β-Amyloid is a short fragment of the APP, typically 40–42 amino acids in length, which accumulates outside the cell during APP processing (Figs. 18-3 and 18-4). The tertiary structure of the 42–amino acid fragment is a β-pleated sheet that renders it insoluble. Consequently, it accumulates slowly, over many years, in the extracellular space and within synapses. In vitro studies confirm that β-amyloid is toxic to surrounding synapses and neurons, causing synaptic membrane destruction and eventual cell death. Transgenic mouse models show a clear association between accumulation of β-amyloid fragments, formation of amyloid plaques, and development of cognitive impairment.

Figure 18-3 Amyloidogenesis in Alzheimer Disease.

Figure 18-4 Amyloid Cascade Hypothesis in Alzheimer Disease.

In vivo, β-amyloid fragments coalesce to form “diffuse” or immature plaques, best seen with silver-staining techniques. Diffuse plaques, however, are not sufficient to produce dementia; many nondemented elderly patients have substantial depositions of diffuse plaques throughout the cortex, a condition termed pathologic aging. It is when these plaques mature into “senile” or neuritic plaques that dementia becomes more likely (Fig. 18-5, top). Senile plaques consist of other substances in addition to β-amyloid, including synaptic proteins, inflammatory proteins, neuritic threads, activated glial cells, and other components. Unlike diffuse plaques, senile plaques are composed of a central core of β-amyloid surrounded by a myriad of proteins and cellular debris. Senile plaques are distributed diffusely in the cortex, typically starting in the hippocampus and the basal forebrain. Senile plaque formation correlates with increasing loss of synapses, which correlates with the earliest clinical sign, namely, short-term memory loss. The anatomic pattern of progression gradually spreads to neocortical and subcortical gray matter of the temporal, parietal, frontal, and, eventually, occipital cortex. Subcortical nuclei become involved relatively late in the process.

Figure 18-5 Microscopic Pathology in Alzheimer Disease.

Neurofibrillary Tangles

The second pathologic hallmark of AD is the neurofibrillary tangle (Fig. 18-5, bottom). These lesions develop and conform to an anatomic pattern that correlates with the clinical syndrome; the number and distribution of tangles are directly related to the severity and clinical features of the dementia. Neurofibrillary tangles form intracellularly, consisting of a microtubule-associated protein, tau, which has a vital role in the maintenance of neuronal cytoskeleton structure and function. Tau is hyperphosphorylated in AD, causing it to dissociate from the cytoskeleton and accumulate, forming a paired helical filament protein structure. The cytoskeleton is compromised structurally and functionally, disrupting normal cell function. The most commonly used pathologic criteria for definitive AD diagnosis at autopsy require the presence of senile plaques and neurofibrillary tangles. Other lesions, such as Hirano bodies, are also seen in AD but have little diagnostic specificity.

Neurotransmitters

In addition to neuronal and synaptic loss, there is a gradual loss of various neurotransmitters. Acetylcholine synthesis is the earliest and most prominently affected. Most acetylcholinergic neurons arise within the nucleus basalis of Meynert in the basal forebrain (see Fig. 18-2). This nucleus is affected relatively early in the process; acetylcholine levels within the brain and spinal fluid of patients with AD quickly decline with disease progression. This observation supported the cholinergic hypothesis—that acetylcholine depletion results in the cognitive decline observed in patients with AD—eventually leading to the first symptomatic treatment of AD.

Risk Factors

Epidemiologic studies identify several potential risk factors for AD. The most consistent risk factors include advanced age, family history (especially in first-degree relatives), and ApoE genotype. Other risk factors include hypertension, stroke, and fasting homocysteine levels (Fig. 18-6). Because vascular risk factors are modifiable, they may affect risk reduction and treatment for patients with AD and those at risk for development of AD.

1. Advanced age is the single consistently identified risk factor for AD across numerous all-international studies. AD incidence and prevalence increase with advancing age, leading to the hypothesis that AD would develop in all individuals if they lived long enough. The true incidence in persons older than age 85 years is difficult to ascertain because of sharp decline in life expectancy. However, there are many instances of nondemented elders where no pathologic evidence of AD is found at autopsy, including in centenarians. Therefore, dementia is not considered a “normal” part of aging.

2. Family history of dementia is another consistent risk factor in many studies; however, the most common form of AD occurs sporadically. Establishing accurate family history of dementia is difficult because many of these patients’ relatives may not have survived into older ages where dementia risk is greatest. Rare, early-onset, presenile (before age 65 years) forms of AD occur with an autosomal-dominant pattern of inheritance. The genetic basis for many hereditary AD forms is identified. Most mutations affect the genes that encode APP and the presenilins. Each mutation leads to increased deposition of amyloid in affected individuals, predisposing to earlier onset. Individuals with trisomy 21 (Down syndrome) also have a high deposition of β-amyloid. AD develops in all patients with Down syndrome by age 35 years.

3. ApoE genotype is another genetic risk factor (Fig. 18-7). The three common allelic forms of this gene, epsilon 2 through 4, are encoded on chromosome 19. The presence of an e4 allele is associated with increased risk of AD and younger age at onset. This risk is greatly increased in e4 homozygotes. Conversely, the e2 allele appears to impart a protective, risk-lowering effect, as replicated in numerous international, population-based studies. The association between the ApoE e4 allele and AD seems to be disease specific. There is no clear association between e4 and other neurodegenerative or amyloid-based diseases.

The mechanism underlying this increased risk associated with the Apo e4 allele is not well understood but may relate to the role of ApoE in cell membrane repair. Phenotypically, the e4 cases have greater amyloid deposition than do the non-e4 cases. Although ApoE genotyping is available, it is not a diagnostic test for AD, nor is it recommended for routine testing. Most patients with AD are non-e4 carriers. ApoE genotyping is largely used in research, primarily as a biological marker to differentiate cases. Some studies suggest differential response to medications in cases stratified by ApoE genotypes.

4. In recent years, cerebrovascular disease and vascular disease risk factors have emerged as significant risk factors for AD. The presence of stroke increases the likelihood of dementia in old age. Diabetes, hypertension, and hyperlipidemia consistently elevate relative risk of dementia across international epidemiologic surveys of AD and dementia. Moreover, multiple observational studies show reduced risk among individuals receiving treatment for these conditions. This connection between AD and cerebrovascular disease may provide an important focus for premorbid dementia prevention. It is unknown whether secondary stroke prevention reduces the likelihood of dementia or its rate of progression. Nevertheless, assessment of stroke risk factors may become increasingly important for the management of dementia patients.

Figure 18-6 Risk Factors for Alzheimer Disease.

Figure 18-7 Possible Factors in Development and Progression of Alzheimer Disease.

