yet sufficiently high to warrant routine use. Formal psychometric testing, although not necessary in every patient with dementia, 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 rarely helpful except 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. Angiography should be considered when cerebral vasculitis or cerebral venous thrombosis is a possible cause of the dementia.
Approximately 10% of all persons over the age of 70 have significant memory loss, and in more than half the cause is AD. It is estimated that the annual total cost of caring for a single AD patient in an advanced stage of the disease is >$50,000. The disease also exacts a heavy emotional toll on family members and caregivers. AD can occur in any decade of adulthood, but it is the most common cause of dementia in the elderly. AD most often presents with an insidious onset of memory loss followed by a slowly progressive dementia over several years. Pathologically, atrophy is distributed throughout the medial temporal lobes, as well as lateral and medial parietal lobes and lateral frontal cortex. Microscopically, there are neuritic plaques containing Aβ, neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau filaments, and accumulation of amyloid in blood vessel walls in cortex and leptomeninges (see “Pathology”). The identification of four different susceptibility genes for AD has provided a foundation for rapid progress in understanding the biologic basis of the disorder.
The cognitive changes of AD tend to follow a characteristic pattern, beginning with memory impairment and spreading to language and visuospatial deficits. Yet, approximately 20% of patients with AD present with nonmemory complaints such as word-finding, organizational, or navigational difficulty. In the early stages of the disease, the memory loss may go unrecognized or be ascribed to benign forgetfulness. Once the memory loss becomes noticeable to the patient and spouse and falls 1.5 standard deviations below normal on standardized memory tests, the term MCI is applied. This construct provides useful prognostic information, because approximately 50% of patients with MCI (roughly 12% per year) will progress to AD over 4 years. Slowly the cognitive problems begin to interfere with daily activities, such as keeping track of finances, following instructions on the job, driving, shopping, and housekeeping. Some patients are unaware of these difficulties (anosognosia), while others remain acutely attuned to their deficits. Changes in environment (such as vacations or hospital stays) may be disorienting, and the patient may become lost on walks or while driving. In the middle stages of AD, the patient is unable to work, is easily lost and confused, and requires daily supervision. Social graces, routine behavior, and superficial conversation may be surprisingly intact. Language becomes impaired—first naming, then comprehension, and finally fluency. In some patients, aphasia is an early and prominent feature. Word-finding difficulties and circumlocution may be a problem even when formal testing demonstrates intact naming and fluency. Apraxia emerges, and patients have trouble performing learned sequential motor tasks. Visuospatial deficits begin to interfere with dressing, eating, or even walking, and patients fail to solve simple puzzles or copy geometric figures. Simple calculations and clock reading become difficult in parallel.
In the late stages of the disease, some persons remain ambulatory but wander aimlessly. Loss of judgment and reasoning is inevitable. Delusions are common and usually simple, with common themes of theft, infidelity, or misidentification. Approximately 10% of AD patients develop Capgras’ syndrome, believing that a caregiver has been replaced by an impostor. In contrast to DLB, where Capgras’ syndrome is an early feature, in AD this syndrome emerges later. Loss of inhibitions and aggression may occur and alternate with passivity and withdrawal. Sleep-wake patterns are disrupted, and nighttime wandering becomes disturbing to the household. Some patients develop a shuffling gait with generalized muscle rigidity associated with slowness and awkwardness of movement. Patients often look parkinsonian (Chap. 30) but rarely have a high-amplitude, rhythmic, resting tremor. In end-stage AD, patients become rigid, mute, incontinent, and bedridden. Help is needed with eating, dressing, and toileting. Hyperactive tendon reflexes and myoclonic jerks (sudden brief contractions of various muscles or the whole body) may occur spontaneously or in response to physical or auditory stimulation. Generalized seizures may also occur. Often death results from malnutrition, secondary infections, pulmonary emboli, heart disease, or, most commonly, aspiration. The typical duration of AD is 8–10 years, but the course can range from 1 to 25 years. For unknown reasons, some AD patients show a steady decline in function, while others have prolonged plateaus without major deterioration.
Early in the disease course, other etiologies of dementia should be excluded (Table 29-1). Neuroimaging studies (CT and MRI) do not show a single specific pattern with AD and may be normal early in the course of the disease. As AD progresses, more distributed but usually posterior-predominant cortical atrophy becomes apparent, along with atrophy of the medial temporal memory structures (Fig. 29-2A, B). The main purpose of imaging is to exclude other disorders, such as primary and secondary neoplasms, vascular dementia, diffuse white matter disease, and NPH; it also helps to distinguish AD from other degenerative disorders with distinctive imaging patterns such as FTD or CJD. Functional imaging studies in AD reveal hypoperfusion or hypometabolism in the posterior temporal-parietal cortex (Fig. 29-2C, D). The EEG in AD is normal or shows nonspecific slowing. Routine spinal fluid examination is also normal. CSF Aβ42 levels are reduced, whereas levels of hyperphosphorylated tau protein are elevated, but the considerable overlap of these levels with those of the normal aged population limits the usefulness of these measurements in diagnosis. The use of blood ApoE genotyping is discussed under “Pathology.” Slowly progressive decline in memory and orientation, normal results on laboratory tests, and an MRI or CT scan showing only distributed or posteriorly predominant cortical and hippocampal atrophy is highly suggestive of AD. A clinical diagnosis of AD reached after careful evaluation is confirmed at autopsy about 90% of the time, with misdiagnosed cases usually representing one of the other dementing disorders described later in this chapter, a mixture of AD with vascular pathology, or DLB.
Alzheimer’s disease. Axial T1-weighted MR images through the midbrain of a normal 86-year-old athlete (A) and a 77-year-old man with AD (B). Note that both individuals have mild sulcal widening and slight dilation of the temporal horns of the lateral ventricles. However, there is a reduction in hippocampal volume in the patient with AD (arrows) compared with the volume of the normal-for-age hippocampus (A). Fluorodeoxyglucose PET scans of a normal control (C) and a patient with AD (D). Note that the patient with AD shows decreased glucose metabolism in the posterior temporoparietal regions bilaterally (arrows), a typical finding in this condition. AD, Alzheimer’s disease; PET, positron emission tomography. (Images courtesy of TF Budinger, University of California.)
Simple clinical clues are useful in the differential diagnosis. Early prominent gait disturbance with only mild memory loss suggests vascular dementia or, rarely, NPH (see later). Resting tremor with stooped posture, brady-kinesia, and masked facies suggest PD (Chap. 30). When dementia occurs after a well-established diagnosis of PD, PDD is usually the correct diagnosis. The early appearance of parkinsonian features in association with fluctuating alertness, visual hallucinations, or delusional misidentification suggests DLB. Chronic alcoholism should prompt the search for vitamin deficiency. Loss of sensibility to position and vibration stimuli accompanied by Babinski responses suggests vitamin B12 deficiency (Chap. 35). Early onset of a focal seizure suggests a metastatic or primary brain neoplasm (Chap. 37). Previous or ongoing depression raises suspicion for depression-related cognitive impairment, although AD can feature a depressive prodrome. A history of treatment for insomnia, anxiety, psychiatric disturbance, or epilepsy suggests chronic drug intoxication. Rapid progression over a few weeks or months associated with rigidity and myoclonus suggests CJD (Chap. 43). Prominent behavioral changes with intact navigation and focal anterior-predominant atrophy on brain imaging are typical of FTD. A positive family history of dementia suggests either one of the familial forms of AD or one of the other genetic disorders associated with dementia, such as HD (see later), FTD (see later), prion disease (Chap. 43), or rare hereditary ataxias (Chap. 31).
