Alzheimer Disease

Alzheimer disease is the most common cause of dementia in the elderly. The disorder almost invariably begins with insidiously progressive short-term memory loss followed by diminished cognitive function in a range of domains that most often include language, visuospatial ability, and praxis. Memory loss is often initially misattributed to normal aging, often leading to a delay in diagnosis. Symptoms reflect the relative density of neuropathology in different regions of the brain: the highest density of β-amyloid plaques and tau neurofibrillary tangles is usually found in the medial temporal lobes, regions critical for the formation of new memories. Other frequently involved areas include the parietal lobes, which are involved in visuospatial processing. The course is relentlessly progressive and universally fatal, leading to death within a few years (median, 5 years) from the time of diagnosis. Death is often from aspiration pneumonia or other complications of the bed-bound end-stage of the illness. While social graces are usually preserved early in the course of the illness, behavioral problems such as aggression, agitation, and episodic delirium often emerge in later stages and are particularly problematic for caretakers. Falls are also common when patients develop postural instability later in the disease course.

Risk factors for Alzheimer disease include age, having a first-degree relative with the disease, diabetes, hypertension, obesity, hypercholesterolemia, tobacco use, low educational attainment, traumatic brain injury, and the APOE ε4 allele. Factors associated with reduced rates of the disease include regular exercise and higher educational attainment. Less than 1 percent of cases are inherited in an autosomal dominant pattern and these are mainly caused by mutations in the genes encoding amyloid precursor protein, presenilin 1, and presenilin 2. There is no treatment that halts the progression of the disease. Centrally acting acetylcholinesterase inhibitors such as donepezil, rivastigmine, and galantamine, and the N -methyl- d -aspartate receptor antagonist memantine will boost cognition at various stages of the illness and may as a result temporarily improve quality of life or delay nursing home placement, although clinical effects are marginal. Ongoing efforts to develop novel treatments have focused on early stages of the disease when pathology is present but obvious clinical symptoms have not yet appeared.

Vascular Dementia

Cerebrovascular disease carves several paths to dementia. The accumulation of multiple large territory infarctions in the setting of atrial fibrillation, intracranial atherosclerosis, or other causes of recurrent large-vessel ischemic stroke results in dementia with cognitive deficits referable to the infarcted brain territories. Because dementia progresses with each successive stroke, patients may demonstrate a stepwise decline in function. However, these patients rarely present to medical care with unexplained cognitive complaints because they are already known to have suffered multiple infarctions.

More common among patients presenting with memory or cognitive dysfunction is dementia resulting from the accumulation of innumerable ischemic lesions in the subcortical and periventricular white matter due to chronic small-vessel disease. The clinical syndrome is one of slowly progressive frontal lobe dysfunction, with problems in working memory and executive function. Involvement of the basal ganglia may result in a shuffling gait and postural instability that resembles parkinsonism. Pathologic examination reveals chronic ischemia with arteriolosclerosis and often amyloid angiopathy of small arterioles. Vascular dementia is the second most common cause of dementia in North America and Europe, accounting for up to 20 percent of cases.

The incidence of vascular dementia increases with age, and patients are more likely to have hypertension, diabetes, hyperlipidemia, atrial fibrillation, or a history of tobacco use. Obesity is also a significant risk factor. Vascular dementia is associated with chronic kidney disease, coronary artery disease, and peripheral vascular disease, although these associations may be mediated by common risk factors. No treatment is known to slow its progression, but physical activity may be protective against the development of vascular dementia. It is not known whether aspirin, smoking cessation, or treatment of vascular risk factors prevents or slows the progression of dementia, but these are all standard aspects of secondary stroke prevention and are therefore often a part of the treatment plan for patients with vascular dementia. The acetylcholinesterase inhibitors donepezil and galantamine have a modest benefit in vascular dementia similar to their effect on cognitive function in Alzheimer disease.

Synucleinopathies

The synucleinopathies include dementia with Lewy bodies, Parkinson disease, and multiple system atrophy. The pathologic hallmark of all synucleinopathies is the Lewy body, composed primarily of insoluble α-synuclein aggregates. These aggregates are not common in normal aging; α-synuclein itself is a normally soluble neuronal protein with uncertain function. The role of Lewy bodies and α-synuclein in the pathogenesis of disease is also not well understood.

