Evidence-Based Reviews

Is it Alzheimer’s? How to pare down the possibilities

Current Psychiatry. 2008 January;7(1):53-66

George T. Grossberg, MD

Mehret Gebretsadik, MD

A clinical guide to rule out other dementing diseases and rare reversible causes.

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References

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2. Hodges JR. Alzheimer’s centennial legacy: origins, landmarks and the current status of knowledge concerning cognitive aspects. Brain 2006;129:2811-22.

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7. Galasko D. Biomarkers for Alzheimer’s disease—clinical needs and application. J Alzheimer’s Dis 2005;8:339-46.

8. Sunderland T, Hampel H, Takeda M, et al. Biomarkers in the diagnosis of Alzheimer’s disease: are we ready? J Geriatr Psychiatry Neurol 2006;19:172-9.

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12. Agency for Health Care Policy and Research Recognition and initial assessment of Alzheimer’s disease and related dementias. Comparison of mental and functional status tests according to three phases of discrimination difficulty. Available at:http://ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat6.table.31677. Accesssed November 6, 2007.

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Accurate and early diagnosis of Alzheimer’s disease (AD) is evolving, and—although not yet definitive—is no longer one of exclusion. With a careful in-office work-up and routine assessment tools, you can accurately identify >90% of patients with late-onset AD.¹

AD is by far the most common cause of dementia in older patients. To help you make the diagnosis, this state-of-the-art article discusses:

AD’s clinical presentation and course
the role of neuropsychological tests for assessing cognitive and functional status
neuropsychiatric and medical findings that differentiate AD from other dementia causes
indications for structural neuroimaging with CT or MRI.

Presentation and course

Variability. AD’s gradual onset and progression are characterized by prominent memory loss, anomia, constructional apraxia, anosognosia, and personality changes with affect deregulation, behavioral disturbance, and distorted perception.¹ Amnesia—particularly deficits in anterograde episodic memory—is the most common presentation, but the disease course is heterogeneous and may be affected by:

patient age at onset
illness severity at diagnosis
comorbid medical and neuropsychiatric illnesses
premorbid cerebral reserves (amount of brain damage a person can sustain before reaching a threshold for the clinical expression of dementia).^1-3

Box 1

Biomarkers show promise to improve AD diagnosis

Researchers are investigating surrogates for detecting Alzheimer’s disease (AD) and monitoring disease progression.⁵

Serum and CSF markers. AD is viewed as a series of sequential events, beginning with beta-amyloid (β-amyloid) accumulation and progressing through a pathophysiologic cascade to cell death, transmitter deficit, and dementia. A unique biomarker may be associated with each event, either in the primary disease process of β-amyloid production and accumulation or intermediate processes such as tau hyperphosphorylation, oxidation, and inflammation.^5,6

These biochemical markers are found more consistently in cerebrospinal fluid (CSF) than peripherally. Lower CSF β-amyloid (especially β-amyloid 42) and higher CSF tau and tau-phosphorylated (p-tau) have been found in AD patients compared with normal and disease controls.⁷ Some overlap exists, however, among AD and other dementias. Other possible serum, CSF, and urine markers include isoprostanes, sulfatides, oxysterols, homocysteine, apolipoprotein E, alpha 1-antichymotrypsin, 3-nitrotyrosine, and more.⁸ No biomarkers are available or recommended for clinical use at this time.

Neuroimaging. Amyloid imaging tracers may increase the capacity of single photon emission computed tomography (SPECT) and positron emission tomography (PET) to detect AD pathology. These tracers have high binding affinity for amyloid and may enable PET/SPECT to detect amyloid deposits in vivo.

Amyloid radioligands are being developed and tested as potential clinical diagnostic tools and surrogate biomarkers of antiamyloid therapies. A radioligand that targets amyloid and neurofibrillary tangles in AD has been developed recently for use as a research tool.

Staging illness severity. AD has 3 clinical stages of cognitive dysfunction:

Mild AD. An individual or close companion may notice increased forgetfulness and word-finding difficulties, a tendency to lose or misplace things, repeated questioning, and some disorientation. Motor skills are intact.

Clinical Point

Clinical assessment has low specificity in advanced stages, where all dementia subtypes are similar and comorbidities confuse the picture

Moderate AD. Cognitive decline continues, memory deteriorates, and self-care ability is markedly impaired. The individual may undergo personality changes, confuse time and place, have trouble communicating and recognizing family members or friends, develop agitation, begin to wander, and experience delusions and hallucinations.

Severe AD. An individual with late-stage disease has severe impairment and can be bedridden, incontinent, and unable to under-stand or speak. Full-time care is required.

Staging informs treatment. In clinical trials, patients with mild-to-moderate AD consistently show small improvements in cognitive and global function when treated with acetylcholinesterase inhibitors (AChEIs) such as donepezil, rivastigmine, and galantamine.⁴ Donepezil also is approved for use in severe AD.

Memantine is indicated for symptomatic treatment of moderate-to-severe AD. It differs in mechanism of action from the AChEIs and is thought to inhibit cytotoxic overstimulation of glutamatergic neurons.⁴ For moderately advanced AD, memantine appears to be beneficial alone or in combination with AChEIs.

Dementia assessment

Clinical assessment has low sensitivity for early-phase AD and compromised specificity in advanced stages, where all dementia subtypes are similar and comorbidities may confuse the picture. Promising surrogate biomarkers and other diagnostic tools are being developed (Box 1),^5-8 but definitive AD diagnosis still requires post-mortem histopathologic examination of the cerebral cortex.

Box 2

Can your AD patient drive or live alone? Consider neuropsychological assessment

Neuropsychological tests disclose a degree of intellectual impairment that correlates with functional impairment and may be particularly useful for assessing:

mild cognitive impairment when diagnosis is doubtful
cases where major lifestyle changes may be required, such as driving cessation or assisted-living placement.

These tests can examine performance across different domains of cognitive function, including orientation, memory, attention, naming, comprehension, and praxis.

Limitations. Neuropsychological tests have limitations, including cost and administration time. Some older patients find the tests distressing or tiring, and those with severe dementia are incapable of participating. Patients’ anxiety about taking tests, poor test-taking skills, low motivation/effort, and language, cultural, and educational variables limit these tests’ usefulness and may influence results.

Interpret a neuropsychological evaluation in the context of other clinical data, such as informant-based history of cognitive decline, evidence of impairment in independent activities of daily living, educational background, depression assessment, sensory impairment, or factors other than dementia that may account for impaired performance.

Source: References 13,14