The most important risk factors for AD are old age and a positive family history. The frequency of AD increases with each decade of adult life, reaching 20–40% of the population over the age of 85. A positive family history of dementia suggests a genetic cause of AD, although autosomal dominant inheritance occurs in only 2% of patients with AD. Female sex may also be a risk factor independent of the greater longevity of women. Some AD patients have a past history of head trauma with concussion. AD is more common in groups with low educational attainment, but education influences test-taking ability, and it is clear that AD can affect persons of all intellectual levels. One study found that the capacity to express complex written language in early adulthood correlated with a decreased risk for AD. Numerous environmental factors, including aluminum, mercury, and viruses, have been proposed as causes of AD, but none has been demonstrated to play a significant role. Similarly, several studies suggest that the use of nonsteroidal anti-inflammatory agents is associated with a decreased risk of AD, but this has not been confirmed in large prospective studies. Vascular disease, and stroke in particular, seems to lower the threshold for the clinical expression of AD. Also, in many patients with AD, amyloid angiopathy can lead to microhemorrhages, large lobar hemorrhages, or ischemic infarctions. Diabetes increases the risk of AD threefold. Elevated homocysteine and cholesterol levels; hypertension; diminished serum levels of folic acid; low dietary intake of fruits, vegetables, and red wine; and low levels of exercise are all being explored as potential risk factors for AD.
At autopsy, the earliest and most severe degeneration is usually found in the medial temporal lobe (entorhinal/perirhinal cortex and hippocampus), lateral temporal cortex, and nucleus basalis of Meynert. The characteristic microscopic findings are neuritic plaques and NFTs. These lesions accumulate in small numbers during normal brain aging but dominate the picture in AD. Increasing evidence suggests that soluble amyloid species called oligomersmay cause cellular dysfunction and represent the early toxic molecule in AD. Eventually, further amyloid polymerization and fibril formation lead to neuritic plaques (Fig. 29-3), which contain a central amyloid core, proteoglycans, Apo ε4, α-antichymotrypsin, and other proteins. Aβ is a protein of 39–42 amino acids that is derived proteolytically from a larger transmembrane protein, amyloid precursor protein (APP), when APP is cleaved by β and γ secretases. The normal function of Aβ is unknown. APP has neurotrophic and neuroprotective properties. The plaque core is surrounded by a halo, which contains dystrophic, tau-immunoreactive neurites and activated microglia. The accumulation of Aβ in cerebral arterioles is termed amyloid angiopathy. NFTs are composed of silver-staining neuronal cytoplasmic fibrils composed of abnormally phosphorylated tau (τ) protein; they appear as paired helical filaments by electron microscopy. Tau binds to and stabilizes microtubules, supporting axonal transport of organelles, glycoproteins, neurotransmitters, and other important cargoes throughout the neuron. Once hyperphosphorylated, tau can no longer bind properly to microtubules and its functions are disrupted. Finally, patients with AD often show comorbid DLB and vascular pathology.
Mature neuritic plaque with a dense central amyloid core surrounded by dystrophic neurites (thioflavin S stain). (Image courtesy of S. DeArmond, University of California; with permission.)
Biochemically, AD is associated with a decrease in the cortical levels of several proteins and neurotransmitters, especially acetylcholine, its synthetic enzyme cho-line acetyltransferase, and nicotinic cholinergic receptors. Reduction of acetylcholine may be related in part to degeneration of cholinergic neurons in the nucleus basalis of Meynert that project throughout the cortex. There is also noradrenergic and serotonergic depletion due to degeneration of brainstem nuclei such as the locus coeruleus and dorsal raphe.
Several genes play important pathogenic roles in at least some patients with AD. One is the APP gene on chromosome 21. Adults with trisomy 21 (Down syndrome) consistently develop the typical neuropathologic hallmarks of AD if they survive beyond age 40. Many develop a progressive dementia superimposed on their baseline mental retardation. APP is a membrane-spanning protein that is subsequently processed into smaller units, including Aβ, which is deposited in neuritic plaques. Aβ peptide results from cleavage of APP by β and γ secretases (Fig. 29-4). Presumably, the extra dose of the APP gene on chromosome 21 is the initiating cause of AD in adult Down syndrome and results in excess cerebral amyloid. Furthermore, a few families with early-onset familial Alzheimer’s disease (FAD) have been discovered to have point mutations in the APP gene. Although very rare, these families were the first examples of single-gene autosomal dominant transmission of AD.
Amyloid precursor protein (APP) is catabolized by α, β, and γ secretases. A key initial step is the digestion by either β secretase (BASE) or α secretase (ADAM10 or ADAM17 [TACE]), producing smaller nontoxic products. Cleavage of the β secretase product by γ secretase (Step 2) results in either the toxic Aβ42 or the nontoxic Aβ40 peptide; cleavage of the α secretase product by γ secretase produces the nontoxic P3 peptide. Excess production of Aβ42is a key initiator of cellular damage in Alzheimer’s disease. Current AD research is focused on developing therapies designed to reduce accumulation of Aβ42by antagonizing β or γ secretases, promoting α secretase, or clearing Aβ42that has already formed by use of specific antibodies.
Investigation of large families with multigenerational FAD led to the discovery of two additional AD genes, the presenilins. Presenilin-1 (PS-1) is on chromosome 14 and encodes a protein called S182. Mutations in this gene cause an early-onset AD (onset before age 60 and often before age 50) transmitted in an autosomal dominant, highly penetrant fashion. More than 100 different mutations have been found in the PS-1 gene in families from a wide range of ethnic backgrounds. Presenilin-2 (PS-2) is on chromosome 1 and encodes a protein called STM2. A mutation in the PS-2 gene was first found in a group of American families with Volga German ethnic background. Mutations in PS-1 are much more common than those in PS-2. The presenilins are highly homologous and encode similar proteins that at first appeared to have seven transmembrane domains (hence the designation STM), but subsequent studies have suggested eight such domains, with a ninth submembrane region. Both S182 and STM2 are cytoplasmic neuronal proteins that are widely expressed throughout the nervous system. They are homologous to a cell-trafficking protein, sel 12, found in the nematode Caenorhabditis elegans. Patients with mutations in these genes have elevated plasma levels of Aβ42, and PS-1 mutations in cell cultures produce increased Aβ42 in the media. There is evidence that PS-1is involved in the cleavage of APP at the gamma secretase site and mutations in either gene (PS-1 or APP) may disturb this function. Mutations in PS-1 have thus far proved to be the most common cause of early-age-of-onset FAD, representing perhaps 40–70% of this relatively rare syndrome. Mutations in PS-1 tend to produce AD with an earlier age of onset (mean onset 45 years) and a shorter, more rapidly progressive course (mean duration 6–7 years) than the disease caused by mutations in PS-2 (mean onset 53 years; duration 11 years). Although some carriers of uncommon PS-2 mutations have had onset of dementia after the age of 70, mutations in the presenilins are rarely involved in the more common sporadic cases of late-onset AD occurring in the general population. Genetic testing for these uncommon mutations is now commercially available. This diagnostic avenue is likely to be revealing only in early-age-of-onset familial AD and should be performed in the context of formal genetic counseling, especially when there are asymptomatic persons at risk.