Clinical Presentation

The early signs of AD may be subtle (Fig. 18-8). In the initial stages of AD, memory losses can be clinically distinguished from normal aging, although formal memory testing is often required to confirm suspicion of early dementia. The early signs of Alzheimer begin insidiously, progress slowly, and are often covered up by patients. Detection may be challenging even for close family members. The physician may observe changes in patient’s pattern of behavior, such as missing appointments or poor compliance with medications. It is important to discuss such issues openly with family members given the patient often cannot recall examples of memory problems. Indeed, it is common for patients to have limited insight into their deficit, and for family members to initiate an evaluation for memory loss. In these early stages, patients maintain their social graces. It is not uncommon during mental status testing to discover the significant cognitive problems concealed by a patient’s friendly and sociable affect. “Very pleasant” patients sometimes fool even seasoned geriatricians. The Alzheimer’s Association lists 10 key warning signs of AD.

Figure 18-8 Alzheimer Disease: Clinical Manifestations, Progressive Phases.

Commonly, AD begins with short-term memory loss, although atypical presentations sometimes develop. Often, patients have increasing forgetfulness of words and names, relying more on lists, calendars, and family members for reminders. Disorganization of appointments, bills, and medications becomes commonplace. Family members often notice increasing repetitiveness, patients asking the same question or repeating the same conversation minutes after it was completed. Patients may forget to convey telephone messages or turn off the stove, or lose track of where they place things. Moreover, their ability to recall these incidents is impaired. They “forget that they forget.” Affected individuals may become suspicious of others, thinking that misplaced items were stolen, for example.

Language function gradually declines. Word-finding and name-finding difficulties are common even in very early stages. Naming impairment and gradual loss of comprehension, expression, or both are universal. The perception of the temporal sequence of events is affected and disorientation eventually becomes pervasive. Geographic orientation declines, first affecting patients’ ability to navigate in unfamiliar environments and later within their homes. Visuospatial skills decline and construction deficits may occur early.

Behavior and personality in patients with AD are often affected; combativeness, irritability, frustration, and anxiety become extremely common. Many patients seek medical attention only when family members are alarmed by behavioral changes, rather than because of their earlier progressive memory loss. Psychotic features may become prominent. Some patients also develop delusional thoughts and hallucinations, most commonly visual or auditory in nature. These may be benign, understated, hidden, or frightening and may lead to severe agitation. Family members may not speak freely in the patient’s presence about these symptoms.

As cognitive and behavioral changes appear, the patients’ ability to maintain personal independence declines. Altered activities that may occur early include medication mismanagement, financial disorganization, burnt pots on the stove, and driving errors. Eventually patients require assistance with activities of daily living: personal hygiene/bathing, eating, dressing, and toileting. Often, by this stage, patients exhibit signs of Parkinsonism characterized by midline rigidity, symmetric bradykinesia and hypokinesia, stooped posture, and shuffling stride. The risk of falling increases. Seizures occur in up to 20% of cases. Myoclonic jerks are increasingly noted in advanced stages.

Later stages of AD are characterized by loss of bladder and then bowel control, failure to recognize family members, and eventually severe akinesia, requiring total nursing care. The most common cause of death is aspiration pneumonia. On average, AD has a duration of approximately 8 years. However, this varies substantially. Some patients live 20 years or more. Nursing care marks an important end point for many patients and their caregivers. The most common causes for nursing home placement include behavioral problems, immobility, and incontinence.

The Alzheimer’s Association provides a staging system to allow doctors and caregivers a frame of reference when discussing the patient’s level of impairment and possible future progression. It is important to emphasize that not every patient will follow through these stages in the same way or at the same rate.

Differential Diagnosis

The absence of motor deficits early in AD differentiates it from most other dementias. Other dementias lacking motor signs include amnestic syndrome (Korsakoff encephalopathy), Pick disease, vascular dementia, and HIV dementia complex. Depression can also produce dementia-like symptoms without motor deficits. Poor concentration and short-term memory impairment result from lack of effort, disinterest, or distractibility. “Pseudo dementia” due to depression is usually not progressive, and functional loss is often disproportionately severe relative to cognitive impairment (Fig. 18-9).

Figure 18-9 Treatable Dementias.

Reversible causes of dementia without motor signs include toxic and metabolic causes of chronic delirium. Chronic use of medication with anticholinergic side effects (e.g., antihistamines and tricyclic antidepressants) is a possible cause of chronic delirium that may mimic AD. β-Blockers, digoxin, H₂ blockers, and various antibiotics may also contribute to chronic delirium. Chronic mass effect, caused by a slow-growing tumor (Fig. 18-9), may also produce reversible cognitive impairment.

Dementia with motor deficits includes a longer list of possibilities. Thyroid disease, vitamin B₁₂ deficiency, and tertiary neurosyphilis are often considered; however, these conditions rarely cause dementia and usually present with characteristic metabolic or sensorimotor symptoms.

Normal pressure hydrocephalus is a relatively uncommon condition that late in its course may be characterized by a significant dementia (see Fig. 32-2). Typically, these individuals present with a broad-based magnetic gait as if their feet were partially glued to the ground. Eventually these patients may become unwittingly incontinent, unaware of their loss of sphincter control as the dementing process evolves. Although these patients most often have no identifiable cause on occasion, they have previously sustained a subarachnoid hemorrhage or meningitis leading to poor cerebrospinal fluid (CSF) reabsorption. This leads to the characteristic hydrocephalus without an associated loss of cortical mantel. A CSF shunt may lead to a remarkable improvement.

The presence of spastic hemiparesis or dysarthria raises suspicion of cerebrovascular disease. Parkinsonism is associated with Parkinson disease (PD) and dementia with Lewy bodies. Progressive ataxia occurs with multisystem atrophy. Chorea characterizes Huntington disease. As AD progresses to late stages, parkinsonism often becomes evident, making clinical differentiation from other parkinsonian diseases more difficult. AD may also coexist with cerebrovascular or Lewy body pathology to produce dementia with motor signs.

Dementia may be further characterized by cortical and subcortical cognitive features, which also helps differentiate between different dementing diseases. Subcortical features include slower mental processing, slow retrieval of information, and often significant extrapyramidal motor signs, including bradykinesia or adventitious movements.

Diagnosis

The subjective complaint of memory impairment is not useful for dementia screening because it is a common complaint in older adults. Prospective evaluation of individuals aged 65 years who have complaints of memory loss show that dementia develops in fewer than 9% within a 5-year follow-up. However, dementia develops during a 5-year prospective follow-up in 50% of patients aged 85 years who had no complaints of memory loss at baseline. Consequently, clinicians must be proactive, particularly with patients aged 85 years or older, and screen for cognitive impairment.

