Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (79 page)
Authors: Mary A. Williamson Mt(ascp) Phd,L. Michael Snyder Md
AD is the most common cause of dementia in the elderly. It begins insidiously and progresses over 5–10 years to severe cortical dysfunction. The incidence of AD doubles every 5 years, starting at 1% in the 60- to 64-year-old age group and rising as high as 40% in the 85- to 89-year-old age group. In patients older than 60 with dementia, the usual causes are AD 60–80%, vascular dementia 10–20%, dementia with Lewy Bodies 10%, frontotemporal dementia 10%, and Parkinson disease with dementia 5%.
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Recent studies now suggest that patients with some types of cancer may have a decreased risk of AD.
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Laboratory testing should be performed to rule out treatable causes of dementia; definitive diagnosis of AD is not currently possible, although newer biomarkers are becoming more useful in suggesting the diagnosis.
Laboratory Findings
Initial screening for patients with dementia should include B
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and thyroid studies to rule out deficiencies. Routine screening labs such as CBC, electrolytes, glucose, renal, and liver functions have not been shown to be helpful in the general population. Screening for neurosyphilis should be undertaken if there is increased suspicion, and testing for RBC folate in alcoholics may be of help in the differentiation of these disorders. In patients with multiple myeloma or breast or prostate cancer, ionized calcium may also be helpful. In patients with rapidly progressing disease or who are under the age of 60, the American Academy of Neurology recommends the following tests: serology, CSF, and EEG.
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The gold standard for the diagnosis of AD is the histologic finding of plaques and fibrillary tangles in the brain on biopsy or at autopsy (see eBook Figure 4-5).
Genetic Testing
Early-onset (<60 years) AD has been associated with three genes seen in approximately 60% of these cases and is transmitted as an autosomal dominant. APP (amyloid precursor protein) on chromosome 1q (also seen in Down syndrome) and PSEN1 (presenilin 1) on chromosome 14q are the more common genes affected, and PSEN2 (presenilin 2) on chromosome 1q is rare. Commercial testing for these genes is not available, and in order to fully rule out abnormalities, full gene sequencing would be needed as numerous mutations have been found. APP mutations increase the production of amyloidogenic Aβ or alter the ratio of Aβ42 to Aβ40. PSEN1 mutations in AD most likely are involved in the γ-secretase cleavage of APP. PSEN2 is similar to PSEN1, affecting cleavage of APP, and also enhances apoptotic activity, leading to neurodegeneration.
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The APOE ε4 gene allele has been associated with both late-onset AD and vascular dementia. The APOE lipoprotein is involved in cholesterol homeostasis and neuronal protection in the brain. It may also participate in Aβ deposition. APOE ε4 may be measured in the serum, and increased levels have been associated with late-onset AD and atherosclerotic vascular disease.
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Genetic testing for late-onset AD is controversial due to the significant number of both false positives and false negatives; in addition, APOE ε4 is a susceptibility gene, and 40% of patients with AD do not carry the APOE ε4 gene.
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Testing for the APOE ε4 allele is available through commercial laboratories. An increased number of APOE ε4 alleles is associated with a greater risk of disease; risk is also dependent on age, gender, and race.
Blood and CSF Testing
Biomarkers including increased levels of tau protein and decreased levels of Aβ40 and 42 in the CSF and plasma may either predict development of or suggest a diagnosis of AD.
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References
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VASCULAR DEMENTIA
First described by Binswanger and Alzheimer, vascular dementia or vascular cognitive impairment is a heterogeneous group of cerebrovascular disorders resulting in dementia. Three pathologic entities contribute to this disorder: cortical infarcts, lacunar infarct, and chronic subcortical ischemia.
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Vascular dementia is the second most common form of dementia in the United States and Europe.
The clinical presentation varies depending on the location of the underlying lesion. Patterns of dementia may be divided into cortical or subcortical ischemic injury with the most severe being those in which there is damage to the region of the thalamus.
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Conditions related to vascular dementia include cerebral amyloid angiopathy, which is caused by the deposition of amyloid in the cerebral vessels resulting in hemorrhage or infarct; cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is caused by a mutation in the NOTCH3 gene resulting in leukoencephalopathy, subcortical infarcts, migraines, and psychiatric symptoms; and mixed dementia of cerebrovascular disease and AD, which is seen in 35–50% of patients with AD.
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Diagnosis is made by neuroimaging (MRI is significantly more sensitive than CT). When evidence of CNS infarction is found, additional testing to determine the stroke subtype or etiology should be undertaken, including carotid artery Doppler, echocardiogram, and Holter monitor. Patients should be screened for hypertension, diabetes, and hyperlipidemia. If a patient has a history suggestive of CADASIL, genetic testing for the NOTCH3 gene is commercially available (see eBook Figure 4-6).
References
1. Kalaria RN. Cerebrovascular disease and mechanisms of cognitive impairment: evidence from clinicopathological studies in humans.
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2. Benitsy S, Gouw AA, Porcher R, et al. Location of lacunar infarcts correlates with cognition in a sample of non-disabled subjects with age-related white-matter changes: the LADIS study.
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FRONTOTEMPORAL DEMENTIA
Frontotemporal dementia (FTD) results from degeneration of the frontal or temporal lobes resulting in personality, language, and behavior abnormalities. It is a group of disorders with onset in the 45–65 age range that may progress to global dementia. This entity was once called Pick disease, but this diagnosis is now reserved for a subset of patients who exhibit Pick bodies (abnormal protein deposition within cells) on autopsy or biopsy.