A discovery of great importance has been that the Apo ε gene on chromosome 19 is involved in the pathogenesis of late-onset familial and sporadic forms of AD. Apo ε participates in cholesterol transport and has three alleles: ε2, ε3, and ε4. The Apo ε4 allele confers increased risk of AD in the general population, including sporadic and late-age-of-onset familial forms. Approximately 24–30% of the nondemented white population has at least one ε4 allele (12–15% allele frequency), and about 2% are ε4/4 homo-zygotes. Among patients with AD, 40–65% have at least one ε4 allele, a highly significant difference compared with controls. Conversely, many AD patients have no ε4 allele, and ε4 carriers may never develop AD. Therefore, ε4 is neither necessary nor sufficient to cause AD. Nevertheless, the Apo ε4 allele, especially in the homozygous state, represents the most important genetic risk factor for AD and acts as a dose-dependent disease modifier, with the earliest age of onset associated with the ε4 homozygosity. Precise mechanisms through which Apo ε4 confers AD risk or hastens onset remain unclear, but ε4 may produce less efficient amyloid clearance. Apo ε can be identified in neuritic plaques and may also be involved in neurofibrillary tangle formation, because it binds to tau protein. Apo ε4 decreases neurite outgrowth in dorsal root ganglion neuronal cultures, perhaps indicating a deleterious role in the brain’s response to injury. Some evidence suggests that the ε2 allele may reduce AD risk, but the issue remains to be clarified. Use of Apo ε testing in AD diagnosis remains controversial. It is not indicated as a predictive test in normal persons because its precise predictive value is unclear, and many individuals with the ε4 allele never develop dementia. Many cognitively normal ε4 heterozygotes and homozygotes show decreased cerebral cortical metabolic function with PET, suggesting presymptomatic abnormalities due to AD or an inherited vulnerability of the AD target network. In demented persons who meet clinical criteria for AD, finding an ε4 allele increases the reliability of diagnosis however, the absence of an ε4 allele cannot be considered evidence against AD. Furthermore, all patients with dementia, including those with an ε4 allele, require a search for reversible causes of their cognitive impairment. Nevertheless, Apo ε4 remains the single most important biologic marker associated with AD risk, and studies of ε4’s functional role and diagnostic utility are progressing rapidly. The ε4 allele is not associated with risk for FTD, DLB, or CJD, although some evidence suggests that ε4 may exacerbate the phenotype of non-AD degenerative disorders. Additional genes are also likely to be involved in AD, especially as minor risk alleles for sporadic forms of the disease. Recent genome-wide association studies have implicated the clusterin (CLU), phosphatidylinositol-binding clathrin assembly protein (PICALM), and complement component (3b/4b) receptor 1 (CR1) genes, and researchers are now working to understand the potential role of these genes in AD pathogenesis. CLU may play a role in synapse turnover, PICALM participates in clathrin-mediated endocytosis, and CR1 may be involved in amyloid clearance through the complement pathway.
TREATMENT Alzheimer’s Disease
The management of AD is challenging and gratifying, despite the absence of a cure or a robust pharmacologic treatment. The primary focus is on long-term amelioration of associated behavioral and neurologic problems, as well as providing caregiver support.
Building rapport with the patient, family members, and other caregivers is essential to successful management. In the early stages of AD, memory aids such as notebooks and posted daily reminders can be helpful. Family members should emphasize activities that are pleasant and curtail those that are unpleasant. In other words, practicing skills that have become difficult, such as through memory games and puzzles, will often frustrate and depress the patient without proven benefits. Kitchens, bathrooms, stairways, and bedrooms need to be made safe, and eventually patients must stop driving. Loss of independence and change of environment may worsen confusion, agitation, and anger. Communication and repeated calm reassurance are necessary. Caregiver “burnout” is common, often resulting in nursing home placement of the patient or new health problems for the caregiver, and respite breaks for the caregiver help to maintain a successful long-term therapeutic milieu. Use of adult day care centers can be helpful. Local and national support groups, such as the Alzheimer’s Association and the Family Caregiver Alliance, are valuable resources. Internet access to these resources has become available to clinicians and families in recent years.
Donepezil (target dose, 10 mg daily), rivastigmine (target dose, 6 mg twice daily or 9.5-mg patch daily), galantamine (target dose 24 mg daily, extended-release), memantine (target dose, 10 mg twice daily), and tacrine are the drugs presently approved by the Food and Drug Administration (FDA) for treatment of AD. Due to hepatotoxicity, tacrine is no longer used. Dose escalations for each of these medications must be carried out over 4–6 weeks to minimize side effects. The pharmacologic action of donepezil, rivastigmine, and galantamine is inhibition of the cholinesterases, primarily acetylcholinesterase, with a resulting increase in cerebral acetylcholine levels. Memantine appears to act by blocking overexcited N-methyl-D-aspartate (NMDA) glutamate receptors. Double-blind, placebo-controlled, crossover studies with cholinesterase inhibitors and memantine have shown them to be associated with improved caregiver ratings of patients’ functioning and with an apparent decreased rate of decline in cognitive test scores over periods of up to 3 years. The average patient on an anticholinesterase compound maintains his or her MMSE score for close to a year, whereas a placebo-treated patient declines 2–3 points over the same time period. Memantine, used in conjunction with cholinesterase inhibitors or by itself, slows cognitive deterioration and decreases caregiver burden for patients with moderate to severe AD but is not approved for mild AD. Each of these compounds has only modest efficacy for AD. Cholinesterase inhibitors are relatively easy to administer, and their major side effects are gastrointestinal symptoms (nausea, diarrhea, cramps), altered sleep with unpleasant or vivid dreams, bradycardia (usually benign), and muscle cramps.
In a prospective observational study, the use of estrogen replacement therapy appeared to protect—by about 50%—against development of AD in women. This study seemed to confirm the results of two earlier case-controlled studies. Sadly, a prospective placebo-controlled study of a combined estrogen-progesterone therapy for asymptomatic postmenopausal women increased, rather than decreased, the prevalence of dementia. This study markedly dampened enthusiasm for hormonal treatments to prevent dementia. Additionally, no benefit has been found in the treatment of AD with estrogen alone.
A randomized, double-blind, placebo-controlled trial of an extract of Ginkgo biloba found modest improvement in cognitive function in subjects with AD and vascular dementia. Unfortunately, a comprehensive 6-year multicenter prevention study using Ginkgo biloba found no slowing of progression to dementia in the treated group.
Vaccination against Aβ42 has proved highly efficacious in mouse models of AD, helping clear brain amyloid and preventing further amyloid accumulation. In human trials, this approach led to life-threatening complications, including meningoencephalitis, but modifications of the vaccine approach using passive immunization with monoclonal antibodies are currently being evaluated in phase 3 trials. Another experimental approach to AD treatment has been the use of β and γ secretase inhibitors that diminish the production of Aβ42, but the first two placebo-controlled trials of γ secretase inhibitors, tarenflurbil and semagacestat, were negative, and semagacestat may have accelerated cognitive decline compared to placebo. Medications that modify tau phosphorylation and aggregation are beginning to be studied as possible treatments for both AD and non-AD tau-related disorders including FTD and PSP.
Several retrospective studies suggest that nonsteroidal anti-inflammatory agents and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) may have a protective effect on dementia, and controlled prospective studies are being conducted. Similarly, prospective studies with the goal of lowering serum homocysteine are underway to slow the progression to dementia, following an association of elevated homocysteine with dementia progression in epidemiologic studies. Finally, there is now a strong interest in the relationship between diabetes and AD, and insulin-regulating studies are being conducted.
Mild to moderate depression is common in the early stages of AD and may respond to antidepressants or cholinesterase inhibitors. Selective serotonin reuptake inhibitors (SSRIs) are commonly used due to their low anticholinergic side effects (escitalopram 5–10 mg daily). Generalized seizures should be treated with an appropriate anticonvulsant, such as phenytoin or carbamazepine. Agitation, insomnia, hallucinations, and belligerence are especially troublesome characteristics of some AD patients, and these behaviors can lead to nursing home placement. The newer generation of atypical antipsychotics, such as risperidone, quetiapine, and olanzapine, are being used in low doses to treat these neuropsychiatric symptoms. The few controlled studies comparing drugs against behavioral intervention in the treatment of agitation suggest mild efficacy with significant side effects related to sleep, gait, and cardiovascular complications, including an increased risk of death. All antipsychotics carry a black-box FDA warning and should be used with caution in the demented elderly; however, careful, daily, nonpharmacologic behavior management is often not available, rendering medications necessary for some patients. Finally, medications with strong anticholinergic effects should be vigilantly avoided, including prescription and over-the-counter sleep aids (e.g., diphenhydramine) or incontinence therapies (e.g., oxybutynin).