Proper clinical assessment requires a detailed history, preferably provided by a trustworthy, knowledgeable informant particularly a spouse or child. The history should describe the cognitive decline, in temporal sequence, from earliest suggestion of cognitive impairment to most recent events. Examination in early stages may reveal no neurologic deficits other than cognitive impairment. In later stages, or in patients with coexisting neuropathology, such as stroke, there may be motor deficits or other focal CNS findings on physical examination.

Mental Status Exam

The mental status examination (see Chapter 2) should assess all major cognitive domains, including Memory, Attention, Language, Construction, Orientation, Praxis, and Executive function (MALCOPE). Standardized global measures of cognitive function such as the MMSE are of limited diagnostic value. The widely used MMSE is relatively insensitive to the milder stages of AD. Other tests, such as the Montreal Cognitive Assessment test, include test items more suited to detecting earlier stages of cognitive impairment allowing improved sensitivity for detecting MCI. Another measure, the Alzheimer Disease 8 (AD8) is an informant-based tool that may shorten screening considerably. It must be emphasized that such instruments are not diagnostic tests, and interpretation of results must take into consideration level of education, native language, and physical or sensory impairment that might affect performance.

Impaired recording of information characterizes the memory loss of early AD. The inability to record information occurs when patients cannot recall information even with practice and when given hints or cues. Additional early cognitive deficits in AD include dysnomia, reduced verbal fluency (especially in word categories), orientation to time, and construction impairment. Having the patient list as many category words as possible within 1 minute provides a test of verbal fluency. For example, patients try to list animals, or words beginning with the letter s.

Clock drawing is useful when testing construction and executive function (Fig. 18-10). Patients draw a clock indicating 1:45, for example, on a blank sheet of paper. Their performance is observed from beginning to end, including the shape and size, number order and placement, hand size and placement, etc. The strategy (or lack thereof) used to draw the clock manifests itself readily, indicating impaired executive function in following a set of rules, or organizing and executing a multistep task. When patients finish, they should try copying a clock that the examiner draws in front of them. The numbers 12, 6, 3, and 9 are placed first, and the hands drawn accurately. If construction problems exist, patients have difficulty with the copy task as well as with the command task. If the copy is good, construction problems may not be a factor in cognitive impairment. There are many standardized, brief mental status tests like these available to clinicians. Routine use of such tests allows for longitudinal assessment and staging of dementia severity.

Figure 18-10 Nondominant Hemisphere Cortical Dysfunction.

Additional Testing

Treatment

Treatment of MCI

There are currently no Food and Drug Administration–approved therapies for MCI. Several studies of currently available AD medications in MCI have shown mixed results. Prescriptions for patients with MCI may not be covered by insurance. The largest of these studies suggested limited benefit for donepezil in MCI for all study participants. It is noteworthy that the effect of donepezil was more pronounced and long-lived in patients with the ApoE e4 allele. The risks and benefits should be discussed carefully with MCI patients before initiating treatment.

Treatment of Alzheimer Disease

General Approach

Much of the management of the patient with AD revolves around family interactions. Caregivers should provide patients with a comforting and respectful living environment. As their cognitive abilities slip away, it is important to provide a setting that preserves patient dignity. AD patients particularly benefit from a structured simple approach to daily life, maintaining a routine of social and physical activities (Fig. 18-12).

Figure 18-12 Daily Living Assessment.

MCI patients and those with very early AD and their caregivers should be counseled regarding driving risk as compared with cognitively healthy elder drivers. It is recommended that a driving performance evaluation be carried out. Even if felt to be safe, these patients should be reassessed on a regular basis, as progression of the disease will unequivocally require them to stop driving at a later stage of their illness.

Once an Alzheimer diagnosis is confirmed, it is imperative to protect the patient, and the public, from potential motor vehicle accidents. It is emphasized that the family and the treating physician assume responsibility for restricting the patient with AD from driving.

The assignment of simple daily chores where the individual can feel productive such as setting the table, folding clothes from the drier, or sweeping the sidewalk is recommended. Use of scheduled bathroom breaks or providing diapers keep the incontinent patient from the embarrassment of having soiled clothes that are socially obvious. Helping these individuals with simple activities of daily living such as dressing or feeding is eventually required. It is very important for the patient to have an easily seen identification bracelet. These patients have a tendency to “sun down,” becoming easily confused in the dark; a simple bedlight can be very helpful for preventing this problem. Have the patient flip through an old photo album to comfort them with familiar, pleasant memories of their younger years, their childhood home, their parents.

As they become increasingly confused, it is typical for Alzheimer’s patients to be more easily agitated; reassurance by relatives is often the best treatment. At times, simple anxiolytic medications, such as the SSRIs, may be useful. Eventually, a number of Alzheimer patients require long-term care to protect their family from the increasingly demanding nursing support that will eventually totally consume them emotionally and physically. The family should be reassured that the patient’s cognitive decline prevents them from harboring any resentment for such a placement, otherwise their feelings of guilt may be overwhelming. This is a most challenging and sad experience for any family; their physicians and caregivers need to be very proactive and supportive.

Cholinesterase Inhibitors

The various agents available include donepezil, rivastigmine, and galantamine. Several studies show these medications reduce the decline on standardized tests better than placebo when used for 6–12 months, but do not slow the degenerative process. These drugs may provide some benefit if taken consistently over time. When initiating therapy patients need to increase the dose gradually. Additionally, the eventual maximum required doses of these medications is not predictable. Cholinesterase inhibitors are generally utilized in patients with mild to moderate AD (Fig. 18-13).

Figure 18-13 Pharmacologic Management.

If these medications are stopped, patients may experience decline to the severity level that they would have reached without the medication. In such cases, restarting the medication may not regain lost ground. These medications are primarily effective at maximal doses. Rivastigmine is most effective at 4.5 or 6 mg twice daily. Recently, rivastigmine became available in transdermal patch form, significantly reducing the rate of side effects. Donepezil is only mildly effective at 5 mg/day, but greater benefit occurs with 10 mg/day doses. Similarly, galantamine should always be titrated to 12 mg twice daily to maximize benefit. Galantamine is available in an extended-release formulation to allow for once-daily dosing. If patients do not tolerate these drugs at lower doses, it is prudent to try a different agent. It is unusual for patients to be unable to tolerate at least one of these three drugs. Typical adverse effects that may cause discontinuation include cholinergic effects, especially vomiting and persistent loose stools.