Parkinsonism is a prominent early feature of most synucleinopathies and describes a clinical syndrome consisting of rigidity, bradykinesia, postural instability, and resting tremor. Rapid eye movement (REM) sleep behavior disorder, in which brainstem projections to the spinal cord that induce atonia during REM sleep are disrupted, causing patients to act out their dreams in dramatic fashion, is another symptom common to the synucleinopathies. REM sleep behavior disorder can precede the onset of parkinsonism in the synucleinopathies by many years.

Tauopathies

The tauopathies are a group of neurodegenerative diseases associated with an abnormal aggregation of tau protein in the brain. The most common is Alzheimer disease, considered separately above.

Frontotemporal Dementia

Frontotemporal dementia is a clinically, pathologically, and genetically diverse disorder. On neuropathologic examination, many cases are associated with inclusions containing tau, a microtubule stabilizing protein. The neuropathology in other cases with similar clinical phenotypes demonstrates inclusions containing TAR DNA-binding protein of 43 kDa (TDP-43) and no tau staining; others are tau negative and TDP-43 negative but positive for the protein fused in sarcoma; and still others are tau negative, TDP-43 negative, fused in sarcoma negative, and ubiquitin positive. Because of overlap between clinical and pathologic subtypes, it is difficult to predict an individual patient’s pathology with certainty using current diagnostic techniques, but in general the clinical syndromes associated with tau inclusions are behavioral variant frontotemporal dementia, progressive nonfluent aphasia, progressive supranuclear palsy, and corticobasal syndrome. Semantic dementia, a variant of frontotemporal dementia with progressive impairment in naming and single-word comprehension, is usually associated with TDP-43 pathology. Many TDP-43 positive cases have comorbid motor neuron disease. There are no specific treatments.

The average age of onset is between 50 and 60 years; the incidence does not increase with age. Frontotemporal dementia accounts for a significant proportion of dementia cases in people aged 45 to 65. The time between onset of symptoms and death is slightly shorter than that in Alzheimer disease. The behavioral variant presents with personality changes, apathy or impulsivity, emotional blunting, loss of empathy and social awareness, lack of insight, mental rigidity, change in eating habits, and poor personal hygiene, all reflecting degeneration predominantly of the non-dominant frontal and temporal lobes ( Fig. 61-1 ). When the pathologic process affects the dominant hemisphere, progressive nonfluent aphasia is the typical phenotype and is associated with fewer behavioral changes and more prominent language difficulties.

Frontotemporal dementia. T1-weighted magnetic resonance image (MRI) of the brain demonstrates atrophy of the non-dominant (right) frontal lobe out of proportion to other areas.

Systemic Diseases Causing Dementia

A number of systemic disorders may cause cognitive decline and mimic Alzheimer disease or other neurodegenerative diseases. These disorders are of importance because they are often treatable. Cognitive decline in most of these conditions is chronic, although occasionally patients present subacutely. Subacute cognitive decline, also referred to as rapidly progressive dementia, has a much wider differential diagnosis that is beyond the scope of this chapter.

Cognitive dysfunction is an increasingly recognized neurologic complication of human immunodeficiency virus (HIV) infection , discussed in Chapter 44 . Previously known by such terms as AIDS dementia complex and HIV encephalopathy, the currently accepted terminology is HIV-associated neurocognitive disorder, with three stages of disease based on neuropsychologic testing: asymptomatic neurocognitive impairment, mild neurocognitive disorder, and HIV-associated dementia. Cognitive impairment is described as subcortical, with impaired information-processing speed, multitasking, decision-making, working memory, and verbal fluency. While the incidence of HIV-associated dementia has declined in the era of antiretroviral therapy, the milder subtypes continue to be common, with 33 percent of patients having asymptomatic neurocognitive impairment and 12 percent mild neurocognitive disorder in a large cohort, raising concern that HIV-associated neurocognitive disorder may represent the effect of a reservoir of viral replication sequestered behind the blood–brain barrier. Current research is aimed at investigating the effect of antiretroviral drugs with high CSF penetration on the prevention of HIV-associated neurocognitive disorder. According to guidelines from the United States Preventive Services Task Force, HIV screening should be a routine part of health care maintenance and, by extension, testing is reasonable in any patient presenting with cognitive symptoms.