Dementia associated with cerebrovascular disease can be divided into two general categories: multi-infarct dementia and diffuse white matter disease (also called leukoaraiosis, subcortical arteriosclerotic leukoencephalopathy, or Binswanger’s disease). Cerebrovascular disease appears to be a more common cause of dementia in Asia than in Europe and North America, perhaps due to the increased prevalence of intracranial atherosclerosis. Individuals who have had several strokes may develop chronic cognitive deficits, commonly called multi-infarct dementia. The strokes may be large or small (sometimes lacunar) and usually involve several different brain regions. The occurrence of dementia depends partly on the total volume of damaged cortex, but it is also more common in individuals with left-hemisphere lesions, independent of any language disturbance. Patients typically report previous discrete episodes of sudden neurologic deterioration. Many patients with multi-infarct dementia have a history of hypertension, diabetes, coronary artery disease, or other manifestations of widespread atherosclerosis. Physical examination usually shows focal neurologic deficits such as hemiparesis, a unilateral Babinski sign, a visual field defect, or pseudobulbar palsy. Recurrent strokes result in a stepwise disease progression. Neuroimaging reveals multiple areas of infarction. Thus, the history and neuroimaging findings differentiate this condition from AD; however, both AD and multiple infarctions are common and sometimes co-occur. With normal aging, there is also an accumulation of amyloid in cerebral blood vessels, leading to a condition called cerebral amyloid angiopathy (without dementia), which predisposes older persons to lobar hemorrhage and brain microhemorrhages. AD patients appear to be at increased risk for amyloid angiopathy, and this may explain some of the observed association between AD and stroke.
Some individuals with dementia are discovered on MRI to have bilateral abnormalities of subcortical white matter, termed diffuse white matter disease, often occurring in association with lacunar infarctions (Fig. 29-5). The dementia may be insidious in onset and progress slowly, features that distinguish it from multi-infarct dementia, but other patients show a stepwise deterioration more typical of multi-infarct dementia. Early symptoms are mild confusion, apathy, anxiety, psychosis, and memory, spatial, or executive deficits. Marked difficulties in judgment and orientation and dependence on others for daily activities develop later. Euphoria, elation, depression, or aggressive behaviors are common as the disease progresses. Both pyramidal and cerebellar signs may be present. A gait disorder is present in at least half of these patients. With advanced disease, urinary incontinence and dysarthria with or without other pseudobulbar features (e.g., dysphagia, emotional lability) are frequent. Seizures and myoclonic jerks appear in a minority of patients. This disorder appears to result from chronic ischemia due to occlusive disease of small, penetrating cerebral arteries and arterioles (micro-angiopathy). Any disease-causing stenosis of small cerebral vessels may be the critical underlying factor, although hypertension is the major cause. The term Binswanger’s diseaseshould be used with caution, because it does not clearly identify a single entity.
Diffuse white matter disease. Axial fluid-attenuated inversion recovery (FLAIR) MR image through the lateral ventricles reveals multiple areas of hyperintensity involving the periventricular white matter as well as the corona radiata and striatum (arrows). While seen in some individuals with normal cognition, this appearance is more pronounced in patients with dementia of a vascular etiology.
Other rare causes of white matter disease also present with dementia, such as adult metachromatic leuko-dystrophy (arylsulfatase A deficiency) and progressive multifocal leukoencephalopathy (JC virus infection). A dominantly inherited form of diffuse white matter disease is known as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Clinically, there is a progressive dementia developing in the fifth to seventh decades in multiple family members who may also have a history of migraine and recurrent lacunar stroke without hypertension. Skin biopsy may show pathognomonic osmophilic granules in the media of arterioles. The disease is caused by mutations in the Notch 3 gene, and genetic testing is commercially available. The frequency of this disorder is unknown, and there are no effective treatments.
Mitochondrial disorders can present with stroke-like episodes and can selectively injure basal ganglia or cortex. Many such patients show other findings suggestive of a neurologic or systemic disorder such as ophthalmoplegia, retinal degeneration, deafness, myopathy, neuropathy, or diabetes. Diagnosis is difficult, but serum or (especially) CSF levels of lactate and pyruvate may be abnormal, and biopsy of affected tissue, preferably muscle, may be diagnostic.
Treatment of vascular dementia must be focused on preventing new ischemic injury by stabilizing or removing the underlying causes, such as hypertension, diabetes, smoking, or lack of exercise. Recovery of lost cognitive function is not likely, although fluctuations with periods of improvement are common.
FRONTOTEMPORAL DEMENTIA, PROGRESSIVE SUPRANUCLEAR PALSY, AND CORTICOBASAL DEGENERATION
Frontotemporal dementia (FTD) often begins in the fifth to seventh decades, and in this age group it is nearly as prevalent as AD. Early studies suggested that FTD may be more common in men than women, although more recent reports cast some doubt on this finding. Unlike in AD, behavioral symptoms predominate in the early stages of FTD. Although a family history of dementia is common, autosomal dominant inheritance is seen in about 10% of all FTD cases. The clinical heterogeneity in familial and sporadic forms of FTD is remarkable, with patients demonstrating variable mixtures of behavioral, language, movement, and motor neuron symptoms. The most common autosomal dominantly inherited mutations causing FTD involve the MAPT or GRN genes, both on chromosome 17. MAPT mutations lead to a change in the alternate splicing of tau or cause loss of function in the tau molecule. With GRN, mutations in the coding sequence of the gene encoding progranulin protein result in mRNA degradation due to nonsense-mediated decay. Progranulin appears to be a rare example of an autosomal dominant mutation that leads to haploinsufficiency, resulting in around one-half the normal level of progranulin protein. Progranulin is a growth factor that binds to tumor necrosis factor (TNF) receptors. How progranulin mutations lead to FTD is unknown. Both MAPT and GRN mutations are associated with parkinsonian features, while ALS is rare with these mutations. In contrast, familial FTD with ALS has been linked to chromosome 9. Mutations in the valosin-containing protein (chromosome 9) and the charged multivesicular body protein 2b (CHMP2b) genes (chromosome 3) also lead to rare autosomal dominant forms of familial FTD. Mutations in the TDP-43 and FUS genes (see later) cause familial ALS, sometimes in association with an FTD syndrome, although a few patients presenting with FTD alone have been reported.
In FTD, early symptoms are divided among behavioral, language, and sometimes motor abnormalities, reflecting degeneration of the anterior insular, frontal, and temporal regions, basal ganglia, and motor neurons. Cognitive testing typically reveals spared memory but impaired planning, judgment, or language. Poor business decisions and difficulty organizing work tasks are common, and speech and language deficits often emerge. Patients with FTD often show an absence of insight into their condition. Common behavioral features include apathy, disinhibition, weight gain, food fetishes, compulsions, and emotional distance or loss of empathy.
Findings at the bedside are dictated by the anatomic localization of the disorder. Asymmetric left frontal cases present with nonfluent aphasia, while left anterior temporal degeneration is characterized by loss of word meaning (semantic dementia). Nonfluent patients quickly progress to mutism, while those with semantic dementia develop features of a multimodal associative agnosia, losing the ability to recognize faces, objects, words, and the emotions of others. Visuoconstructive ability, arithmetic calculations, and navigation often remain normal late into the illness. Recently it has become apparent that many patients with nonfluent aphasia progress to clinical syndromes that overlap with PSP and corticobasal degeneration (CBD) and show these pathologies at autopsy. This left hemisphere presentation of FTD has been called primary progressive aphasia with nonfluent and semantic variants. In contrast, right frontal or temporal cases show profound alterations in social conduct, with loss of empathy, disinhibition, and antisocial behaviors predominating. There is a striking overlap among FTD, PSP, CBD, and motor neuron disease; ophthalmoplegia, dystonia, swallowing symptoms, and fasciculations are common at presentation of FTD or emerge during the course of the illness.
The distinguishing anatomic hallmark of FTD is a focal atrophy of frontal, insular, and/or temporal cortex, which can be visualized with neuroimaging studies and is often profound at autopsy (Figs. 29-6 and 29-7). Despite the appearance of advanced FTD, however, the atrophy often begins focally in one hemisphere before spreading to anatomically interconnected regions, including basal ganglia. Microscopic findings seen across all patients with FTD include gliosis, microvacuolation, and neuronal loss, but the disease is subtyped according to the protein composition of neuronal and glial inclusions, which contain either tau or TDP-43 in at least 90% of patients, with the remaining 10% showing inclusions containing FUS (Fig. 29-8).