Memantine

Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist that is approved for patients with moderate to severe AD. The involvement of glutamate-mediated neurotoxicity in the pathogenesis of AD is a hypothesis that is gaining increased acceptance. The keystone underlying this proposal is the assumption that glutamate receptors, in particular of the NMDA type, are overactivated in a tonic rather than a phasic manner in AD. Such continuous, mild, chronic activation may lead to neuronal damage/death. Memantine may improve memory by restoring homeostasis in the glutamatergic system—too little activation is bad, too much is even worse. Furthermore, memantine shows promise when used in combination with cholinesterase inhibitors. Memantine is primarily used as a supplemental medication in moderate to severe stages of AD. Clinical trials demonstrated that in combination with donepezil, there is improved stability of cognitive performance for 6–12 months compared to donepezil or memantine alone.

The current pharmacologic treatment of AD is purely symptomatic. Long-term benefits of these medications may include a delay in need for nursing home placement. For example, using donepezil for 9–12 months may delay nursing home placement by approximately 20 months. However, functional decline continues and reasonable expectations for the effects of these medications must be emphasized to patients and their families. These treatments are associated with reduced behavioral problems and may reduce the need for sedatives in some patients. Determination of medication efficacy is challenging. When the maximum dosage is reached, annual follow-up examination is beneficial.

Repeated standardized mental status examinations are helpful. For example, the average rate of decline on the MMSE in AD is approximately 3 points per year. When a patient shows less than 3 points of decline, the medication may be helping. This method approximates the same measurements used in clinical trials of AD to assess medication efficacy. Such tests, in combination with the caregivers’ subjective impressions, can help determine whether to continue or change medications.

Other potential therapies do not have unequivocal evidence to support their use. Ginkgo biloba may be useful with various unspecified (mixed) dementia, but efficacy data are lacking. Ginkgo showed no benefit versus placebo for treatment of AD in a large NIH-sponsored clinical trial. There is no reproduced clinical study to support utilization of anti-inflammatories (shown to lower the risk of AD in epidemiologic studies) or antioxidants. Estrogen treatment is not effective in the treatment of AD, and postmenopausal estrogen replacement in midlife may increase risk of dementia.

AD treatments of the future will likely focus on preventive strategies, including cerebrovascular risk factors in premorbid individuals at risk. For patients already demonstrating overt AD, there is increasing interest in disease-modifying therapies. Most noteworthy are a group of drugs that reduce accumulation of β-amyloid in the brain. These include a range of agents from γ-secretase inhibitors to monoclonal antibodies against amyloid.

Dementia with Lewy Bodies

Clinical Vignette

A 78-year-old man is referred for evaluation of intermittent confusion. During the past 3 years, he had developed depression with prominent psychotic features requiring two psychiatric hospitalizations. The patient was initially very depressed and withdrawn. A trial of fluoxetine led to some disorientation and anxiety. When his hallucinations became persistently threatening, and his family could no longer distract his attention, he was switched to quetiapine. Initially, he had a poor response to low doses; gradual increases in dosage led to severe drowsiness and stiff gait. His first inpatient stay was related to increasing agitation at home because of vivid hallucinations characterized by a sensation of intruders coming into his home. During this hospitalization, he was treated with risperidone. Although his psychotic symptoms seemed to improve, he developed severe stiffness and a shuffling gait, prone to falling. Despite such he remained on this drug for nearly a year.

Once the medication was discontinued, the patient became more alert and his gait improved. However, he never returned to baseline, remaining slower than his baseline. Moreover, he appeared more forgetful, needing frequent reminders and prompts to complete tasks. Some days he seemed intoxicated, confused, disoriented, lethargic, and withdrawn. On other days, he appeared brighter, more alert, and competent. Subsequently, his psychotic symptoms returned; this led to his second psychiatric hospitalization. Formal mental status testing demonstrated significant impairment of both memory and visuospatial processing. A second trial of low-dose risperidone subdued the patient once again, but his mobility deteriorated to the point of needing a wheelchair.

During neurologic assessment, his wife revealed he had experienced severe nightmares over the past 10 years, causing him to yell, punch, and kick in his sleep. This forced his wife to sleep in another room. He fell out of bed a number of times. The patient never recalled these events. His exam was notable for an MMSE score of 22/30 and moderate symmetrical extrapyramidal motor signs, including, retropulsion, bradykinesia, and rigidity. There was no significant tremor. He did not initiate conversation and his affect was generally flat. Brain MRI showed diffuse atrophy and minimal microvascular changes. There were no metabolic signs of toxic/metabolic encephalopathy. Electroencephalography (EEG) revealed bitemporal slowing without epileptiform discharges or rhythmic abnormality.

Treatment with rivastigmine, a cholinesterase inhibitor, led to significant reduction in confusion and hallucinations. He was then taken off risperidone and remained psychiatrically stable for over a year. Although his Parkinsonism persisted, he no longer needed an assistive device to get around. Attempts at treatment with levodopa failed due to confusion and recurrent hallucinations. This patient’s neurologic status slowly declined, with occasional bouts of agitated confusion. After a 5-year period nursing home placement was necessitated.

Pathogenesis

Lewy bodies (LBs), originally described at the turn of the 20th century in the substantia nigra of patients with PD, also occur in widespread areas of the cortex and other subcortical nuclei in many cases of Parkinsonism with dementia. Neurodegenerative changes with LB formation were first linked with dementia in the 1960s. Early case descriptions noted LBs distributed diffusely within the cerebral cortex and brainstem and were termed diffuse Lewy body disease. Subsequent neuropathologic studies found a surprisingly high frequency of LB pathology in the brains of patients with AD. These cases commonly show coexisting AD lesions and LBs and were classified as LB variant of AD.

In general, “variant” cases demonstrated relatively less AD pathology (especially NFTs) than pure AD cases matched for clinical dementia severity. Reports of Lewy neurites located in the CA2 region of the hippocampus suggest that dementia with Lewy bodies (DLB) is a unique neurodegenerative cause of dementia, independent of AD pathology. Interestingly, LBs are also found in the brains of patients with hereditary AD, suggesting a possible pathophysiologic link between these disorders. And LBs are occasionally found in the brains of nondemented elders. Few familial cases of DLB are described, and there are no known mutations associated with hereditary DLB.

A definitive pathologic diagnosis of DLB requires only the presence of cortical LB pathology, regardless of coexisting AD pathology. Many of these cases also fulfill pathologic criteria for a definitive diagnosis of AD and clinical criteria for a diagnosis of probable or possible AD. Consequently, controversy surrounds this diagnosis, and no agreement exists on a single-disease classification of cases with concomitant LB and AD pathology. Dementia autopsy series suggest that DLB is the second most common cause of elderly dementia after AD. Clinical epidemiologic studies are lacking.

