Postgraduate Medicine: Is it Alzheimer's disease or something else? Is it Alzheimer's disease or something else?

10 disorders that may feature impaired memory and cognition Anna M. Barrett, MD VOL 117 / NO 5 / MAY 2005 / POSTGRADUATE MEDICINE

CME learning objectives To be able to recognize the manifestations of common treatable conditions that cause memory loss and cognitive impairment To become aware of the relative frequency of disorders that cause dementia in elderly persons To review standard diagnostic and treatment strategies for neurosystemic disorders that cause Alzheimer's disease-like symptoms The author discloses no financial interests in this article.

Preview: Patients who have the classic combination of progressive memory loss and problems retrieving stored knowledge that is characteristic of Alzheimer's disease may actually have another, treatable disorder. In these cases, appropriate evaluation can reveal the true diagnosis and guide therapy to stabilize or improve thinking and avert other complications. In this article, Dr Barrett explores 10 conditions that may be mistaken for Alzheimer's disease.

Alzheimer's disease is an obvious diagnosis in patients who have the classic combination of gradual, early memory loss and cognitive problems in multiple domains with little or no attention disorder or delirium. However, other, treatable conditions can mimic this stereotypic pattern, including depression, stroke, Parkinson's disease, vitamin B12 deficiency, thyroid disorders, thiamine deficiency, primary gastrointestinal disorders, structural brain lesions, cancer, and neurosyphilis (table 1). Aggressively managing these disorders early in the disease process may improve the patient's thinking and daily function. A thorough evaluation can help physicians differentiate these treatable conditions from Alzheimer's disease and guide the appropriate course of therapy (table 2). 1. Depression Epidemic in elderly populations in the United States, depression affects at least one in four people older than 65 years and is well known to cause memory loss, attention deficits, and initiation problems (pseudodementia of depression)(1,2). However, depression can also cause cognitive problems such as word-finding difficulty (anomia), which is characteristic of early Alzheimer's disease(3). Some elderly persons are unaware of their mood state (alexithymia) and deny sadness, guilt, and the other usual symptoms of dysthymia. A physician who recognizes signs of sadness or anxiety (eg, crying during the examination) and pays attention to reported vegetative

symptoms and signs (eg, early-morning awakening, weight loss) may be able to detect depression. Is depression in elderly persons completely separate from early Alzheimer's disease? This is controversial. Older people with depression may be at increased risk for dementia(4). However, in some older people, depression may be a variant of Alzheimer's disease. The low levels of the neurotransmitter serotonin that cause depression may occur before the low levels of acetylcholine that cause memory loss--although both systems function abnormally later. Reactive depression with enough functional impact to require medication is also common in early Alzheimer's disease. However, until there is clear evidence that cognitive difficulty caused by depression is only an Alzheimer's disease variant, patients with symptoms of depression without obvious cognitive abnormalities (eg, left-right disorientation, aphasia, inability to copy drawings) should not be given the diagnosis of dementia. Instead, their depression should be treated with the appropriate therapeutic dosage of an antidepressant(1). A physician needs to ensure that the dose is adjusted to adequate (maximal) levels for 4 to 8 weeks before deciding that a particular antidepressant is ineffective for that patient. The patient can subsequently be observed for development of other cognitive symptoms. 2. Stroke Dementia due to a stroke or multi-infarct state(5) shares a cognitive constellation with Alzheimer's disease. This constellation includes memory disorder, linguistic abnormality (eg, anomia), abnormal skilled movement of the hands (limb apraxia), and trouble with calculations (not due solely to attention but even when using pencil and paper), left-right orientation, naming fingers, and writing; this latter tetrad defines Gerstmann's syndrome, which may be associated with lesions of the left parietal cortex. Visuospatial abnormalities (such as those manifested by abnormal clock drawing or copying of a complex figure) are common in both stroke and Alzheimer's disease. However, a patient with one or more strokes that affect the posterior parietal regions, either directly injuring the parietal cortex or disrupting its white-matter input from another region or the thalamus, may also evince parietal behavioral abnormalities. Thus, brain imaging in a patient with possible Alz- heimer's disease is crucial to detecting subclinical stroke(6). On physical examination, patients who have had a stroke may demonstrate gait dysfunction (ie, lower-body parkinsonism, including shuffling gait, retropulsion, and loss of postural reflexes), early urinary incontinence (before becoming dependent for functional activities) and, on neurologic examination, reflex or motor asymmetry. Taking a history of cognitive abilities and neurologic cognitive examination often reveal prominent early problems with initiation, motivation, or organization of thinking (frontal lobe disorder). If the primary problem is disruption of cortical-cortical connections, stored long-term memories may be relatively spared, prompting caregiver comments such as, "She remembers what happened a long time ago better than I do." Structural brain lesions due to stroke can produce other sensory, motor, or cognitive symptoms. Depression, common in stroke patients, can also affect thinking and memory. 3. Parkinson's disease Parkinson's disease and other neurodegenerative disorders are common. Early neurodegenerative motor function disorders affect thinking disproportionately in a subset of patients. Thus, Parkinson's disease, a