Frontotemporal dementia (FTD). Coronal MRI sections from representative patients with behavioral variant FTD (left), semantic dementia (center), and progressive nonfluent aphasia (right). Areas of early and severe atrophy in each syndrome are highlighted (white arrowheads). The behavioral variant features anterior cingulate and frontoinsular atrophy, spreading to orbital and dorsolateral prefrontal cortex. Semantic dementia shows prominent temporopolar atrophy, more often on the left. Progressive nonfluent aphasia is associated with dominant frontal opercular and dorsal insula degeneration.
Voxel-based morphometry analysis showing differing patterns of brain atrophy in three variants of progressive aphasia, including nonfluent (red), semantic (green), and logo-pedic subtypes (blue). Voxel-based morphometry allows comparison of MRI gray matter volumes between patient groups and control subjects, as shown here. (Image courtesy of M Gorno-Tempini, University of California at San Francisco; with permission.)
Frontotemporal dementia syndromes are united by underlying frontotemporal lobar degeneration pathology, which can be divided according to the presence of tau, TPD-43, or fused in sarcoma (FUS) inclusions in neurons and glia. Correlations between clinical syndrome and major molecular category are shown with colored shading.
A toxic gain of function related to tau underlies the pathogenesis of many familial cases and is presumed to be a factor in sporadic tauopathies, although loss of tau microtubule stabilizing function may also play a role. TDP-43 and FUS, in contrast, are RNA/DNA binding proteins whose roles in neuronal function are still being actively investigated. Loss of cortical serotonergic inner-vation is seen in many patients. In contrast to AD, the cholinergic system is relatively spared in FTD.
Historically, Pick’s disease was described as a progressive degenerative disorder characterized by selective involvement of the anterior frontal and temporal neocortex and pathologically by intraneuronal cytoplasmic inclusions (Pick bodies). Classical Pick bodies are argyrophilic, staining positively with the Bielschowsky silver method and also with immunostaining for tau (Fig. 29-9). Subsequent pathologic studies revealed a significant subset of patients with silver-negative, tau-negative inclusions, which have since been shown mainly to contain TDP-43, although a minority stain only for FUS. Although the nomenclature used to describe these patients has continued to evolve, the term FTD is increasingly used to refer to the clinical syndromes, while frontotemporal lobar degeneration (FTLD) refers to the underlying pathology, with three major subtypes recognized: FTLD-tau, FTLD-TDP, and FTLD-FUS. Despite significant progress, available data do not yet allow a reliable prediction of underlying pathology based on clinical features. Accordingly researchers continue to seek serum, CSF, or neuroimaging biomarkers that will afford greater diagnostic accuracy, defined as concordance with neuropathology.
Pick’s disease, a subtype of frontotemporal lobar degeneration (FTLD)-tau. Pick bodies, shown here in the dentate gyrus of a patient with advanced bvFTD, consist of loosely arranged paired helical and straight filaments and stain positively for hyperphosphorylated tau. Classical Pick’s disease is seen in only 10–20% of patients with frontotemporal dementia. Scale bar represents 50 microns. (CP-13 antibody courtesy of P. Davies.)
The burden on caregivers of patients with FTD is extremely high because the illness disrupts core emotional and personality functions of the loved one. Treatment is symptomatic, and there are currently no therapies known to slow progression or improve symptoms. Many of the behaviors that accompany FTD, such as depression, hyperorality, compulsions, and irritability, can be ameliorated with antidepressants, especially SSRIs. The co-association with motor disorders such as parkinsonism necessitates the careful use of antipsychotics, which can exacerbate this problem.
Progressive supranuclear palsy (PSP) is a degenerative disease that involves the brainstem, basal ganglia, limbic structures, and selected areas of cortex. Clinically, this disorder begins with falls and executive or subtle personality changes (such as mental rigidity, impulsivity, or apathy). Shortly thereafter, a progressive oculomotor syndrome ensues that begins with square wave jerks, followed by slowed saccades (vertical worse than horizontal) before resulting in progressive supranuclear ophthalmoparesis. Dysarthria, dysphagia, and symmetric axial rigidity can be prominent features that emerge at any point in the illness. A stiff, unstable posture with hyperextension of the neck and a slow, jerky, toppling gait is characteristic. Frequent unexplained and sometimes spectacular falls are common secondary to a combination of axial rigidity, inability to look down, and bad judgment. Even once patients have severely limited voluntary eye movements, they retain oculocephalic reflexes (demonstrated using a vertical doll’s head maneuver); thus, the oculomotor disorder is supranuclear. The dementia overlaps with FTD, featuring apathy, frontal-executive dysfunction, poor judgment, slowed thought processes, impaired verbal fluency, and difficulty with sequential actions and with shifting from one task to another. These features are common at presentation and often precede the motor syndrome. Some patients begin with a nonfluent aphasia or motor speech disorder and progress to classical PSP. Response to L-dopa is limited or absent; no other treatments exist. Death occurs within 5–10 years of onset. At autopsy, accumulation of hyperphosphorylated tau is seen within neurons and glia. Neuronal inclusions often take the form of neurofibrillary tangles (NFTs), which may be large, spherical, and coarse when found in brainstem oculomotor control system neurons. These characteristic tau inclusions are called globose tangles, and may be found in multiple subcortical structures (including the subthalamic nucleus, globus pallidus, substantia nigra, locus coeruleus, periaqueductal gray, superior colliculi, oculomotor nuclei, and dentate nucleus). Neocortical NFTs, like those in AD, often take on a more flame-shaped morphology, but on electron microscopy PSP tangles can be shown to consist of straight tubules rather than the paired helical filaments found in AD. Furthermore, PSP is associated with prominent tau-positive glial pathomorphologies, such as tufted and thorny astrocytes.
In addition to its overlap with FTD and CBD (see later), PSP is often confused with idiopathic Parkinson’s disease (PD). Although elderly patients with PD may have restricted upgaze, they do not develop downgaze paresis or other abnormalities of voluntary eye movements typical of PSP. Dementia occurs in ~20% of patients with PD, often due to the emergence of a full-blown DLB syndrome. Furthermore, the behavioral syndromes seen with DLB differ from PSP (see later). Dementia in PD becomes more likely with increasing age, increasing severity of extrapyramidal signs, a long disease duration, and the presence of depression. Patients with PD who develop dementia also show cortical atrophy on brain imaging. Neuropathologically, there may be Alzheimer’s disease–related changes in the cortex, DLB-related α-synuclein inclusions in both the limbic system and cortex, or no specific microscopic changes other than gliosis and neuronal loss. Parkinson’s disease is discussed in detail in Chap. 30.
Corticobasal degeneration (CBD) is a slowly progressive dementing illness associated with severe gliosis and neuronal loss in both the cortex and basal ganglia (substantia nigra and striatopallidum). Some patients present with a unilateral onset with rigidity, dystonia, and apraxia of one arm and hand, sometimes called the alien limb when it begins to exhibit unintended motor actions, while in other instances the disease presents as a progressive behavioral, executive, or language syndrome or as progressive symmetric parkinsonism. Some patients begin with a progressive nonfluent aphasia or a progressive motor speech disorder. Eventually CBD becomes bilateral and leads to dysarthria, slow gait, action tremor, and dementia. The microscopic features include ballooned, achromatic, tau-positive neurons with astrocytic plaques and other dystrophic glial tau pathomorphologies that overlap with those seen in PSP. Most specifically, CBD features a severe tauopathy burden in the subcortical white matter, consisting of threads and oligodendroglial coiled bodies. The condition is rarely familial, the cause is unknown, and there is no specific treatment.