Lewy bodies are intracytoplasmic inclusion bodies. They are the hallmark histopathologic lesions of primary PD where these occur within neurons of the substantia nigra and other brainstem nuclei. A spherical shape and eosinophilic staining properties characterize LBs morphologically (Fig. 18-14). The center stains densely, and a pale halo surrounds it. In cases of PD with dementia, LBs occur in cortical neurons and other gray matter regions. Cortical LBs are characterized by irregular shapes and do not have the characteristic pale halo seen with PD. Hence, cortical LBs can easily be missed with routine neuropathologic staining techniques. Moreover, LBs do not stain with silver-based stains often used to identify neuropathologic lesions in AD. A synaptic protein called alpha synuclein is the major LB component. Specific immunohistochemical stains for α-synuclein greatly improve LB detection throughout the brain. Ubiquitin staining also detects these lesions well. The function of α-synuclein is not completely understood. It may have a role in regulating presynaptic, nerve-terminal vesicular function. Mutations in the α-synuclein gene produce a mixed phenotype within members of affected kindred. Symptoms are predominantly PD-like, with cases of dementia occurring less frequently. α-Synuclein appears to be the main pathologic substrate in multiple systems atrophy (MSA) as well.

Figure 18-14 Dementia with Lewy Bodies and Huntington Chorea.

Clinical Presentation and Differential Diagnosis

DLB patients characteristically have cognitive decline, behavioral change, and motor dysfunction. The most crucial component for this clinical diagnosis is dementia, although the initial manifestations of DLB may be characteristically motor or behavioral impairment. A critical clinical feature of DLB is fluctuating mental status, which may be dramatic, ranging from relatively lucid to severe confusion. Episode duration and frequency vary greatly, lasting minutes, days, or weeks. Awareness and arousal levels may vary and include periodic somnolence and unresponsiveness. Transient neurologic symptoms (i.e., dysarthria, dizziness, or unexplained falls) may occur. Such episodes may suggest complex partial seizures, delirium, or transient ischemic attacks. Although patients with AD have “good and bad days,” the fluctuations of patients with DLB are more pronounced. Clinical assessments may vary significantly from visit to visit. Caregivers often become stressed by the unpredictability of symptoms.

The cognitive impairment in DLB may be similar to that in AD, although there are some important differences. The memory loss in DLB tends to be less severe than in AD; however, retrieval deficits are more pronounced than encoding deficits. Therefore, patients with DLB have a greater problem retrieving previously learned information and show a greater benefit with cueing than do patients with AD. In AD, encoding difficulty predominates, and consequently, patients do not benefit as much from practice or from cueing. In DLB, visuospatial and construction skills may be impaired earlier than in AD. Patients with DLB may present with geographic disorientation in familiar neighborhoods or even in their own homes while their memory is mildly impaired. Executive function is also impaired significantly earlier in DLB than in AD, manifested as impaired problem solving, inability to complete tasks, and marked disorganization of daily activities. Formal neuropsychological tests help to differentiate AD from DLB, particularly in early disease stages.

Prominent psychotic features, including hallucinations and delusions, also develop in patients with DLB, although such symptoms are not typically seen early in the disease course. In DLB, psychosis can be an early and severely disabling feature, sometimes heralding the onset of dementia. Recurrent vivid and detailed visual hallucinations are particularly prevalent in DLB. The emotional response to these hallucinations ranges from relative indifference to severe agitation and combativeness. Agitation typically occurs when the patient has little insight or the hallucinations are perceived as threatening. Hallucinations having other sensory (i.e., nonvisual) also occur but are less specific for DLB. Delusions are frequently bizarre, complex, and unrelated to cognitive impairment. In contrast, delusions in patients with AD often occur from misinterpretation secondary to forgetfulness. For example, patients with AD may become suspicious of others when they cannot find things they misplaced. Other behavioral problems such as depression and anxiety also occur frequently but are not unique to DLB (Table 18-1).

Table 18-1 Comparison of DLB and AD Manifestations

Manifestation	DLB	AD
Memory loss	Less pronounced, poor retrieval	Characteristic, poor encoding
Visuospatial and construction skills	Severely impaired early	Mildly impaired early
Executive function	Impaired earlier	Impaired later
Fluctuating mental status	Pronounced	Less pronounced
Psychotic features	Can be prominent early	Not typical early
Delusions	Bizarre, unrelated to impaired cognitive function	Often related to memory loss
Depression and anxiety	Common	Common
Parkinsonism	Within 1–2 years of dementia	Later in disease course

AD, Alzheimer disease; DLB, dementia with Lewy bodies.

Motor signs of DLB include all the typical features of PD; however, here the bradykinesia and rigidity are more characteristic, whereas tremor is relatively uncommon. Signs tend to be distributed more symmetrically and axially than they are in PD. Unexplained falls occur early and often in patients with DLB, unlike postural instability in PD, which tends to mark more advanced disease. Response to dopaminergic medications is limited or absent with DLB, although they may exacerbate hallucinations. Parkinsonism is also seen in advanced AD and in frontotemporal dementia. When Parkinsonism occurs within 1–2 years of dementia, either before or after the onset of cognitive decline, DLB is a prime consideration in the differential diagnosis.

Diagnosis

The clinical evaluation for DLB is similar to that for AD. Formal neuropsychological tests can be useful early in the course to differentiate DLB from AD or other dementing illnesses. There are no specific findings on blood or spinal fluid analysis. Brain MRI and CT do not reveal any specific abnormalities. Volumetric MRI studies suggest there is relative sparing of hippocampal volumes in DLB cases. EEG shows nonspecific abnormalities, including focal or diffuse brain wave slowing. PET imaging may be helpful in the future, particularly in highlighting affected dopaminergic systems.

Treatment

Cholinergic CNS deficits occur in DLB as they do in AD. Some studies suggest that DLB is associated with greater cholinergic deficit than is AD. In theory, cholinesterase inhibitors—donepezil, rivastigmine, and galantamine—should be effective, and small, controlled clinical trials show that these medications have a favorable effect on cognitive outcome measures in DLB. The duration of drug benefit is not established but may be similar to that in AD. Cholinesterase inhibitors offer only symptomatic benefits, having no known effect on the degenerative process. Therefore, patients can delay cognitive progression for a limited amount of time only. It is not clear when these drugs truly lose their efficacy. As in AD, drug discontinuation, especially after several years of treatment, may result in rapid cognitive and functional decline. These drugs may reduce the extent and severity of cognitive fluctuations and behavioral problems throughout the disease course.

