Dementia and Systemic Disease

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 are more closely linked to the relative density of tau neurofibrillary tangles than β-amyloid plaques in different brain regions; the highest density of 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 4 to 8 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, the presence of the APOE ε4 allele, having a first-degree relative with the disease, low educational attainment, traumatic brain injury, tobacco use, hearing loss, diabetes, hypertension, obesity, hypercholesterolemia, sleep-disordered breathing, social isolation, and depression. Factors associated with reduced rates of the disease include regular exercise, social engagement, and higher educational attainment. Whether addressing these risk factors prevents Alzheimer disease remains unclear. 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.

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. 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 in many series is the second most common cause of dementia in North America and Europe, accounting for nearly 15 percent of cases.

The incidence of vascular dementia increases with age, and patients are more likely to have hypertension, diabetes, hyperlipidemia, atrial fibrillation, obesity, or a history of tobacco use. 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 its development. 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. Donepezil, rivastigmine, galantamine, and memantine have a modest benefit in vascular dementia similar to their effect on cognitive function in Alzheimer disease, but no benefit on global functioning.

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. Dysautonomia (e.g., postural hypotension, constipation, urinary incontinence), olfactory dysfunction, and mood disorders are also common early features of this group of disorders.