PARKINSON’S DISEASE DEMENTIA AND DEMENTIA WITH LEWY BODIES
The parkinsonian dementia syndromes are under increasing study, with many cases unified by Lewy body and Lewy neurite pathology that ascends from the low brainstem up through the substantia nigra, limbic system, and cortex. The DLB clinical syndrome is characterized by visual hallucinations, parkinsonism, fluctuating alertness, falls, and often RBD. Dementia can precede or follow the appearance of parkinsonism. Hence, one pathway occurs in patients with long-standing PD without cognitive impairment, who slowly develop a dementia that is associated with visual hallucinations and fluctuating alertness. When this occurs after an established diagnosis of PD, many use the term Parkinson’s disease dementia (PDD). In others, the dementia and neuropsychiatric syndrome precede the parkinsonism, and this constellation is referred to as DLB. Both PDD and DLB may be accompanied or preceded by symptoms referable to brainstem pathology below the substantia nigra, and many researchers conceptualize these disorders as points on a spectrum of α-synuclein pathology.
Patients with PDD and DLB are highly sensitive to metabolic perturbations, and in some patients the first manifestation of illness is a delirium, often precipitated by an infection, new medicine, or other systemic disturbance. A hallucinatory delirium induced by L-dopa, prescribed for parkinsonian symptoms attributed to PD may likewise provide the initial clue to a PDD diagnosis. Conversely, patients with mild cognitive deficits and hallucinations may receive typical or atypical antipsychotic medications, which induce profound parkinsonism at low doses due to a subclinical DLB-related nigral dopaminergic neuron loss. Even without an underlying precipitant, fluctuations can be marked in DLB, with episodic confusion or even stupor admixed with lucid intervals. However, despite the fluctuating pattern, the clinical features persist over a long period, unlike delirium, which resolves following correction of the inciting factor. Cognitively, DLB features relative preservation of memory but more severe visuospatial and executive deficits than patients with early AD.
The key neuropathologic feature in DLB is the presence of Lewy bodies and Lewy neurites throughout specific brainstem nuclei, substantia nigra, amygdala, cingulate gyrus, and, ultimately, the neocortex. Lewy bodies are intraneuronal cytoplasmic inclusions that stain with periodic acid–Schiff (PAS) and ubiquitin but are now identified with antibodies to the presynaptic protein, α-synuclein. They are composed of straight neurofilaments 7–20 nm long with surrounding amorphous material and contain epitopes recognized by antibodies against phosphorylated and nonphosphorylated neurofilament proteins, ubiquitin, and α-synuclein. Lewy bodies are typically found in the substantia nigra of patients with idiopathic PD, where they can be readily seen with hematoxylin-and-eosin staining. A profound cholinergic deficit, owing to basal forebrain and pedunculopontine nucleus involvement, is present in many patients with DLB and may be a factor responsible for the fluctuations, inattention, and visual hallucinations. In patients without other pathologic features, the condition is sometimes referred to as diffuse Lewy body disease. In patients whose brains also contain a substantial burden of amyloid plaques and NFTs, the condition is sometimes called the Lewy body variant of Alzheimer’s disease.
Due to the overlap with AD and the cholinergic deficit in DLB, cholinesterase inhibitors often provide significant benefit, reducing hallucinosis, stabilizing delusional symptoms, and even helping with RBD in some patients. Exercise programs maximize motor function and protect against fall-related injury. Antidepressants are often necessary. Atypical antipsychotics may be required for psychosis but can worsen extrapyramidal syndromes, even at low doses, and increase risk of death. As noted earlier, patients with DLB are extremely sensitive to dopaminergic medications, which must be carefully titrated; tolerability may be improved by concomitant use of a cholinesterase inhibitor.
OTHER CAUSES OF DEMENTIA
Prion diseases such as Creutzfeldt-Jakob disease (CJD) are rare neurodegenerative conditions (prevalence ~1 per million) that produce dementia. CJD is a rapidly progressive disorder associated with dementia, focal cortical signs, rigidity, and myoclonus, causing death <1 year after first symptoms appear. The rapidity of progression seen with CJD is uncommon in AD so that the distinction between the two disorders is usually straightforward. CBD and DLB, more rapid degenerative dementias with prominent movement abnormalities, are more likely to be mistaken for CJD. The differential diagnosis for CJD includes other rapidly progressive dementing conditions such as viral or bacterial encephalitides, Hashimoto’s encephalopathy, CNS vasculitis, lymphoma, or paraneoplastic syndromes. The markedly abnormal periodic complexes on EEG and cortical ribbon and basal ganglia hyperintensities on MR diffusion-weighted imaging are highly specific diagnostic features of CJD, although rarely prolonged focal or generalized seizures can produce a similar imaging appearance. Prion diseases are discussed in detail in Chap. 43.
Huntington’s disease (HD) (Chap. 30) is an autosomal dominant, degenerative brain disorder. HD clinical hallmarks include chorea, behavioral disturbance, and executive impairment. Symptoms typically begin in the fourth or fifth decade, but there is a wide range, from childhood to >70 years. Memory is frequently not impaired until late in the disease, but attention, judgment, awareness, and executive functions are often deficient at an early stage. Depression, apathy, social withdrawal, irritability, and intermittent disinhibition are common. Delusions and obsessive-compulsive behavior may occur. Disease duration is typically around 15 years but is quite variable.
Normal-pressure hydrocephalus (NPH) is a relatively uncommon but treatable syndrome. The clinical, physiologic, and neuroimaging characteristics of NPH must be carefully distinguished from those of other dementias associated with gait impairment. Historically, many patients treated for NPH have suffered from other dementias, particularly AD, vascular dementia, DLB, and PSP. For NPH, the clinical triad includes an abnormal gait (ataxic or apractic), dementia (usually mild to moderate, with an emphasis on executive impairment), and urinary urgency or incontinence. Neuroimaging reveals enlarged lateral ventricles (hydrocephalus) with little or no cortical atrophy, although the sylvian fissures may appear propped open (so-called “boxcarring”), which can be mistaken for perisylvian atrophy. This syndrome is a communicating hydrocephalus with a patent aqueduct of Sylvius (Fig. 29-10), in contrast to aqueductal stenosis, in which the aqueduct is small. Lumbar puncture opening pressure falls in the high normal range, and the CSF protein, glucose, and cell counts are normal. NPH may be caused by obstruction to normal CSF flow over the cerebral convexities and delayed resorption into the venous system. The indolent nature of the process results in enlarged lateral ventricles with relatively little increase in CSF pressure. Presumed stretching and distortion of subfrontal white matter tracts may lead to clinical symptoms, but the precise underlying pathophysiology remains unclear. Some patients provide a history of conditions that produce meningeal scarring (blocking CSF resorption) such as previous meningitis, subarachnoid hemorrhage, or head trauma. Others with long-standing but asymptomatic congenital hydrocephalus may have adult-onset deterioration in gait or memory that is confused with NPH. In contrast to AD, the patient with NPH complains of an early and prominent gait disturbance without cortical atrophy on CTor MRI.
Normal-pressure hydrocephalus. A. Sagittal T1-weighted MR image 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 MR images demonstrate dilation of the lateral ventricles. This patient underwent successful ventriculoperitoneal shunting.
Numerous attempts to improve NPH diagnosis with various special studies and predict the success of ventricular shunting have been undertaken. These tests include radionuclide cisternography (showing a delay in CSF absorption over the convexity) and various efforts to monitor and alter CSF flow dynamics, including a constant-pressure infusion test. None has proven to be specific or consistently useful. A transient improvement in gait or cognition may follow lumbar puncture (or serial punctures) with removal of 30–50 mL of CSF, but this finding has also not proved to be consistently predictive of postshunt improvement. Perhaps the most reliable strategy is a period of close inpatient evaluation before, during, and after lumbar CSF drainage. Occasionally, when a patient with AD presents with gait impairment (at times due to comorbid subfrontal vascular injury) and absent or only mild cortical atrophy on CT or MRI, distinguishing NPH from AD can be challenging. Hippo-campal atrophy on MRI favors AD, whereas a characteristic “magnetic” gait with external hip rotation, low foot clearance and short strides, along with prominent truncal sway or instability, favors NPH. The diagnosis of NPH should be avoided when hydrocephalus is not detected on imaging studies, even if the symptoms otherwise fit. Thirty to fifty percent of patients identified by careful diagnosis as having NPH will improve with ventricular shunting. Gait may improve more than cognition, but many reported failures to improve cognitively may have resulted from comorbid AD. Short-lasting improvement is common. Patients should be carefully selected for shunting, because subdural hematoma, infection, and shunt failure are known complications and can be a cause for early nursing home placement in an elderly patient with previously mild dementia.
