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. 26 and illustrated in a video library in Chap. e10; memory loss is discussed in Chap. e9.
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. 26). 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 ventromedial 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 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 371-1. 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 undertreated. 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.
Table 371-1 Differential Diagnosis of Dementia
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Table 371-1 Differential Diagnosis of Dementia
|Most Common Causes of Dementia|
Diffuse white matter disease (Binswanger's)
|Less Common Causes of Dementia|
Thiamine (B1): Wernicke's encephalopathya
‘B12 (subacute combined degeneration)a
Nicotinic acid (pellagra)a
Endocrine and other organ failure
Adrenal insufficiency and Cushing's syndromea
Hypo- and hyperparathyroidisma
Papovavirus (JC virus)(progressive multifocal leukoencephalopathy)
Tuberculosis, fungal, and protozoala
Head trauma and diffuse brain damage
Chronic subdural hematomaa
Primary brain tumora
Metastatic brain tumora
Paraneoplastic limbic encephalitis
Drug, medication, and narcotic poisoninga
Heavy metal intoxicationa
Dialysis dementia (aluminum)
Dementia with Lewy bodies
Progressive supranuclear palsy
Hereditary ataxias (some forms)
Motor neuron disease ...
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