When psychotic features are disabling, use of atypical neuroleptic agents is common, similar to their efficacy in cases of PD with psychotic features. The efficacy of these drugs for DLB has not been studied in controlled clinical trials. As atypical neuroleptics produce fewer extrapyramidal adverse effects than “typical” neuroleptics, this must be an important consideration when treating DLB patients. However these atypical neuroleptics are associated with increased morbidity and mortality in nursing home patients. Their use in the elderly population with dementia, therefore, requires careful assessment of risk and benefit and close monitoring if used at all.

Additionally, patients with DLB often exhibit sensitivity to various centrally acting drugs, most prominently to neuroleptic medications, and may become completely incapacitated by severe akinesia, dystonia, or delirium. The incidence of neuroleptic malignant syndrome in DLB is unknown. Good clinical judgment and conservative dosing strategies should be used in every case. The treatment of psychotic features in DLB is one of the most challenging management issues. If at all possible, neuroleptic medication should be avoided.

Often, psychotic symptoms distress caregivers more than patients, but this should not prompt immediate initiation of such medications. Recently, use of cholinesterase inhibitors, such as rivastigmine, was shown to reduce hallucinations in patients with DLB. Therefore, cholinesterase inhibitors remain the first line of treatment in DLB, including cases with prominent psychotic features. Treatment of motor symptoms is based largely on anecdotal reports. Dopaminergic drugs may be tried with caution in selected cases; however, psychosis may be exacerbated, and efficacy is often minimal.

As in AD, caregiver counseling about the disease course and realistic treatment expectations is paramount for successful monitoring, intervention, and improved quality of life. The most common causes for nursing home placement in the demented population include psychosis with behavioral problems and parkinsonism. Patients with DLB are therefore at high risk for early nursing home placement. As in AD, use of cholinesterase inhibitors may help to delay nursing home placement.

Frontotemporal Lobar Dementia

Clinical Vignette

During the preceding 2-year period, a 55-year-old man previously regarded by his family as “thoughtful, accomplished, and intelligent,” began neglecting both his home and occupational responsibilities. He became increasingly inflexible and uncaring. At work he missed several deadlines, and clients complained that he “forgot” about them. Consequently, he stopped working. He became more impulsive, driving late at night without reason. He obsessively checked his furnace numerous times each day and night.

Concomitantly his wife became increasingly tearful and anxious; however he seemed unconcerned about her turmoil and unaware of his own personality changes. His personal hygiene declined; he stopped shaving and dressed sloppily. At social functions, he interrupted conversations, touched people inappropriately, and spoke in a tasteless and loud fashion, often embarrassing his wife. Despite these changes, he continued to garden and perform other favored activities, albeit with less attention to detail.

On examination, he was disheveled, malodorous, and unshaven, wearing unwashed clothes. He spoke out of turn and repeatedly said, “I have to go.” At times he attempted to leave the examination room, but returned with gentle coaxing. His affect was otherwise flat. He gave concrete, terse responses to questions, mostly affirmative, negative, or stating, “I don’t know.” Naming was impaired. He followed some simple commands, but more complex sequences were incomplete or disorganized. His memory was relatively intact, although retrieval of relatives’ names was impaired. He listed only five animals in 1 minute, a significant impairment given his postgraduate education level. Other than motor impersistence and a mild rooting reflex, bilaterally, the results of his primary neurologic examination were relatively unremarkable. During the next 2 years, he became increasingly withdrawn, spoke less, and required prompting for virtually every activity.

A brain MRI demonstrated lateral frontal lobe atrophy albeit slightly asymmetric, as it affected the left side slightly more than the right. Blood work, CSF studies, and EEG results were unremarkable.

Pathogenesis

This case exemplifies evolving dementia related to a degenerative process primarily confined to the frontal and temporal lobes. A previously accomplished individual initially demonstrated signs of intellectual decline, diminished sense of responsibility, and loss of social graces punctuated by a disinhibited personality. More than a century ago, Arnold Pick was the first to describe behavioral and personality changes associated with frontotemporal atrophy. He subsequently also was the first to recognize progressive aphasia and progressive apraxia syndromes on the basis of focal lobar atrophy. Concomitantly, Alois Alzheimer described the histopathology of what came to be known as Pick disease or FTD.

Frontotemporal dementia features were subsequently described in other, pathologically different processes, including corticobasal degeneration, motor neuron disease (MND)–type dementia, primary progressive aphasia (PPA), and dementia lacking distinctive histology. Additionally the presence of diseased subcortical regions leads to extrapyramidal features, including akinesia and rigidity. In other cases, similar pathologic features appear in cortical regions other than the frontal or temporal lobes. For example, in PPA, parietal cortical involvement may predominate. The term frontotemporal dementia does not fully account for the spectrum linking pathology and clinical phenomenology. As the disease progresses, lobar degeneration occurs, often asymmetrically and bilaterally. The term Pick complex has been suggested, instead of FTD, to provide a more inclusive diagnostic entity to encompass the pathologic and clinical features of these dementias inclusively. Perhaps, more specifically, the term frontotemporal lobar degeneration (FTLD) encompasses the myriad pathologic substrates of this primary neurodegenerative dementia, whereas the terms FTD, PPA, CBD, etc. describe the corresponding clinical syndromes.

The basic histopathology of FTLD is rather nonspecific, characterized by gliosis, neuronal loss, and spongiform degeneration in superficial cortical layers, with predilection for frontal and temporal lobes. The molecular pathology, however, involves several proteins (tau and TDP-43) distributed in different cortical and subcortical distributions, and corresponds to specific clinical manifestations of various FTD syndromes. The formation of Pick bodies and Pick cells occurs in less than 25% of cases. Pick bodies are round, argyrophilic intracytoplasmic inclusions, easily detected by most silver-staining techniques and mildly eosinophilic on standard hematoxylin and eosin staining. Cortical Pick bodies form in small neurons; they are pathognomonic for Pick disease when they occur in the dentate gyrus. Pick cells are large, ballooned neurons that affect superficial cortical cells. In many cases, evidence exists of complement and microglial activation, suggesting that inflammatory mechanisms may play a role in pathogenesis. In Pick disease, degeneration is restricted to frontal and temporal lobes, producing a characteristic “knife-edge” atrophy of sulci.

A positive labeling for pathologic tau protein within Pick bodies, astrocytes, and oligodendrocytes is common thread in the pathogenesis of these disorders, termed tauopathies. Associated dementias of the tauopathy group (FTLD-tau), besides Pick disease, include progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and amyotrophic lateral sclerosis–Parkinsonism complex of Guam (ALS-PDC). Tau is involved in the pathogenesis of AD. However, the mechanism by which tau is affected in AD and Pick disease differs. A range of mechanisms may transform tau, determining the final pathologic and clinical picture.

