Dementia is a progressive cognitive disorder that results in disability for affected individuals and an increasing burden for caregivers and the health care system. Formally defined, it is characterized by impairment in at least two or more cognitive domains, including short- and long-term memory, abstract thinking, language, judgment, or other higher cortical functions (4). Patients also frequently exhibit behavioral disturbance such as depression, anxiety, agitation, aggression, and psychosis. These cognitive and behavioral changes impair the affected individual’s ability to function normally in their occupation, interpersonal interactions, and eventually self-care. These clinical manifestations must not be due to an underlying psychiatric condition or delirium. After excluding these and other causes of cognitive dysfunction with appropriate diagnostic studies, the clinician can make a clinical diagnosis of dementia. In multiple clinical and pathologic series of dementia, Alzheimer’s disease (AD) is the most common cause of dementia and will be the main focus of discussion in this chapter. Table 21-3 lists the most common causes of dementia encountered in one recent autopsy series and their relative frequencies, also illustrating that dementia with mixed underlying pathology is common (9).

Individuals suffering from dementia require increasing supervision as the disease progresses. The costs of diagnostic evaluation and pharmacotherapy are overshadowed by the costs of skilled care and the emotional burden on caregivers. The economic burden of such care is staggering (25). The cost of such increasing care is particularly concerning considering the aging demographic of the United States and other developed countries. Age-specific prevalence of AD shows a disturbing trend; from age 65 to 69 years, prevalence is approximately 2%, increasing to 35% to 40% in individuals aged 85 and older (55,56). Incidence of AD also increases with age (7). In the United States, the “baby boomer” generation is entering retirement and also, unfortunately, the age of increased risk for development of dementia. Assuming these observations of increased prevalence of dementia with increased age persist in this population, the cost of care may be insurmountable unless more effective preventive or symptomatic treatments are developed.

The greatest risk factor for the development of dementia is increasing age. Other risk factors include a history of stroke (65), midlife hypertension (46), diabetes mellitus (6), head injury (39), and education level (15). There are genetic causes and risk factors specific to different forms of dementia, and these will be discussed in the following sections.

Given increasing life expectancy due to improvements in prevention and treatment of many common general medical conditions, more individuals are living to ages where the prevalence of cognitive dysfunction increases. However, cognitive dysfunction is not encountered uniformly in older individuals, and attempts to differentiate between normal cognitive performance and cognitive impairment can be challenging in some circumstances. The “gray” zone between normal cognition and dementia has been a subject of
intense research interest, prompting establishment of a practice parameter for evaluation and management of such patients, with the clinical designation of mild cognitive impairment (MCI) (97). Current clinical criteria for MCI are outlined in Table 21-4. Patients with MCI do not meet clinical criteria for dementia but suffer from memory or other cognitive dysfunction of sufficient degree to be recognized by the patient and ideally corroborated by a reliable informant. The cognitive dysfunction should not significantly interfere with the affected individual’s functional status.

Amnestic MCI is the best characterized subtype and is associated with a high risk of conversion to AD over time, with approximately 10% to 12% of affected individuals converting to AD per year (95) and approximately 80% of patients converting to AD by 6 years (99). Neuroimaging of patients with amnestic MCI demonstrates patterns of medial temporal lobe atrophy that are predictive of conversion to AD (53). Pathologic studies of patients with a clinical diagnosis of amnestic MCI support these clinical observations, with demonstration of intermediate neuropathologic findings between neurofibrillary changes of normal aging and early AD (96). Although there are no approved treatments for MCI, a recent study suggests that a subset of patients may benefit from treatment with a cholinesterase inhibitor (ChEI) (98). Other subtypes of MCI are not as clearly characterized as amnestic MCI but, in some cases, represent early stages of other non-AD dementias (132). For example, isolated mild impairment of language function may be a precursor to the clinical syndrome of primary progressive aphasia. Further longitudinal studies of the various subtypes of MCI and their clinical outcomes are needed to clarify these relationships.

After AD, dementia with Lewy bodies (DLB) is felt to be one of the most common causes of degenerative dementia, accounting for up to 15% to 25% of cases of dementia (77). Increasing recognition of this distinct presentation of dementia has yielded consensus criteria for the clinical and neuropathologic diagnosis of DLB (2,77). The core clinical diagnostic features of DLB are shown in Table 21-6. Key clinical features of DLB include cognitive impairment, neuropsychiatric disturbance, parkinsonism, sleep disorders, and autonomic dysfunction. Although cognitive dysfunction in DLB can resemble that of AD, often there are prominent executive and visuospatial deficits that can be identified in the office or on formal neuropsychological assessment (29,85). Fluctuations consisting of dramatic changes in level of arousal or cognitive function are also typical of DLB, but the basis for these fluctuations is not well understood. The most prominent neuropsychiatric feature of DLB is vivid, formed visual hallucinations (1), but depression and delusions can also occur. The parkinsonism of DLB can be identical to that encountered in idiopathic PD, but some patients exhibit a more prominent postural tremor, and others exhibit myoclonus. REM sleep behavior disorder commonly occurs in DLB as well as other synucleinopathies (12). This often dramatic condition involves loss of normal muscle atonia during REM sleep, resulting in the patient acting out their dreams, sometimes violently. Other sleep disturbances such as obstructive sleep apnea, restless legs syndrome, and periodic limb movement in sleep can also occur (13). Autonomic dysfunction, including orthostatic hypotension, urinary incontinence, and sexual dysfunction, is also common in DLB (8).

Gross pathology in DLB is often unremarkable, aside from pallor of the substantia nigra similar to that seen in PD. The histopathologic hallmark of DLB is the presence of cortical and subcortical Lewy bodies, readily visible with alpha-synuclein immunohistochemical staining (118). Lewy bodies identified in the
intermediolateral column of the spinal cord may be related to the autonomic dysfunction frequently observed in DLB patients (45). One important aspect of the neuropathology of DLB is the frequent coexistence of AD pathology, estimated in approximately 80% of cases with limbic and neocortical Lewy body pathology (67). The genetics of DLB are not well understood, but the clinical features have been reported in a kindred carrying an alpha-synuclein mutation (69) and in several other families (32,124). A family history of dementia also appears to be associated with risk of developing DLB, similar to that observed in AD (113).

Because risk of cognitive impairment and vascular disease both increase with age, it is not surprising that these two conditions often coexist. Although less common than AD, it is estimated that vascular dementia (VaD) represents close to 18% of incident dementia (31). Prevalence estimates of VaD vary widely in the literature, likely due to the use of different diagnostic criteria. A community-based autopsy series estimates that pure VaD is the cause of approximately 13% of dementia cases and an additional 12% with coexistent AD (64). There is little doubt that cerebrovascular disease can result in cognitive dysfunction, either alone or in combination with neurodegenerative conditions. Clearly large or multiple infarcts involving eloquent cortex can result in cognitive impairment. Strategically located smaller infarcts affecting hippocampal formations, thalamus, and other subcortical structures have been implicated in significant cognitive dysfunction (73), as has widespread lacunar cerebrovascular disease (130). These observations led to the development of consensus diagnostic criteria for diagnosis of probable VaD (104), which are summarized in Table 21-7.