Dementia can accompany chronic alcoholism (Chap. 56) and may result from associated malnutrition, especially of B vitamins, particularly thiamine. Other poorly defined aspects of chronic alcoholism may, however, also produce cerebral damage. A rare idiopathic syndrome of dementia and seizures with degeneration of the corpus callosum has been reported primarily in male Italian red wine drinkers (Marchiafava-Bignami disease).
Thiamine (vitamin B1) deficiency causes Wernicke’s encephalopathy (Chap. 28). The clinical presentation features a malnourished patient (frequently but not necessarily alcoholic) with confusion, ataxia, and diplopia resulting from inflammation and necrosis of periventricular midline structures, including dorsomedial thalamus, mammillary bodies, midline cerebellum, periaqueductal gray matter, and trochlear and abducens nuclei. Damage to the dorsomedial thalamus correlates most closely with the memory loss. Prompt administration of parenteral thiamine (100 mg intravenously for 3 days followed by daily oral dosage) may reverse the disease if given in the first days of symptom onset. However, prolonged untreated thiamine deficiency can result in an irreversible dementia/amnestic syndrome (Korsakoff’s syndrome) or even death.
In Korsakoff’s syndrome, the patient is unable to recall new information despite normal immediate memory, attention span, and level of consciousness. Memory for new events is seriously impaired, whereas knowledge acquired prior to the illness remains relatively intact. Patients are easily confused, disoriented, and cannot store information for more than a few minutes. Superficially, they may be conversant, engaging, and able to perform simple tasks and follow immediate commands. Confabulation is common, although not always present. There is no specific treatment because the previous thiamine deficiency has produced irreversible damage to the medial thalamic nuclei and mammillary bodies. Mammillary body atrophy may be visible on MRI in the chronic phase (Fig. 28-7).
Vitamin B12 deficiency, as can occur in pernicious anemia, causes a megaloblastic anemia and may also damage the nervous system (Chap. 35). Neurologically, it most commonly produces a spinal cord syndrome (myelopathy) affecting the posterior columns (loss of vibration and position sense) and corticospinal tracts (hyperactive tendon reflexes with Babinski signs); it also damages peripheral nerves (neuropathy), resulting in sensory loss with depressed tendon reflexes. Damage to myelinated axons may also cause dementia. The mechanism of neurologic damage is unclear but may be related to a deficiency of S-adenosyl methionine (required for methylation of myelin phospholipids) due to reduced methionine synthase activity or accumulation of methylmalonate, homocysteine, and propionate, providing abnormal substrates for fatty acid synthesis in myelin. The neurologic sequelae of vitamin B12deficiency may occur in the absence of hematologic manifestations, making it critical to avoid using the CBC and blood smear as a substitute for measuring B12 blood levels. Treatment with parenteral vitamin B12 (1000 μg intramuscularly daily for a week, weekly for a month, and monthly for life for pernicious anemia) stops progression of the disease if instituted promptly, but complete reversal of advanced nervous system damage will not occur.
Deficiency of nicotinic acid (pellagra) is associated with skin rash over sun-exposed areas, glossitis, and angular stomatitis. Severe dietary deficiency of nicotinic acid along with other B vitamins such as pyridoxine may result in spastic paraparesis, peripheral neuropathy, fatigue, irritability, and dementia. This syndrome has been seen in prisoners of war and in concentration camps but should be considered in any malnourished individual. Low serum folate levels appear to be a rough index of malnutrition, but isolated folate deficiency has not been proved as a specific cause of dementia.
CNS infections usually cause delirium and other acute neurologic syndromes. However, some chronic CNS infections, particularly those associated with chronic meningitis (Chap. 41), may produce a dementing illness. The possibility of chronic infectious meningitis should be suspected in patients presenting with a dementia or behavioral syndrome, who also have headache, meningismus, cranial neuropathy, and/or radiculopathy. Between 20 and 30% of patients in the advanced stages of HIV infection become demented (Chap. 42). Cardinal features include psychomotor retardation, apathy, and impaired memory. This syndrome may result from secondary opportunistic infections but can also be caused by direct infection of CNS neurons with HIV. Neurosyphilis was a common cause of dementia in the preantibiotic era; it is now uncommon but can still be encountered in patients with multiple sex partners, particularly among patients with HIV. Characteristic CSF changes consist of pleocytosis, increased protein, and a positive Venereal Disease Research Laboratory (VDRL) test.
Primary and metastatic neoplasms of the CNS (Chap. 37) usually produce focal neurologic findings and seizures rather than dementia, but if tumor growth begins in the frontal or temporal lobes, the initial manifestations may be memory loss or behavioral changes. A paraneoplastic syndrome of dementia associated with occult carcinoma (often small cell lung cancer) is termed limbic encephalitis. In this syndrome, confusion, agitation, seizures, poor memory, emotional changes, and frank dementia may occur. Paraneoplastic encephalitis associated with NMDA receptor antibodies presents as a progressive psychiatric disorder with memory loss and seizures; affected patients are often young women with ovarian teratoma (Chap. 44).
A nonconvulsive seizure disorder may underlie a syndrome of confusion, clouding of consciousness, and garbled speech. Often, psychiatric disease is suspected, but an EEG demonstrates the epileptic nature of the illness. If recurrent or persistent, the condition may be termed complex partial status epilepticus. The cognitive disturbance often responds to anticonvulsant therapy. The etiology may be previous small strokes or head trauma; some cases are idiopathic.
It is important to recognize systemic diseases that indirectly affect the brain and produce chronic confusion or dementia. Such conditions include hypothyroidism; vasculitis; and hepatic, renal, or pulmonary disease. Hepatic encephalopathy may begin with irritability and confusion and slowly progress to agitation, lethargy, and coma.
Isolated vasculitis of the CNS (CNS granulomatous angiitis) (Chap. 27) occasionally causes a chronic encephalopathy associated with confusion, disorientation, and clouding of consciousness. Headache is common, and strokes and cranial neuropathies may occur. Brain imaging studies may be normal or nonspecifically abnormal. CSF analysis reveals a mild pleocytosis or protein elevation. Cerebral angiography can show multifocal stenoses involving medium-caliber vessels, but some patients have only small-vessel disease that is not revealed on angiography. The angiographic appearance is not specific and may be mimicked by atherosclerosis, infection, or other causes of vascular disease. Brain or meningeal biopsy demonstrates endothelial cell proliferation and mono-nuclear infiltrates within blood vessel walls. The prognosis is often poor, although the disorder may remit spontaneously. Some patients respond to glucocorticoids or chemotherapy.
Chronic metal exposure represents a rare cause of dementia. The key to diagnosis is to elicit a history of exposure at work or home. Chronic lead poisoning from inadequately fire-glazed pottery has been reported. Fatigue, depression, and confusion may be associated with episodic abdominal pain and peripheral neuropathy. Gray lead lines appear in the gums, usually accompanied by an anemia with basophilic stippling of red blood cells. The clinical presentation can resemble that of acute intermittent porphyria, including elevated levels of urine porphyrins as a result of the inhibition of δ-aminolevulinic acid dehydrase. The treatment is chelation therapy with agents such as ethylenediamine tetraacetic acid (EDTA). Chronic mercury poisoning produces dementia, peripheral neuropathy, ataxia, and tremulousness that may progress to a cerebellar intention tremor or choreoathetosis. The confusion and memory loss of chronic arsenic intoxication is also associated with nausea, weight loss, peripheral neuropathy, pigmentation and scaling of the skin, and transverse white lines of the fingernails (Mees’ lines). Treatment is chelation therapy with dimercaprol (BAL). Aluminum poisoning is rare but was documented with the dialysis dementia syndrome, in which water used during renal dialysis was contaminated with excessive amounts of aluminum. This poisoning resulted in a progressive encephalopathy associated with confusion, nonfluent aphasia, memory loss, agitation, and, later, lethargy and stupor. Speech arrest and myoclonic jerks were common and associated with severe and generalized EEG changes. The condition has been eliminated by the use of deionized water for dialysis.