disorder that features resting tremor, slowed movement, and gait disorder, sometimes first manifests as amnesia and cognitive problems (usually frontal lobe dysfunction). Masked facial expression, soft voice, tiny handwriting (micrographia), cogwheel rigidity of the limbs, and gait problems, including asymmetrical or decreased arm swing and abnormal postural reflexes, are obvious on physical examination. Interestingly, patients may not be aware of motor difficulties and may be skeptical of the diagnosis. The relatively rare syndromes of progressive supranuclear palsy (prevalence, 1 in 50,000 persons in the general population) and cortical basal ganglionic degeneration (prevalence, 1 in 100,000 persons)(7) are both "Parkinson's disease-plus syndromes," in which patients typically have cognitive abnormalities and abnormal voluntary movement without tremor. Variants of both of these syndromes, in which only cognitive abnormalities were seen in the first several years of the disease, have been reported. In addition to Parkinson's disease, other primarily motor conditions (eg, amyotrophic lateral sclerosis(8)) or social or emotional neurodegenerative conditions (eg, frontal-temporal or Pick's disease-complex dementias(9)) also may first manifest as isolated amnesia that resembles Alzheimer's disease. Neurodegenerative motor disorders are also highly associated with depression and its attendant cognitive effects(7). 4. Vitamin B12 deficiency A part of the classic dementia workup, along with thyroid function tests and luetic antibody assay, vitamin B12 assay may detect an abnormally low level of the vitamin in persons older than 60 years, in whom the deficiency is estimated to affect 10% to 15%(10). Hematologic abnormalities may not occur with vitamin B12 deficiency, particularly if the nervous system is involved(11). Vitamin B12 injections should improve mentation and prevent the disability associated with progressive myelopathy and peripheral neuropathy. Like depression, vitamin B12 deficiency is more common in Alzheimer's disease,(12) although it is unclear why. Physicians need to monitor mental status in patients with vitamin B12 deficiency whose clinical profile is otherwise consistent with Alzheimer's disease. If cognitive abnormalities progress after vitamin B12 levels normalize, a diagnosis of both conditions can be made. 5. Thyroid disorders Thyroid disease, especially hypothyroidism, is common in elderly persons(13). However, apathetic hyperthyroidism (ie, paradoxical presentation of hyperthyroidism with fatigue, psychomotor slowing, depression, and weight gain) also occurs in this population. History taking, physical examination, and testing for thyrotropin and free or total thyroxine levels are appropriate. Rarely, elderly persons with autoimmune hypothyroidism have a condition called Hashimoto's encephalopathy, which features cognitive abnormalities (usually a delirium state but sometimes a strokelike syndrome)(14). Patients are screened for Hashimoto's encephalopathy with thyroid auto-antibody testing. Thyroid hormones are unlikely to be directly involved in this condition, which may respond to corticosteroid treatment. However, a normal thyrotropin level does not exclude central hypothyroidism, which may not be as rare in elderly persons as previously assumed(15). 6. Thiamine deficiency Acute thiamine deficiency, which often occurs in persons with alco-

