Alzheimer's disease (AD) is a progressive neurodegenera-tive disease, affecting memory, intellectual functions, and behavior. The prevalence of Alzheimer's disease is increasing with the growing percentage of the population over age 65. Remarkably, 15% of persons over age 65, and up to 50% of persons over age 80, may meet diagnostic criteria for AD (Evans et al., 1996; Pfeffer, Afifi, & Chance, 1987). Approximately 14 million persons are expected to have AD by the middle of the twenty-first century.
The pathology of AD involves the degeneration of select cortical regions and ascending brain-stem systems, including the cholinergic basal forebrain. These structures exhibit pathological hallmarks of neurofibrillary tangles within neurons and extracellular senile plaques containing Ap40 and Ap42. There are other pathological changes, however, including synaptic and neuronal loss, vascular changes, granulovacuolar degeneration and alterations to endosomal/lysosomal systems, and signs of inflammation and oxidative stress (Terry, 1994).
Genetic research has provided key insights into the biology of AD. Early-onset familial AD is linked to mutations in the p amyloid precursor protein (APP), presenilin 1, and presenilin 2 (Hardy & Selkoe, 2002). Late-onset familial and sporadic AD is associated with Apo E. Increased amounts of Ap42, derived from APP, resulting from mutations in APP and presenilins alike (Hardy & Selkor, 2002), may enhance Ap aggregation (Jarrett & Lansbury, 1993). Apo E genotype influences AD susceptibility, perhaps via increased Ap deposition (Schmechel et al., 1993). Numerous studies confirm that the e4 allele increases AD risk and decreases age of onset (Corder et al., 1993; Farrer et al., 1997).
The clinical presentation of AD usually begins with
Table 1. NINDS-ARDA Criteria for Probable Alzheimer's Disease and DSM-IV Criteria for Dementia of the Alzheimer's Type
A. Include the following:
1. Dementia established by clinical examination and documented by the Mini-Mental Test, Blessed Dementia Scale, or some similar examination, and confirmed by neuropsy-chological tests
2. Deficits in two or more areas of cognition
3. Progressive worsening of memory and other cognitive functions
4. No disturbance of consciousness
5. Onset between ages 40-90, most often after age 65
6. Absence of systemic disorders or other brain diseases that in and of themselves could account for the progressive deficits in memory and cognition
B. The diagnosis is supported by the following:
1. Progressive deterioration of specific cognitive functions, such as language (aphasia), motor skills (apraxia), and perception (agnosia)
2. Impaired activities of daily living and altered patterns of behavior
3. Family history of similar disorders, especially if confirmed neurohistopathologically
A. The development of multiple cognitive deficits manifested by both:
1. Memory impairment (impaired ability to learn new information or to recall previously learned information) and
2. One (or more) of the following cognitive disturbances:
a. Aphasia (language disturbance)
b. Apraxia (impaired ability to carry out motor activities despite intact motor function)
c. Agnosia (failure to recognize or identify objects despite intact sensory function)
d. Disturbance in executive functioning (i.e., planning organizing, sequencing)
B. Each of the cognitive deficits in Criteria A1 and A2 causes significant impairment in social or occupational functioning and represents a decline from a previous level of functioning.
C. The course is characterized by gradual onset and continuing cognitive decline.
D. The cognitive deficits in Criteria A1 and A2 are not due to any of the following:
1. Other central nervous system conditions that cause progressive deficits in memory and cognition (e.g., cerebrovascular disease, Parkinson's disease, Huntington's disease, subdural hematoma, normal pressure hydrocephalus, brain tumor)
2. Systemic conditions that are known to cause dementia (e.g., hypothyroidism, vitamin B12 or folic acid deficiency, hypercalcemia, neurosyphilis, HIV infection)
3. Substance-induced conditions
E. The deficits do not occur exclusively during the course of a delirium.
F. The disturbance is not better accounted for by another Axis I disorder (e.g., Major Depressive Disorder, Schizophrenia)
memory loss and mild cognitive impairment, which slowly worsen over years (Cummings & Cole, 2002). In early stages there is frequent repetition of stories and questions, misplacing of belongings, geographic disorientation, dys-nomia, and difficulty managing finances or handling complex tasks. Sleep disturbances, depression, psychosis, and other neuropsychiatric problems commonly evolve. Assistance is eventually needed for dressing, bathing, meals, and other activities. Individuals often become lost in familiar surroundings and have reduced comprehension. Late stages often bring agitation and aggression, profound cognitive impairment, and loss of control of bodily functions. These disabilities often lead to institutionalization, increased risk of decubitus ulcers, aspiration pneumonia, and urosepsis from indwelling catheters.
Diagnosis of AD is based on the clinical features and the exclusion of other etiologies (Knopman et al., 2001). Two commonly used diagnostic criteria are listed in Table 1. Confirmation of cognitive impairment is important. Common screening tools for dementia include the Mini-Mental State Exam, the Mattis Dementia Rating Scale, and the clock drawing test (Folstein, Folstein, & McHugh, 1975; Kirby et al., 2001; Mattis, 1976).
