ALZHEIMER’S DISEASE ASSOCIATED WITH REDUCED LIFE EXPECTANCY

A study of community-dwelling elderly persons who received a diagnosis of Alzheimer’s disease revealed that “survival duration was shorter than predicted on the basis of US population data.” The study, published in the April 6 Annals of Internal Medicine, demonstrated significant associations between reduced survival and the following findings at diagnosis: increased severity of cognitive impairment, decreased functional level, history of falls, findings of frontal release signs, and abnormal gait.

Eric B. Larson, MD, MPH, and colleagues at the University of Washington in Seattle examined 521 persons (60 and older) with newly diagnosed Alzheimer’s disease enrolled between 1987 and 1996 in the Seattle Group Health Cooperative Alzheimer’s disease registry. Baseline measurements for the study population included demographic features, Mini-Mental State Examination (MMSE) score, Blessed Dementia Rating Scale (BDRS) score, duration since reported onset of symptoms, associated symptoms, comorbid conditions, and selected signs. The main outcome rating was survival.

Dr. Larson and colleagues reported that median survival from initial diagnosis of Alzheimer’s disease was 4.2 years for men and 5.7 years for women. “Men had poorer survival across all age-groups compared with females,” the investigators wrote, and “survival was decreased in all age-groups compared with the life expectancy of the US population.”

Statistically significant predictors of mortality included baseline MMSE score of 17 or less, baseline BDRS score of 5.0 or greater, presence of frontal lobe release signs, presence of extrapyramidal signs, gait disturbance, history of falls, congestive heart failure, ischemic heart disease, and diabetes at baseline, the investigators reported. “These results should be useful to patients and families experiencing Alzheimer’s disease, other caregivers, clinicians, and policymakers when planning for future care needs,” they concluded.

In an accompanying editorial, Kenneth E. Covinsky, MD, MPH, and Kristine Yaffe, MD, concurred with the researchers’ conclusion. “Larson and colleagues’ article can help patients, caregivers, and clinicians to establish priorities in their respective roles,” they said. “Clinicians should be able to apply the findings of this rigorous, carefully conducted study to their patients with newly diagnosed dementia.”

However, Drs. Covinsky and Yaffe, from the University of California, San Francisco, voiced a note of caution against overly alarmist interpretation of the results of the study. While they acknowledged Dr. Larson and colleagues’ finding that “Alzheimer’s disease reduced life expectancy by about half” compared to the US Census expectations, they noted “a subtle but clinically important distinction” between examining survival after a diagnosis of Alzheimer’s disease—as the Larson study did—and survival after onset of the disease. “Since cognitive decline is often insidious, identifying the precise time when a patient first meets diagnostic criteria for dementia is difficult without frequent cognitive testing. This complicates the interpretation of such risk factors as gait disturbance or severity of cognitive impairment,” they observed. “It is not clear whether patients with these risk factors have worse survival because they have more aggressive forms of dementia or because these risk factors signify patients whose dementia was diagnosed at a later point in its natural history.”

Nevertheless, they praised the work of Larson and colleagues for illuminating an important aspect of the physician-patient relationship in the care of patients with Alzheimer’s disease. “Thinking of dementia as a progressive, chronic disease may help clinicians reset their priorities to focus on palliative care planning and to assess their patients’ preferences for care.… Our duty to our patients extends to advocating changes that will give patients and caregivers better access to the care they need.”

Covinsky KE, Yaffe K. Dementia, prognosis, and the needs of patients and caregivers. Ann Intern Med. 2004; 140:573-574.
Larson EB, Shadlen M-F, Wang L, et al. Survival after initial diagnosis of Alzheimer disease. Ann Intern Med. 2004;140:501-509.

LATE-ONSET SEIZURES—A MARKER OF INCREASED STROKE RISK?

British researchers found that “onset of seizures in late life is associated with a striking increase in the risk of stroke,” according to a report in the April 10 Lancet. Data for the study were drawn from the UK General Practice Research Database on 4,709 persons who had seizures beginning at 60 or older and 4,709 randomly selected age- and sex-matched controls with no history of seizure. Paul Cleary, MD, of Gartnavel General Hospital in Glasgow, and colleagues investigated the hypothesis that seizure onset in persons of this age-group with no overt history of stroke might be a marker of increased stroke risk. Persons with a history of cerebrovascular disease, other brain injury, brain tumor, drug or alcohol misuse, or dementia were excluded, they noted. There were 2,044 men in the cohort; the median year of birth was 1920.

The investigators ascertained that more strokes occurred among patients in the study cohort (471) than in the control group (207). Statistical analysis revealed that “the relative hazard of stroke at any point for patients in the study cohort was 2.89 compared with patients in the control group,” they reported. This can be compared with the relative risk of 1.4 associated with low HDL-cholesterol concentrations, the doubling of risk associated with smoking, and the doubling to tripling of risk associated with lack of exercise, they commented.