Other FTD cases demonstrate no significant tau labeling. Many of these conditions are associated with intracytoplasmic and intranuclear aggregates of the ubiquinated protein called TDP-43. These forms of FTLD (FTLD-U) occur in the behavioral subtype of FTD (bvFTD), FTD in motor neuron disease (FTD-MND), semantic dementia (SD), and progressive nonfluent aphasia (PNFA).

There are other non-tauopathy and non-TDPopathy related molecular pathologies producing FTD syndromes. Familial forms of FTLD are quite common (up to 40% of cases). Four genes for FTLD are identified: the microtubule-associated protein tau gene (MAPT) associated with tau aggregates, the progranulin gene (PGRN) associated with TDP-43 aggregates, the charged multivesicular body protein 2B gene (CHMP2B), and the valosin-containing protein gene (VCP).

Clinical Presentation

Frontotemporal dementia/Pick disease accounts for approximately 15–20% of all degenerative dementias. The typical age of onset is broad, ranging from 21 to 75 years, usually affecting persons aged 45–60 years. Men and women are equally affected. The median illness duration is 8 years, although this ranges from 2 to 20 years. Family history is present in more than 50% of cases.

Behavior Subtype of Frontotemporal Dementia (bvFTD)

The distinguishing clinical features of bvFTD and Pick disease are striking behavioral and personality changes. Most patients are unaware of their problem. There is often a major breakdown in social behavior, personal hygiene, and affect. Mental processes become concrete and perseverative (Fig. 18-15). Three major behavioral subtypes include disinhibition, apathy, and stereotypic behavior.

a Disinhibited patients exhibit overactivity, restlessness, inattention and distractibility, impulsivity, lack of application, and impersistence. There is mental disorganization and frequent set shifting, moving unproductively from one activity or conversation topic to the next. Demeanor is often inappropriately jocular and socially inappropriate. Some exhibit signs of the Klüver–Bucy syndrome, namely, hyperorality, hypersexuality, and utilization behavior. These patients frequently gain weight rapidly as a result of overeating. They may impulsively touch or pick up objects within sight or within reach. In extreme cases, incontinence of stool and urine may be associated with coprophagia, sometimes in an otherwise alert and oriented patient.

b Apathetic patients lack motivation and appear pseudo-depressed. Left alone, they spend the day sitting or lying in bed. They stop bathing and grooming and dress sloppily. Behavior is “economical,” with minimal expenditure of energy or mental effort. These patients often have prolonged response latency to questions, although the eventual answer is often accurate. There is economy of speech, with many responses characterized by single words or short phrases with no attempt at elaboration. Speech prosody may be lost. Perseveration of verbal and motor activity is common. There may be a loss of concern for self and others because patients become emotionally shallow. Apathetic states are commonly mistaken for depression, and treatment with antidepressants is typically not effective.

c Stereotypic behavior includes repetitive, ritualistic, and idiosyncratic behaviors. These individuals require a rigid daily routine, becoming agitated when their routine is interrupted. They may repeat, perseverate, the same story verbatim and with the same prosodic inflection numerous times during a single clinic visit. This is akin to “listening to a broken record.” They evidence mental inflexibility and difficulty shifting mindset. Ritualistic behaviors, picking lint from the floor, rearranging the silverware drawer, rewriting a letter, etc., have a compulsive quality absent the anxiety associated with obsessive-compulsive disorder. The clinical features often overlap during the course of illness.

Figure 18-15 Lobar Dementias.

Patients may present with predominant apathetic features only to later develop increasingly disinhibited or stereotypic behavior or both. As symptoms progress, most patients experience akinesia, progressive rigidity, mutism, and incontinence, requiring total nursing care. Features of disinhibition are associated with degeneration within the orbital frontal and adjacent temporal lobes. Apathetic features correlate with degenerative changes within the dorsolateral frontal lobes. Stereotypic behavior type seems to correlate with more widespread involvement of frontal and temporal lobes, although greater emphasis may exist in the region of the cingulate gyrus.

Cognitive function may be relatively spared initially, so that mental status examination may be notable only for distractibility, inattentiveness, or perseveration rather than clear impairment of memory or constructional apraxia. One of the more striking cognitive features of bvFTD is executive dysfunction seen on sorting and sequencing tasks, loss of verbal fluency, and impairment in general problem-solving skills.

Frontotemporal Lobar Degeneration with Motor Neuron Disease

Frontotemporal lobar degeneration with motor neuron disease presents most often in men younger than age 65 years. Characteristic FTD typically precedes onset of motor neuron symptoms, and disinhibited-type behaviors predominate. The motor neuron component leads to a more rapid decline and death in these cases. Consequently, akinesia and mutism are not often seen. The duration of illness is typically 2–3 years. A family history of disease is only occasionally found.

Primary Progressive Aphasia

Primary progressive aphasia (PPA) presents in fluent and nonfluent subtypes. In both conditions, progressive aphasia is the predominant clinical feature, often remaining the only feature throughout the illness. Typically women, patients with fluent PPA usually present between the ages of 50 and 65 years. Illness duration ranges from 3 to 15 years. There is gradual loss of comprehension and naming, with relatively less impairment in reading and writing. Behavioral features include mental rigidity, stereotypic behaviors, self-centeredness, and disregard for personal safety. Many patients are easily agitated. Memory, calculations, and constructional skills are relatively spared, whereas visual agnosia and prosopagnosia may occur relatively early.

Semantic Dementia may present as a fluent progressive aphasia and visual agnosia. Nonfluent PPA patients typically present at the same ages. Men and women are affected equally. Illness duration is between 4 and 12 years. There is overall good comprehension, with impaired verbal expression. Patients have effortful, agrammatic, stuttering speech, with impaired repetition and word retrieval. Reading and writing are also affected, but less so than speech. These individuals are aware of their impairment and become frustrated and depressed easily. Behavioral problems develop later in the disease and may include any FTD symptoms. Nevertheless, the focal characteristic of PPA clinically differentiates it from classic FTD.

Diagnosis

Brain MRI, important for excluding other mechanisms for frontal lobe syndromes such as tumor or infection, may demonstrate atrophy predominating within frontal and temporal lobes in neurodegenerative disease. Brain imaging may show focal lobar or asymmetric atrophy in PPA cases. EMG in cases of FTD/MND may be diagnostic. Brain SPECT may show deficits in a similar distribution, although it does not have a sensitivity that provides a definitive diagnosis. Brain FDG-PET scans are useful in distinguishing FTLD from AD. EEG is normal, especially early in the disease course. Blood work and CSF studies are not helpful. Formal neuropsychological tests are helpful in localizing deficits in cortical function.

Treatment

Treatment of FTD is supportive. There is no proven benefit to using the cholinesterase inhibitors, commonly used in AD. Caregiver education and reduction of caregiver stress are essential in successful management of agitation and other behavioral problems. When patients become aggressive and combative, caregivers tend to oppose their behavior. Distraction and redirection are more effective than verbal instruction in these instances.

Limited use of sedatives is recommended to avoid overmedication. Paradoxically, benzodiazepines may exacerbate agitation in some patients. SSRIs may reduce anxiety and restlessness. Other drugs, including mood stabilizers, and atypical anxiolytics (e.g., trazodone, buspirone), sometimes help with problematic behavior when used as monotherapy or in combination. There are few randomized clinical trials of classic and atypical neuroleptics in FTD, but they may be necessary in cases of aggressive or violent behavior.

Vascular Cognitive Impairment

Clinical Vignette

A 67-year-old man with a history of hypertension and coronary artery disease, who had lived alone since his wife’s death 3 years previously, came to the clinic at his daughter’s insistence because he had become increasingly complacent and inactive. The daughter noted that he had stopped fixing his own meals and might not eat unless she brought something to him. He tended to eat junk food and sweets. She was unsure whether he was taking his antihypertensive medications regularly. He had neglected housework and the yard, stopped balancing his checkbook, and decreased participation in social activities.

The patient reported dizziness, and gradually worsening unsteady gait. Although he had not fallen, he felt off balance especially when turning. He also reported urinary frequency and occasional incontinence. He denied depression but was not particularly happy. He gave up previous interests because they were “too much to keep track of.”

Five years previously, the patient had experienced a stroke causing transient weakness on the right side but no residual deficit. Approximately 1 year previously, he had stayed in the hospital for a transient ischemic attack characterized by transient right-sided weakness and dysarthria. Brain MRI showed extensive subcortical and periventricular white matter changes and numerous microvascular infarcts in the basal ganglia.

On exam, his affect was flat; he was slow to respond. Mental status examination results showed impaired motor sequencing, executive dysfunction, and memory impairment. He could not spell world backward. He was able to register four words but recalled only one of four spontaneously. With cueing, he recalled all four items. He could not draw a clock to command but copied a clock, drawn by the examiner, well. He had evidence of a wide-based, spastic gait, with bilateral Babinski signs. Stride and arm-swing amplitudes were reduced. Muscle stretch reflexes were brisk throughout. His blood pressure was 160/86 mm Hg. Repeated MRI demonstrated progressive subcortical and periventricular microvascular changes. Blood test results revealed normal cell counts, a normal B₁₂ level, and a normal TSH level. Serum RPR was nonreactive. The fasting serum homocysteine level was slightly increased, at 17 mol/L.

Pathogenesis

The association between cerebrovascular disease and dementia has been recognized for many years. Some authors propose using the term vascular cognitive impairment (VCI) to describe the contribution of cerebrovascular disease to various dementia syndromes. This applies whether the dementia is primarily related to cerebrovascular disease or mixed with another dementing disorder. Indeed in the early and mid-20th century, cerebrovascular disease was postulated to be the specific etiology for senile dementia. It was not until the 1960s, that AD was recognized to be the most common pathophysiologic mechanism for the majority of individuals who have dementia. In subsequent decades, the concept of VCI underwent several revisions. Given the wide array of clinical syndromes possible with stroke, VCI presentation varies considerably. The heterogeneity of stroke complicates one’s ability to specifically define VCI as a single clinical entity with specific diagnostic criteria. Autopsy series show cerebrovascular disease coexisting with AD, and influencing clinical dementia, in approximately 20% of dementia cases.

Vascular cognitive impairment occurs when multiple cerebral infarcts or hemorrhages cause enough neuronal or axonal loss to impair cognitive function. The core pathologic VCI syndromes include (1) lacunar disease (penetrator-vessel disease), (2) multi-infarct dementia (MID; medium- and large-vessel disease), (3) strategic single-infarct dementia (thalamus, angular gyrus, e.g.), and (4) Binswanger dementia. These conditions are not mutually exclusive; there are many instances wherein the patient has a mixture of small-vessel and medium-vessel infarcts. Furthermore, age-related microvascular disease, frequently defined by brain MRI scans of elderly patients, may also contribute to the onset, progression, and symptoms of old-age dementia.

Epidemiology

The risk of VCI increases with age just as the risk of stroke increases with age. Most epidemiologic studies of dementia do not differentiate among AD, cerebrovascular, and mixed dementia. The prevalence of a pure vascular cause of dementia in autopsy studies is probably less than 10% of old-age dementia cases. However, the prevalence of VCI may be much greater. There is often a prevalence of patients with mixed dementia, including the effects of both vascular and neurodegenerative disorders; this in fact may be much higher than current estimates. In general, diagnostic criteria for VCI lack sufficient sensitivity and specificity to recognize cases of VCI reliably. Many patients may also have other dementia types, like AD, DLB, or normal pressure hydrocephalus. Interestingly, cerebrovascular disease is extremely common and shares several risk factors for AD. These include hypertension, diabetes, and hyperlipidemia. Recent investigations also suggest a link between AD and metabolic syndrome. Stroke is identified more commonly in AD patients than in age-matched controls. It is, therefore, reasonable to suspect that cerebrovascular disease contributes significantly to old-age dementia.

Clinical Presentation and Differential Diagnosis

The potential for prevention of VCI highlights the importance of recognizing and treating the various vascular causes that may predispose to or contribute to dementia. Standard criteria for diagnosing vascular dementia are difficult to define given the variable nature of cognitive deficits following stroke, mainly depending upon the anatomical location of the stroke. The most common dementia is AD, typically characterized by short-term memory loss in the early stages. While vascular dementia may present in this way, it is not necessarily the “cardinal” feature of VCI. The cognitive consequence of stroke may include executive dysfunction, neglect, or aphasia. Additionally, the degree of cerebrovascular disease progression varies greatly. Residual symptoms following acute stroke may seem to initially but incompletely improve and then later on contribute to eventual cognitive dysfunction in the setting of mixed demention. Moreover, there is now considerable evidence that stroke increases the risk of AD. “Silent” lacunar infarcts are particularly associated with increased risk of AD.

Almost all standard diagnostic criteria for VCI require imaging studies demonstrating evidence of stroke (Fig. 18-16). However, there is no specific characteristic appearance on imaging studies that provide a diagnosis of VCI per se. The absence of specific cerebrovascular lesions of course mitigates this diagnosis. MRI is more sensitive than CT in showing subcortical and periventricular white matter changes consistent with small-vessel disease, and smaller infarcts. Therefore, a VCI diagnosis requires recognition of various syndromic features to correlate with findings on imaging studies.