holism, causes Wernicke-Korsakoff syndrome, an encephalopathy in which a delirium state coincides with eye movement abnormalities and ataxia. Vestibular abnormalities and other neurologic symptoms can also occur. Elderly persons who have poor nutrition may be at high risk of this syndrome--even if they do not abuse alcohol. In one series,(16) formal assays showed that 20% to 40% of geriatric inpatients and outpatients had moderate to severe thiamine deficiency. Alcoholism causes amnesia, and alcoholism can go undetected in the estimated 6% to 16% of elderly persons affected, particularly in those who began heavy drinking in their 40s or 50s (late-onset alcoholic pattern). Elderly persons who abuse alcohol moderately or heavily are also at high risk for depression and suicide(17). 7. Primary gastrointestinal conditions Perhaps surprisingly, several primary gastrointestinal disorders--Whipple's disease, vitamin E deficiency, and niacin deficiency (pellagra)--can cause brain abnormalities and dementia. In general, these conditions have a prominent attention and executive function component, and cognitive functions (old knowledge such as identifying right and left, names, visuospatial information) are relatively spared. However, in early stages of central nervous system involvement, these primary gastrointestinal disorders may all cause relatively isolated amnesia(18). The classic presentation of Whipple's disease with central nervous system involvement, which may occur even in patients without gastrointestinal symptoms, is a Parkinson's disease-plus syndrome that resembles progressive supranuclear palsy(7). It features frontal-subcortical dementia, disordered eye movement and gait, and slowed, small limb movements. A rhythmic movement of the eyes, face, and even shoulders and arms (oculomasticatory myorhythmia)(8) may also occur. 8. Structural brain lesions The most important reason for brain imaging in dementia, even in patients without risk factors for stroke, may be to detect structural lesions (eg, tumor, arteriovenous malformation, hemorrhage) of the right or, sometimes, left parietal cortex in patients who have signs and symptoms that are characteristic of Alzheimer's disease. The parietal cortex is not directly connected with motor output systems, and paralysis and abnormal reflexes may be absent despite significant mass effect. Although other abnormalities (ie, sensory, complex behavioral, and visual-focal deficits) may occur, patients are usually unaware of these deficits (anosognosia), and they may be missed on a cursory examination or by an examiner unfamiliar with neurologic signs. The rare subdural hematoma or other lesion outside the brain (eg, a dural arteriovenous malformation) that produces abnormal mental status because of accumulation of toxic metabolites, vascular steal effect, or induced nonconvulsive seizure is still worth looking for. These lesions may be treated with operative and interventional radiologic procedures(19). 9. Cancer Amnesia and changes in mood or personality, delirium, or seizures can indicate paraneoplastic limbic encephalitis, a rare remote effect of cancer associated with non-small-cell lung cancer but also with thymoma, Hodgkin's disease, and cancer of the breast, colon, bladder, and testicle(18). Most patients with limbic encephalitis are not known to have cancer until their mental status changes. Anti-Hu or anti-Ta (also called anti-Ma2) antibodies may be detectable in serum and cerebrospinal fluid, although rare antibodies, or no antibodies, may also be found. Most

commonly, limbic encephalitis occurs rapidly, over days to weeks, and may be accompanied by other neurologic symptoms (eg, ataxia, visual changes, neuropathy). In one series,(20) treatment of the primary tumor was associated with neurologic improvement in up to 64% of patients. 10. Neurosyphilis Paretic neurosyphilis, a rare parenchymal form of neurosyphilis and the first mental disorder associated with specific cerebral disease,(8) has decreased substantially in prevalence since the 1980s. However, it is still a major cause of morbidity in patients with HIV infection or AIDS; in 2000, prevalence of paretic neurosyphilis in this group was 1%. Many experts no longer recommend routine rapid plasma reagin (RPR) or VDRL screening for patients with classic symptoms of Alzheimer's disease, because false-positive results due to the patient's age or to cross-reactivity with comorbid conditions may outnumber true positive results. However, I do not agree with this recommendation. First, too few physicians adequately screen for HIV infection risk factors in elderly patients. Second, an RPR or VDRL test that produces a false-positive result can be followed with a sensitive fluorescent treponemal antibody absorption (FTA-ABS) test. Third, detection of other systemic disorders that can cause a positive RPR test result (eg, lupus) is not trivial. Lastly, further complications of tertiary syphilis can be prevented with a relatively benign antibiotic treatment. I routinely include RPR testing in dementia screening. Physicians need to consider ordering FTA-ABS testing alone if the clinical picture strongly suggests paretic neurosyphilis (ie, disinhibited frontotemporal dementia) or tabes dorsalis; false-negative RPR and VDRL test results occur at high rates in elderly patients with these conditions. Conclusion Unfortunately, the scope of this article does not allow an exhaustive discussion of every disorder that could cause cognitive symptoms--particularly those associated with attention disorders and delirium. Drug-induced delirium (eg, due to use of benzodiazepines or anticholinergics), sleep disorders (causing attention disorder and amnesia), and other, rare systemic diseases have not been discussed here. However, it should be clear that a number of disorders other than Alzheimer's disease can cause progressive memory loss and functional disability. Most patients with the treatable disorders discussed here do not fully recover their premorbid cognitive abilities after starting appropriate therapy. However, their symptoms may stabilize for long periods, and they may be protected from other significant consequences of their disorder. Crucial testing includes brain imaging (especially magnetic resonance imaging for patients with prominent motor or initiation abnormalities or isolated memory impairment), a vitamin B12 assay, thyroid function (thyrotropin and free or total thyroxine) testing, RPR or FTA-ABS testing, and a clinical neurologic examination to detect reflex abnormalities, paresis or gait disorder, and disproportionate frontal-subcortical impairment relative to loss of cognitive skills. The results of testing help guide decisions about appropriate diagnosis, management, and care for these patients and their families. References Lavretsky H, Kumar A. Clinically significant non-major depression: old concepts, new insights. Am J Geriatr Psychiatry 2002;10(3):239-55 McNeil JK. Neuropsychological characteristics of the dementia syndrome of depression: onset, resolution, and three-year follow-up. Clin Neuro-psychol 1999;13(2):136-46

