Evidence-Based Reviews

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

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

References

1. Cummings JL. Clinical evaluation as a biomarker for Alzheimer’s disease. J Alzheimer’s Dis 2005;8:327-37.

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

3. Stern Y. Cognitive reserve and Alzheimer disease. Alzheimer Dis Assoc Disord 2006;20:112-7.

4. Lleó A, Greenberg SM, Growdon JH. Current pharmacotherapy for Alzheimer’s disease. Annu Rev Med 2006;57:513-33.

5. Kennedy GJ, Golde TE, Tarriot PN, Cummings JL. Amyloid-based interventions in Alzheimer’s disease. CNS Spectr 2007;12: 1(suppl 1):1-14.

6. Van der Flier WM, Scheltens P. Use of laboratory and imaging investigations in dementia. J Neurol Neurosurg Psychiatry 2005;76:45-52.

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.

9. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state.” A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12(3):189-98.

10. Perneczky R, Wagenpfeil S, Komossa K, et al. Mapping scores onto stages: Mini-Mental State Examination and Clinical Dementia Rating. Am J Geriatr Psychiatry 2006;14:139-44.

11. Tariq SH, Tumosa N, Chibnall JT, et al. Comparison of the Saint Louis University mental status examination and the Mini-Mental State Examination for detecting dementia and mild neurocognitive disorder—a pilot study. Am J Geriatr Psychiatry 2006;14(11):897-9.

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.

13. Sano M. Neuropsychological testing in the diagnosis of dementia. J Geriatr Psychiatry Neurol 2006;19:155-9.

14. Mohs RC. Neuropsychological assessment of patients with Alzheimer’s disease. In: Psychopharmacology—the fourth generation of progress American College of Neuropsychopharmacology. Available at: http://www.acnp.org/ g4/GN401000133/Default.htm. Accessed November 6, 2007.

15. Morris JC. Dementia update 2005. Alzheimer Dis Assoc Disord 2005;19:100-17.

16. Clarfield AM. Reversible dementia—the implications of a fall in prevalence. Age Ageing 2005;34:544-5.

17. Roberts JS, Cupples LA, Relkin NR, et al. Genetic risk assessment for adult children of people with Alzheimer’s disease: the Risk Evaluation and Education for AD (REVEAL) study. J Geriatr Psychiatry Neurol 2005;18:250-5.

18. Frisoni GB. Structural imaging in the clinical diagnosis of Alzheimer’s disease: problems and tools. J Neurol Neurosurg Psychiatry 2001;70:711-18.

19. Ramani A, Jensen JH, Helpern JA. Quantitative MR imaging in Alzheimer disease. Radiology 2006;241(1):26-44.

20. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984;34(7):939-44.

21. Diagnostic and statistical manual of mental disorders 4th ed text rev. Washington, DC: American Psychiatric Association; 2000.

22. Roberts JS, Barber M, Brown T, et al. Who seeks genetic susceptibility testing for Alzheimer’s disease? Findings from a multi-site, randomized clinical trial. Genet Med 2004;6(4):197-203.

23. Van der Flier WM, Scheltens P. Epidemiology and risk factors of dementia. J Neurol Neurosurg Psychiatry 2005;76:2-7.

24. Blacker D, Lovestone S. Genetics and dementia nosology. J Geriatr Psychiatry Neurol 2006;19:186-91.

25. Busse A, Bischkopf J, Reidel-Heller SG, Angermeyer MS. Subclassifications for mild cognitive impairment: prevalence and predictive validity. Psychol Med 2003;33(6):1029-38.

26. Rasquin SM, Lodder J, Visser PJ, et al. Predictive accuracy of MCI subtypes for Alzheimer’s disease and vascular dementia in subjects with mild cognitive impairment: a 2-year followup study. Dement Geriatr Cogn Disord 2005;19(2-3):113-19.

27. Boyle PA, Wilson RS, Aggarwal NT, et al. Mild cognitive impairment: risk of Alzheimer disease and rate of cognitive decline. Neurology 2006;67:441-5.

28. Geser F, Wenning GK, Poewe W, McKeith I. How to diagnose dementia with Lewy bodies: state of the art. Mov Disord 2005;20(suppl 12):S11-S20.

29. Hardy J. The relationship between Lewy body disease, Parkinson’s disease, and Alzheimer’s disease. Ann NY Acad Sci 2003;991:167-70.

30. Jellinger KA. Vascular-ischemic dementia: an update. J Neural Transm 2002;62(suppl):1-23.

31. McKhann GM, Albert MS, Grossman M, et al. Clinical and pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal Dementia and Pick’s Disease. Arch Neurol 2001;58:1803-9.

32. Boxer AL, Miller BL. Clinical features of frontotemporal dementia. Alzheimer Dis Assoc Disord 2005;19(suppl):S3-S6.

33. Boeve BF. A review of the non-Alzheimer dementias. J Clin Psychiatry 2006;67(12):1985-2001.

History and physical exam. Depending on the AD stage at presentation, patients might not be a reliable source of information. For a realistic and unbiased history and evaluation, assess the patient separately and obtain collateral information from reliable informants.

In typical cases, the history guides the physical/neurologic examination. Advancing age and family history are confirmed risk factors for AD; others may include:

female gender (after age 80)
cardiovascular disease (such as cerebral infarcts, hypertension, elevated cholesterol/homocysteine, smoking, and diabetes mellitus)
history of head trauma, especially with loss of consciousness.