Recurrent head trauma in professional boxers may lead to a dementia sometimes called the “punch-drunk” syndrome, or dementia pugilistica. The symptoms can be progressive, beginning late in a boxer’s career or even long after retirement. The severity of the syndrome correlates with the length of the boxing career and number of bouts. Early in the condition, a personality change associated with social instability and sometimes paranoia and delusions occurs. Later, memory loss progresses to full-blown dementia, often associated with parkinsonian signs and ataxia or intention tremor. At autopsy, the cerebral cortex may show changes similar to AD, although NFTs are usually more prominent than amyloid plaques (which are usually diffuse rather than neuritic). Superficial layer NFT aggregates have been reported to differentiate these patients from those with more typical AD. Also, there may be loss of neurons in the substantia nigra. Chronic subdural hematoma (Chap. 36) is also occasionally associated with dementia, often in the context of underlying cortical atrophy from conditions such as AD or HD.
Transient global amnesia (TGA) is characterized by the sudden onset of a severe episodic memory deficit, usually occurring in persons over the age of 50 years. Often the amnesia occurs in the setting of an emotional stimulus or physical exertion. During the attack, the individual is alert and communicative, general cognition seems intact, and there are no other neurologic signs or symptoms. The patient may seem confused and repeatedly ask about his or her location in place and time. The ability to form new memories returns after a period of hours, and the individual returns to normal with no recall for the period of the attack. Frequently no cause is determined, but cerebrovascular disease, epilepsy (7% in one study), migraine, or cardiac arrhythmias have all been implicated. A Mayo Clinic review of 277 patients with TGA found a history of migraine in 14% and cerebrovascular disease in 11%, but these conditions were not temporally related to the TGA episodes. Approximately one-quarter of the patients had recurrent attacks, but they were not at increased risk for subsequent stroke. Rare instances of permanent memory loss after sudden onset have been reported, usually representing ischemic infarction of the hippocampus or medial thalamic nucleus bilaterally.
The ALS/parkinsonian/dementia complex of Guam is a rare degenerative disease that has occurred in the Chamorro natives on the island of Guam. Individuals may have any combination of parkinsonian features, dementia, and motor neuron disease. The most characteristic pathologic features are the presence of NFTs in degenerating neurons of the cortex and substantia nigra and loss of motor neurons in the spinal cord, although recent reanalysis has shown that some patients with this illness also show coexisting TDP-43 pathology. Epidemiologic evidence supports a possible environmental cause, such as exposure to a neurotoxin or an infectious agent with a long latency period. One interesting but unproven candidate neurotoxin occurs in the seed of the false palm tree, which Guamanians traditionally used to make flour. The ALS syndrome is no longer present in Guam, but a dementing illness with rigidity continues to be seen.
Rarely, adult-onset leukodystrophies, lysosomal storage diseases, and other genetic disorders can present as a dementia in middle to late life. Metachromatic leukodys-trophy (MLD) causes a progressive psychiatric or dementia syndrome associated with extensive, confluent frontal white matter abnormality. MLD is diagnosed by measuring arylsulfatase A enzyme activity in white blood cells. Adult-onset presentations of adrenoleukodystrophy have been reported in female carriers, and these patients often feature spinal cord and posterior white matter involvement. Adrenoleukodystrophy is diagnosed with measurement of plasma very long chain fatty acids. CADASIL is another genetic syndrome associated with white matter disease, often frontally and temporally predominant. Diagnosis is made with skin biopsy, which shows osmophilic granules in arterioles, or, increasingly, through genetic testing for mutations in Notch 3 (see earlier). The neuronal ceroid lipofuscinoses are a genetically heterogeneous group of disorders associated with myoclonus, seizures, and progressive dementia. Diagnosis is made by finding curvilinear inclusions within white blood cells or neuronal tissue.
Psychogenic amnesia for personally important memories can be seen. Whether this results from deliberate avoidance of unpleasant memories, outright malingering, or from unconscious repression remains unknown and probably depends on the patient. Event-specific amnesia is more likely to occur after violent crimes such as homicide of a close relative or friend or sexual abuse. It may develop in association with severe drug or alcohol intoxication and sometimes with schizophrenia. More prolonged psychogenic amnesia occurs in fugue states that also commonly follow severe emotional stress. The patient with a fugue state suffers from a sudden loss of personal identity and may be found wandering far from home. In contrast to neurologic amnesia, fugue states are associated with amnesia for personal identity and events closely associated with the personal past. At the same time, memory for other recent events and the ability to learn and use new information are preserved. The episodes usually last hours or days and occasionally weeks or months while the patient takes on a new identity. On recovery, there is a residual amnesia gap for the period of the fugue. Very rarely does selective loss of autobiographic information reflect a focal injury to the brain areas involved with these functions.
Psychiatric diseases may mimic dementia. Severely depressed or anxious individuals may appear demented, a phenomenon sometimes called pseudodementia. Memory and language are usually intact when carefully tested, and a significant memory disturbance usually suggests an underlying dementia, even if the patient is depressed. Patients in this condition may feel confused and unable to accomplish routine tasks. Vegetative symptoms, such as insomnia, lack of energy, poor appetite, and concern with bowel function, are common. Onset is often more abrupt, and the psychosocial milieu may suggest prominent reasons for depression. Such patients respond to treatment of the underlying psychiatric illness. Schizophrenia is usually not difficult to distinguish from dementia, but occasionally the distinction can be problematic. Schizophrenia generally has a much earlier age of onset (second and third decades) than most dementing illnesses, and is associated with intact memory. The delusions and hallucinations of schizophrenia are usually more complex and bizarre than those of dementia. Some chronic schizophrenics develop an unexplained progressive dementia late in life that is not related to AD. Conversely, FTD, HD, vascular dementia, DLB, AD, or leukoencephalopathy can begin with schizophrenia-like features, leading to the misdiagnosis of a psychiatric condition. Later age of onset, significant deficits on cognitive testing, or the presence of abnormal neuroimaging point toward a degenerative condition. Memory loss may also be part of a conversion disorder. In this situation, patients commonly complain bitterly of memory loss, but careful cognitive testing either does not confirm the deficits or demonstrates inconsistent or unusual patterns of cognitive problems. The patient’s behavior and “wrong” answers to questions often indicate that he or she understands the question and knows the correct answer.
Clouding of cognition by chronic drug or medication use, often prescribed by physicians, is an important cause of dementia. Sedatives, tranquilizers, and analgesics used to treat insomnia, pain, anxiety, or agitation may cause confusion, memory loss, and lethargy, especially in the elderly. Discontinuation of the offending medication often improves mentation.
The major goals of dementia management are to treat correctable causes and to provide comfort and support to the patient and caregivers. Treatment of underlying causes might include 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 the most frequently useful approach employed in a dementia clinic. 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 may respond to therapy. Antidepressants, such as SSRIs (Chap. 54), which feature anxiolytic properties but few cognitive side effects provide the mainstay of treatment when necessary. Anticonvulsants are used to control 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 infection, or 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 anticholinergics 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 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). Other compounds, such as anti-inflammatory agents, are being investigated in the treatment or prevention of AD. These approaches are reviewed in the treatment sections for individual disorders earlier in this chapter. 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.
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, short-term tasks, walks, and simple physical exercises. For many demented patients, memory for events is worse than for routine activities, and they may still be able to take part in physical activities such as walking, bowling, dancing, and golf. Demented patients usually 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 caretaker are useless and sometimes harmful. Explanation, 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 home, 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 breaks. 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.