Georgieff N, Dominey PF, Michel F, et al. Anomia in major depressive state. Psychiatry Res 1998;77(3):197-208 Berger AK, Fratiglioni L, Forsell Y, et al. The occurrence of depressive symptoms in the preclinical phase of AD: a population-based study. Neurology 1999;53(9):1998-2002 Martinez-Lage P, Hachinski V. Multi-infarct dementia. In: Barnett HJ, Mohr JP, Stein BM, et al, eds. Stroke: pathophysiology, diagnosis and management. 3rd ed. New York: Churchill Livingstone, 1998:875-94 Ross GW, Bowen JD. The diagnosis and differential diagnosis of dementia. Med Clin North Am 2002;86(3):455-76 Jankovic JJ, Tolosa E, eds. Parkinson's disease and movement disorders. 4th ed. Lippincott Williams & Wilkins, 2002:152, 190 Rowland LP, ed. Merritt's neurology. 10th ed. New York: Lippincott Williams & Wilkins, 2000:182-8, 212, 710-3 Barrett AM. Pick disease. Available at: http://www.emedicine.com/neuro/topic311.htm. Accessed March 15, 2005 Baik HW, Russell RM. Vitamin B12 deficiency in the elderly. Annu Rev Nutr 1999;19:357-77 Dharmarajan TS, Norkus EP. Approaches to vitamin B12 deficiency: early treatment may prevent devastating complications. Postgrad Med 2001;110(1):99-105 Wang HX, Wahlin A, Basun H, et al. Vitamin B12 and folate in relation to the development of Alzheimer's disease. Neurology 2001;56(9):1188-94 Diez JJ. Hypothyroidism in patients older than 55 years: an analysis of the etiology and assessment of the effectiveness of therapy. J Gerontol A Biol Sci Med Sci 2002;57(5):M315-20 Jameson JL, Weetman AP. Disorders of the thyroid gland. Available at: http://harrisons.accessmedicine.com/server-java/Arknoid/amed/harrisons/c o_chapters/ch330/ch330_p01.html?searchterm=jameson%20weetman>;. Accessed March 15, 2005 Wardle CA, Fraser WD, Squire CR. Pitfalls in the use of thyrotropin concentration as a first-line thyroid-function test. (Letter) Lancet 2001;357(9261):1013-4 Pepersack T, Garbusinski J, Robberecht J, et al. Clinical relevance of thiamine status amongst hospitalized elderly patients. Gerontology 1999;45(2):96-101 Menninger JA. Assessment and treatment of alcoholism and substance-related disorders in the elderly. Bull Menninger Clin 2002;66(2):166-83 Geschwind MD, Jay C. Assessment of rapidly progressive dementia. Available at: http://harrisons.accessmedicine.com/server-java/Arknoid/amed/harrisons/e x_editorials/edl3506_p01.html?searchterm=geschwind%20md%20jay%20c;. Accessed March 15, 2005 Bernstein R, Dowd CF, Gress DR. Rapidly reversible dementia. Lancet 2003;361(9355):392 Gultekin SH, Rosenfeld MR, Voltz R, et al. Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumour association in 50 patients. Brain 2000;123(Pt 7):1481-94 Dr Barrett was associate professor of neurology and neural and behavioral sciences, Pennsylvania State College of Medicine, Hershey. She is now director of the Stroke Rehabilitation Research Program, Kessler Medical Rehabilitation Research and Education Corporation, West Orange, New Jersey. Correspondence: Anna M. Barrett, MD, Stroke Rehabilitation Research Program, Kessler Medical Rehabilitation Research and Education Corporation, 1199 Pleasant Valley Way, West Orange, NJ 07052. E-mail: abarrett@kmrrec.org.

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