Clinical Point

Apraxia, aphasia, and cortical visual impairment may reflect focal signs of atypical AD

Assess premorbid functioning and existing medical conditions. Apraxia, aphasia, and cortical visual impairment may reflect focal signs of atypical AD; consider other neurologic signs in the context of clinical data.

Early and accurate diagnosis of AD is challenging in patients with mixed dementias, comorbid neurologic diseases, or atypical features. Patients with these presentations may require referral to an expert clinician, extensive workup, or longitudinal follow-up before the diagnosis becomes clear.

Neuropsychological testing. Most mental status tests examine orientation, attention/concentration, learning, memory, language, and constructional praxis. The Folstein Mini-Mental State Examination (MMSE)⁹ is the most widely used and well-validated mental status test. A score of 10 to 20 on the MMSE is generally considered as moderate AD, and 10 Other mental status testing options include:

Blessed Information-Memory-Concentration (BIMC)
Blessed Orientation-Memory-Concentration (BOMC)
Short Test of Mental Status (STMS)
Saint Louis University Mental Status (SLUMS).^11,12

Neuropsychological tests have limitations, but they can supplement clinical cognitive assessment by detecting milder cases and may help answer questions about a patient’s ability to drive or live alone (Box 2).^13,14

Reversible causes. If the patient is generally healthy, a core of laboratory tests is recommended in the diagnostic workup (Table 1).^6,15 Other options include:

CSF examination for atypical presentations, such as unusually rapid symptom progression, altered consciousness, or other neurologic manifestations
EEG to differentiate delirium, seizure disorders, encephalopathies, or a rapidly progressing dementia such as CreutzfeldtJakob disease.

Clinical Point

Structural neuroimaging with noncontrast CT or MRI is appropriate in the initial evaluation of patients with dementia

Only 1% of dementia causes are considered reversible,¹⁶ but keep them in mind in the AD differential diagnosis (Table 2). Depression, vitamin B12 deficiency, medication side effects, and hypothyroidism are common comorbidities in elderly patients, particularly in those with suspected dementia. Correcting these problems might or might not reverse the dementia.

Because delirium may be the initial presentation of AD or reversible causes, re-evaluate patients for dementia after delirium clears.

Neuroimaging. Structural neuroimaging with a noncontrast CT or MRI is appropriate in the initial evaluation of patients with dementia.¹⁷ More routinely, it is used to exclude rare but potentially correctable dementia causes, such as space-occupying lesions.¹⁸ Hippocampal and entorhinal volume are measured most often in discriminating AD from non-demented aging and other dementias.¹⁹

Positron emission tomography (PET) using fluorine-18-labeled deoxyglucose (FDG) may help differentiate characteristic patterns of cerebral hypometabolism in the temporoparietal lobes in AD from fronto-temporal dementia (FTD) and other less common dementias, particularly during the earliest stages of the disease.¹⁹ Medi-care reimbursement for brain PET is limited to differentiating FTD from AD.

Table 1

Recommended lab tests for Alzheimer’s disease workup

Test	Rationale
CBC	Anemia and signs of infection
Vitamin B12	Related to reversible dementia, anemia
Folate	Related to reversible dementia, anemia
Homocysteine	More accurate than individual B12/folate tests
C-reactive protein	Ongoing inflamatory reaction
Thyroid function	Hypothyroidism (reversible dementia)
Liver function	Metabolic causes of cognitive impairment
Renal function	Uremia, metabolic causes of cognitive impairment
Electrolytes	Hypo/hypernatremia as a cognitive impairment cause
Glucose	Recurrent hypoglycemia, diabetes mellitus
Lipid panel	Vascular dementia risk factor
Baseline ECG	Cardiac abnormalities as vascular risk factors
STS (optional)	Neurosyphilis
CBC: complete blood count; ECG: electrocardiogram;
STS: serologic test for syphilis
Source: Adapted from references 6,15

Table 2

Detecting causes of potentially reversible cognitive impairment

Cause	Examples	Suggested tests
Space-occupying lesions	Subdural hematoma, benign tumors, hydrocephalus	CT/MRI without contrast
Infectious diseases	AIDS dementia complex, syphilis, Lyme disease	Serologic tests
Endocrinopathies/ metabolic/autoimmune disorders	Hypothyroidism, Cushing’s disease, uremia, hepatic encephalopathy, Wilson’s disease, recurrent hypoglycemia, chronic hypocalcemia, multiple sclerosis, disseminated SLE, sarcoidosis	Thyroid panel, renal and liver function tests, electrolytes, slit lamp test, serum ceruloplasmin
Psychiatric	Depression, alcohol dependence	Geriatric Depression Scale, assess vitamin deficiency states
Nutritional deficiencies	Vitamin B12, thiamine (Wernicke-Korsakoff syndrome), pyridoxine, niacin (pellagra)	Vitamin B12, homocysteine
Medication effects	Benzodiazepines, barbiturates, anticholinergics, opioid analgesics, antihypertensives, antiarrhythmics, antidepressants, anticonvulsants, cardiac drugs such as digitalis and derivatives (among others)	Review patients’ medications for drugs that can cause cognitive changes
Others	Autoimmune diseases, heavy metals, illicit drugs, obstructive sleep apnea	Drug screens and specific tests

Diagnostic criteria

NINCDS-ADRDA. Neuropsychological AD assessment criteria developed by the National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) classify AD as probable, possible, or definite: