LITERATURE MONITOR:RECENT ARTICLES OF INTEREST IN NEUROLOGY

DECLINE IN STROKE INCIDENCE OUTPACES DROP IN LIFETIME RISK

During the past 50 years, the incidence of stroke has declined significantly, but the lifetime risk of stroke has not significantly decreased, reported Raphael Carandang, MD, and colleagues in the December 27, 2006, JAMA.

The researchers determined long-term trends in the incidence, lifetime risk, severity, and 30-day mortality of clinical stroke among original and offspring cohorts of the Framingham Study. During three consecutive periods (1950-1977, 1978-1989, and 1990-2004), 9,152 men and women 55 or older were assessed. Among all participants, there were 1,030 incident clinical strokes; 450 of these occurred in men, and 629 were ath­erothrombotic brain infarctions. For every 1,000 person-years, the age-adjusted incidence of first stroke in men was 7.6 between 1950 and 1977, 6.2 between 1978 and 1989, and 5.3 between 1990 and 2004; in women, first stroke incidence was 6.2, 5.8, and 5.1, respectively. In addition, the age-adjusted incidence of atherothrombotic brain infarctions for every 1,000 person-years in women was 3.7 between 1950 and 1977, 3.4 between 1978 and 1989, and 2.9 between 1990 and 2004, but it did not reach significance in men (4.9, 3.7, and 3.6, respectively).

There was a decrease in lifetime risk at age 65 in both men (from 19.5% to 14.5%) and women (from 18.0% to 16.1%) that did not reach statistical significance. Age-adjusted stroke severity remained unchanged at 47% and 48% across the three time periods; between the first two periods, there was an apparent increase from 40% to 60% in stroke severity in women, but this change did not reach statistical significance. Furthermore, 30-day mortality did decrease significantly in men (from 23% to 14%) but not significantly in women (from 21% to 20%).

“Given that the age-adjusted annual incidence and 10-year cumulative incidence has decreased over the last 50 years, the trend in lifetime risk of clinical stroke and atherothrombotic brain infarction is likely due to increasing life expectancy, which partially offsets the decreases in annual and shorter-term risk,” Dr. Carandang and colleagues stated. In addition, the researchers posited that “greater diagnostic sensitivity for small, less severe strokes may have offset the increasing prevalence of more severe strokes expected with an aging population” and that the nonsignificant trend of greater stroke severity among women may be related to older age at initial stroke.

“These sobering trends emphasize that while improved control of risk factors has lowered incidence of stroke, there is a need for greater primary prevention efforts to reduce the lifetime risk, severity, and 30-day mortality following stroke,” concluded Dr. Carandang and colleagues.

Suggested Reading
Carandang R, Seshadri S, Beiser A, et al. Trends in incidence, lifetime risk, severity, and 30-day mortality of stroke over the past 50 years. JAMA. 2006;296:2939-2946.

ANTIPSYCHOTICS ARE NOT ASSOCIATED WITH COGNITIVE DECLINE IN ALZHEIMER'S DISEASE

Patients with Alzheimer’s disease who take any or only atypical antipsychotics may be no more likely to experience cognitive decline than those who do not, reported researchers in the January 2007 Journal of Neurology, Neurosurgery, and Psychiatry.

Gill Livingston, MD, MBChB, FRCPsych, and colleagues recruited 224 patients with Alzheimer’s disease and used three measures of cognition to compare those taking antipsychotic drugs for more than six months with those who were not. From 184 remaining participants at six months,  162 of them were included for severe-impairment battery an­alysis. Among these 162 participants, 30 were taking antipsychotics, including risperidone (23), olanzapine (3), quetiapine (2), chlorpromazine (1), and sulpiride (1). The researchers found no significant difference in cognitive decline between those taking antipsychotics and those who were not, as measured by the severe impairment battery analysis, the Mini-Mental State Examination, and the Alzheimer’s Disease Assessment Scale—Cognitive Subscale. Furthermore, “an increased dose did not correlate with greater cognitive decline, suggesting no causative relationship between cognitive decline and antipsychotic prescription,” Dr. Livingston’s team stated.

The researchers also found no significant association between cognitive decline and antipsychotic dosages at baseline or chlorpromazine equivalents at six months, as measured by the severe-impairment battery analysis. Greater baseline cognitive impairment was the only predictor of increased cognitive decline.

“We used three validated measures of cognition, all of which showed the same result and controlled for potential confounders,” Dr. Livingston and colleagues pointed out. “In addition, the results were the same when we included the whole cohort rather than the select group of patients with potential to change who had been taking antipsychotics continuously. We can therefore state confidently that any difference in cognitive deterioration over six months was not of the magnitude reported by earlier studies.” However, the researchers added that clinicians should still “remain cautious” when prescribing antipsychotics to Alzheimer’s disease patients.

In an accompanying editorial, David Ames, MD, FRCPsych, FRANZCP, noted, “Of course it is true that too many old people with dementia are treated too often and for too long with antipsychotic drugs, and efforts to diminish the prevalence of such prescriptions is to be greatly applauded, but the merit of the ... [present] study is in examining in an everyday context the potential negative consequences of novel antipsychotic use, which have caused great concern in recent years.” Dr. Ames added, “I am relieved to find that my inability to manage every single person I see with dementia and distressing ideas ... without occasional use of a novel antipsychotic drug in an n = 1 trial, may not be wholly irresponsible.”

Suggested Reading
Livingston G, Walker AE, Katona CLE, Cooper C. Antipsychotics and cognitive decline in Alzheimer’s disease: the LASER-Alzheimer’s disease longitudinal study. J Neurol Neurosurg Psychiatry. 2007;78:25-29.
Ames D. Antipsychotics, cognitive decline and death in Alzheimer’s disease: the London and South-East Region Alzheimer’s Disease longitudinal study. J Neurol Neurosurg Psychiatry. 2007;78:2.

HIGHER URIC ACID LEVELS MAY BE ASSOCIATED WITH COGNITIVE DECLINE

Elevated uric acid levels still within normal range may increase the risk of cognitive decline among elderly patients, reported David J. Schretlen, PhD, and colleagues in the January 2007 Neuropsychology.

Researchers studied 96 elderly adults with serum uric acid levels that ranged from 1.5 to 7.1 mg/dL for women and 1.5 to 7.6 mg/dL for men. Participants who had normal but mildly elevated uric acid levels were 2.7 to 5.9 times more likely than participants with low-moderate levels to show below average performance on three cognitive measures: processing speed, working memory, and verbal learning/memory. After controlling for age, gender, race, education, diabetes, hypertension, smoking, and alcohol abuse, the investigators found that the association between high uric acid levels and below average performance on measures of working memory and verbal learning/memory remained significant.

Additionally, uric acid levels were higher for men (4.96 mg/­­dL) than for women (4.09 mg/dL) and for participants with hypertension (4.87 mg/dL) than those without (4.24 mg/dL). Fourteen patients with diabetes mellitus and eight patients with self-reported past or current alcohol abuse or dependence also had higher levels than those without either of those two conditions, although these differences were not significant.

Dr. Schretlen and colleagues pointed out that cerebrovascular disease can facilitate the development of cognitive impairment in patients with diabetes and hypertension, thus raising the possibility that high uric acid levels may affect cognitive functioning via cerebrovascular changes. However, despite a study showing that CSF uric acid levels were increased in vascular dementia patients but decreased in Alzheimer’s disease patients compared with healthy controls, uric acid’s antioxidant properties have been shown to protect against Parkinson’s disease and Alzheimer’s disease. To explain this discrepancy, the researchers posited that in certain conditions, uric acid can obtain pro-oxidant properties that damage the vascular endothelium, and it may play an important role in the development of accelerated atherosclerosis.

Dr. Schretlen’s team also acknowledged that serum uric acid levels may have increased in response to another pathologic process that resulted in the cognitive impairment seen in their study cohort. However, the investigators noted that their findings could have “broad public health implications” due to the fact that their results were based on a broadly representative community sample.

“In any case, the present findings point to a relationship between uric acid and cognitive functioning that is at least partly independent of most cerebrovascular risk factors,” the researchers stated. “These findings suggest that high normal concentrations of serum uric acid should be added to the growing list of cardiovascular and metabolic biomarkers of mild cognitive impairment among elderly adults.”

Suggested Reading
Schretlen DJ, Inscore AB, Jinnah HA, et al. Serum uric acid and cognitive function in community-dwelling older adults. Neuropsychology. 2007;21:136-140.

NEW BRAIN IMAGING TECHNIQUE MAY DETECT ALZHEIMER'S DISEASE EARLIER

A new brain imaging method for detecting Alzheimer’s disease may improve on current techniques by providing greater accuracy in differentiating persons with mild cognitive impairment from those with Alzheimer’s disease and those with normal aging, according to the December 21, 2006, New England Journal of Medicine.

Gary W. Small, MD, and colleagues assessed 83 volunteers with self-reported memory problems who had undergone neurologic and psychiatric evaluation and positron-emission tomography (PET). Twenty-five of these volunteers had Alzheimer’s disease, 28 had mild cognitive impairment, and the remaining 30 had no cognitive impairment and were classified as healthy controls. After injection of 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-napthyl}ethylidene)malononitrile (FDDNP), PET was performed on the participants. In addition, all patients underwent 2-deoxy-2-[F-18]fluoro-D-glucose (FDG) PET, while 72 of the patients underwent MRI.

Average values for the temporal, parietal, posterior cingulate, and frontal regions with FDDNP-PET binding were significantly lower among healthy controls than among patients with mild cognitive impairment; these values were also lower in patients with mild cognitive impairment than in patients with Alz­heimer’s disease. FDDNP-PET showed greater diagnostic accuracy than did metabolism on FDG-PET or volume on MRI. In addition, an autopsy evaluation of one of the patients with Alz­heimer’s disease revealed that brain regions with high FDDNP-binding values in vivo were characterized by high concentrations of plaques and tangles.

FDDNP-PET, noted Dr. Small’s team, “is potentially useful as a noninvasive method to determine regional cerebral patterns of amyloid plaques and tau neurofibrillary tangles,” given the technique’s ability to differentiate patients with mild cognitive impairment from those with Alzheimer’s disease and from those without any cognitive impairment in the pres­ent study. FDDNP-PET’s greater ability to distinguish between Alzheimer’s disease, mild cognitive impairment, and normal aging in the present cohort may be due to the fact that FDDNP binds to both plaques and tangles in the frontal and temporal, but not in the parietal, regions. This finding suggests that “FDDNP labels regional tau tangles and thus differentiates frontotemporal dementia from Alzheimer’s disease according to the binding patterns,” the researchers pointed out.

Suggested Reading
Small GW, Kepe V, Ercoli LM, et al. PET of brain amyloid and tau in mild cognitive impairment. N Engl J Med. 2006;355:2652-2663.

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