Laboratory testing is important in evaluation of cogni-tively impaired individuals to rule out other causes of dementia (Table 2). Blood tests evaluate metabolic, hormonal, and nutritional derangements. New tests can aid in diagnosis of atypical cases. Cerebrospinal fluid analysis of tau and Ap42 provides reasonable sensitivity and specificity for AD (Andreasen et al., 2001; Hulstaert et al., 1999) but is limited by its invasiveness. Genetic testing for Apo E and presenilin is commercially available, but its role in AD diagnosis is often misunderstood. Apo E genotyping is not indicated for AD diagnostic testing (Liddell, Lovestone, & Owen, 2001; Post et al., 1997) and adds little to the sensitivity and specificity of clinical judgement. Many patients with sporadic late-onset AD do not have an e4 allele, and many patients with an e4 allele do not have AD. In families with autosomal dominant early-onset AD, genetic testing can often determine the mutation (Lidell et al., 2001), but these cases collectively account for less than 2% of all AD (Saunders, 2001). Presenilin testing should only be performed with appropriate genetic counseling.
Neuroimaging is essential to rule out conditions such as subdural hematomas, hydrocephalus, and space-occupying lesions (Small & Leiter, 1998). Noncontrast computed tomography or magnetic resonance imaging are suitable for most cases. Positron emission tomography and single photon emission computerized tomography scanning of patients with AD characteristically reveals hypometabolism in the parietotemporal region, even in preclinical individuals at high genetic risk for disease (Small et al., 1995). However, these studies are expensive and not widely available. They are most useful when attempting to discriminate AD from other neurodegenerative conditions that show distinct regional patterns of hypometabolism. Imaging research is
Table 2. Disease Processes That Should Be Considered in the Differential Diagnosis of Dementia and Their Principle Method of Evaluation
Treatable causes of dementia that must be excluded primarily by serologic studies:
• Vitamin B12 deficiency
• Folate deficiency
• Hypo- or hypernatremia
• Renal dysfunction
• Liver dysfunction
• Chronic drug intoxication
• HIV infection
Treatable causes of dementia that must be excluded primarily by neuroimaging studies:
• Normal pressure hydrocephalus
• Subdural hematoma
• Multi-infarct dementia
• Subcortical arteriosclerotic encephalopathy (Binswanger's disease)
• Space-occupying lesions (tumor, abscess, etc.)
• Demyelinating diseases (multiple sclerosis, PML) Other causes of dementia that may be excluded by EEG:
• Subclinical seizures
• Creutzfeld-Jakob disease (CSF 14-3-3 protein also diagnostic) Other causes of dementia that must be excluded primarily by clinical features:
• Pseudodementia (depression)
• Pick's disease and Frontotemporal dementias
• Parkinson's disease
• Progressive Supranuclear Palsy
• Diffuse Lewy Body disease
• Cortical-basal-ganglionic degeneration
• Huntington's disease evolving rapidly, promising more sensitive and specific tools for future clinical use.
Current therapies for AD are primarily based on augmenting the central cholinergic system (Doody et al., 2001). Available acetylcholinesterase inhibitor drugs have similar efficacy. Donepezil, rivastigmine, and galantamine have been shown to be effective in several large double-blind placebo-controlled clinical trials (Dooley & Lamb, 2000; Lamb & Goa, 2001; Olin & Schneider, 2002). Many patients may not show immediate clinical benefit, but over time (e.g., 6-12 months) they tend to show less decline than untreated subjects. These drugs have efficacy for cognitive symptoms as well as for behavioral problems; they delay the need for institutionalization and also reduce the overall economic burden.
Other therapies employed in the treatment of AD include the use of vitamin E, an antioxidant that appears to delay progression of the disease (Sano et al., 1997). Epidemiolog-ical studies have provided indirect evidence that other medications are associated with reduced AD risk, including es trogen, nonsteroidal anti-inflammatory drugs (NSAIDs), statins, folic acid, and vitamin supplementation (Cummings & Cole, 2002; DeKosky, 2001; Kukull & Bowen, 2002). However, prospective clinical studies are essential to determine if these treatments are effective and safe. Unfortunately, prospective double-blind studies have failed to show efficacy of estrogen replacement or NSAIDs (Aisen, 2002; Mulnard et al., 2000); further study is necessary. Until safety and efficacy issues are addressed with prospective studies, precautions against use of any unproven agents for AD should be heeded because of the risk of serious adverse events.
Finally, psychotherapy and education are often needed to help families as they come to terms with a patient's changing abilities and experience the grief associated with perceived loss, and to provide more effective care (Cooke et al., 2001; Gitlin et al., 2001; Hepburn et al., 2001). Although the diagnosis may be perceived by some as catastrophic news, education and contact with community support such as the Alzheimer's Association and other such groups may help lessen the anxiety and fear of the unknown, and enable individuals to function better and longer within their families and in their own homes.
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