Public health efforts directed at screening and treatment have led to a decline in the prevalence of the neurologic complications of syphilis ( Chapter 40 ). Tertiary syphilis is therefore a less important cause of dementia than in the past. General paresis, or the dementia caused by syphilis, is a result of direct infection of neural tissue by Treponema pallidum and occurs decades after the primary infection. Patients develop progressive memory loss and personality change. Because non-treponemal tests such as the rapid plasma reagin (RPR) and Venereal Disease Research Laboratory (VDRL) can be negative in late syphilis, a treponemal test such as the fluorescent treponemal antigen absorption and a lumbar puncture should be performed when the disease is suspected. Lymphocyte count and protein concentration are usually elevated in the spinal fluid.

Rarely, chronic meningitis such as that caused by Mycobacterium tuberculosis ( Chapter 41 ) or Cryptococcus neoformans ( Chapter 46 ) may lead to chronic cognitive decline. Usually the dementia in these cases is accompanied by systemic symptoms of chronic infection such as weight loss, night sweats, and occasional fever. Cognitive symptoms typically have features of delirium including waxing and waning levels of alertness and attention. These conditions are readily distinguished from neurodegenerative diseases with a lumbar puncture demonstrating inflammatory spinal fluid.

In addition to fatigue, cold intolerance, hair loss, myxedema, and weakness, hypothyroidism is associated with cognitive dysfunction. The symptoms are usually slowed cognitive processing, impaired learning, and depression. The disorder is readily diagnosed by checking serum levels of thyroid-stimulating hormone.

Deficiency of vitamin B ₁₂ is associated with an increased risk of developing Alzheimer disease, vascular dementia, and Parkinson disease, but there is no compelling evidence that treatment of the deficiency prevents the development of dementia or improves outcomes in patients who have already developed it. However, there are rare cases of patients presenting with dementia and vitamin B ₁₂ deficiency who have demonstrated sustained recovery after vitamin supplementation, and therefore a trial of this benign treatment is a reasonable approach to these patients.

Structural lesions such as a chronic subdural hematoma, tumors, and hydrocephalus may also lead to dementia. It is for this reason that brain imaging is part of the standard workup for dementia; brain imaging will reveal an abnormal finding that was otherwise unsuspected in 5 percent of cases. Although subdural hematoma may present with seizures or focal neurologic deficits, in some cases the hematoma expands slowly and causes only cognitive symptoms, with subtle or no motor signs. Similarly, brain tumors can mimic neurodegenerative disease, with slow-growing low-grade tumors more likely to do so than glioblastomas or metastases. Symptoms depend on the location of the tumor. Frontal tumors may cause behavioral symptoms such as apathy, loss of insight and judgment, and difficulty with working memory and executive function. Temporal lesions may result in progressive aphasia and memory loss.

Communicating hydrocephalus is associated classically with the triad of dementia, incontinence, and gait disorder, but patients often present with only one of these symptoms. The dementia is typically characterized by frontal lobe dysfunction with symptoms similar to those seen in vascular dementia, although descriptions of large series with robust cognitive testing are lacking. The gait disorder is typically a gait initiation failure, often described as a magnetic gait, where the feet appear stuck to the floor. Treatment is placement of a ventriculoperitoneal shunt. When the diagnosis is suspected after careful correlation between the history, neurologic findings, and brain imaging demonstrating ventriculomegaly out of proportion to sulcal atrophy ( Fig. 61-2 ), a lumbar puncture should be performed. Because hydrocephalus with elevated intracranial pressure can lead to an identical clinical presentation, measurement of the opening pressure is critical. A good response to ventriculoperitoneal shunt is predicted if the patient’s symptoms improve after a large volume (30 to 50 ml) of cerebrospinal fluid is removed. Importantly, many cases of so-called normal-pressure hydrocephalus will turn out to be early presentations of a neurodegenerative condition; this possibility should be excluded.

Communicating hydrocephalus. T2-weighted MRI of the brain showing ventriculomegaly out of proportion to sulcal atrophy.

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