The findings “suggest that a patient who presents with seizures for the first time in late life, when there is no apparent predisposing cause, should be deemed to be at increased risk of stroke,” the investigators observed. “Such patients should be screened for vascular risk factors and treated appropriately.” Based on their results, further research to assess the benefit of specific interventions against stroke in elderly patients with epilepsy is warranted, they concluded.

In an accompanying editorial, Cathie L. M. Sudlow, MD, of the Department of Clinical Neurosciences at the University of Edinburgh, remarked that the implication of the findings by Dr. Cleary and colleagues “is that otherwise unexplained epilepsy in older people may be due to—and so be a marker of—occult cerebrovascular disease. If so, we would expect to find an excess of vascular risk factors and of subsequent vascular events other than stroke in these patients. It would be interesting, and should be possible, to look for these associations.”

Cleary P, Shorvon S, Tallis R. Late-onset seizures as a predictor of subsequent stroke. Lancet. 2004;363:1184-1186.
Sudlow CLM. Epilepsy and stroke. Lancet. 2004;363:1175-1176.

IS THERE A CORRELATION BETWEEN SMOKING AND SUBARACHNOID HEMORRHAGE?

A strong, positive association was found between cigarette smoking and subarachnoid hemorrhage, especially for aneurysmal subarachnoid hemorrhage and women, which is virtually eliminated within a few years of smoking cessation. As reported in the March issue of Stroke, researchers concluded that larger opportunities exist for preventing subarachnoid hemorrhage through smoking avoidance and cessation programs.

Craig S. Anderson, PhD, from the University of Auckland in New Zealand, based his research team’s findings on 432 incident cases of subarachnoid hemorrhage frequency that were matched to 473 community subarachnoid hemorrhage-free controls. Dr. Anderson and his colleagues sought to determine dose-dependent associations of active and passive smoking (at home) and smoking cessation with subarachnoid hemorrhage.

Compared with subjects who never smoked and were not exposed to passive smoking, the adjusted odds ratio for subarachnoid hemorrhage among current smokers was 5.0. For past smokers the odds ratio was 1.2 and for at-home smokers, 0.9. Current and lifetime exposures showed a clear dose-dependent effect, and risks appeared more prominent in women and for aneurysmal subarachnoid hemorrhage. About one in three cases of subarachnoid hemorrhage could be attributed to current smoking, but the risks declined quickly after smoking cessation, even among heavy smokers, according to the investigators.

“This population-based, case-control study shows that cigarette smokers have five times the risk of subarachnoid hemorrhage compared with nonsmokers and that about one third of all cases of subarachnoid hemorrhage could be attributed to current smoking,” Dr. Anderson and his colleagues stated. “In addition,” they reported, “cigarette smoking was found to be both a short- and long-term risk factor for subarachnoid hemorrhage in both men and women, with potentially greater risks for aneurysmal subarachnoid hemorrhage in women.” However, despite the strong, direct dose-response relationship between smoking and subarachnoid hemorrhage seen in their study, “the risks appear to diminish rapidly and largely disappear within a few years of quitting, even in those with the heaviest exposure defined by either dose or duration of smoking,” the researchers noted. “In contrast, there was no significant effect of passive smoking at home, either alone or on top of active smoking, on the risk of subarachnoid hemorrhage,” they added.

Anderson CS, Feigin V, Bennett D, et al. Active and passive smoking and the risk of subarachnoid hemorrhage: an international population-based case-control study. Stroke. 2004;35:633-637.

IS COGNITIVE SUPPORT THE KEY TO LINKING VITAMIN EFFECTS, APOE, AND MEMORY IMPAIRMENT?

Among healthy people 75 and older who have the apolipoprotein E epsilon4 (APOE epsilon4) genotype, low levels of vitamin B12 are associated with significantly worse performance on memory tests—but only in circumstances of low cognitive support, according to a report in the April issue of Neuropsychology.

Researchers from the Karolinska Institutet in Stockholm examined a sample of inhabitants of the Kungsholmen parish in Stockholm who were participating in a multidisciplinary study that included medical examination, social and family interviews, blood analysis, and cognitive testing. Of 528 persons evaluated, 130 were excluded due to DSM-III-R diagnosis of dementia or depression, 37 for incomplete vitamin B12 or folate data, 16 for taking vitamin B12 or folate supplements, 32 for abnormally high folate levels, and 113 for unavailable APOE data.

The remaining sample of 167 persons (mean age, 82.81; 134 women) were tested for APOE epsilon4 status and vitamin B12 and folate levels. The investigators reported that 118 participants were APOE epsilon4–negative; of these, 54 had low B12 level. Forty-nine participants were APOE epsilon4–positive; 28 of these patients had low B12 levels.

All study participants were given a series of episodic memory measures. Two lists of 12 semantically unrelated, concrete nouns were presented bimodally at either rapid (two seconds per word) or slow (five seconds per word) rates. Participants were allowed two minutes immediately after presentation for oral free recall, the investigators said. A further word list of 12 nouns belonging to four taxonomic categories was also administered. In this test, study participants were given two minutes for free recall, followed by a cued recall in which the category title was given and 30 seconds was allowed for subsequent recall. The tests thus demonstrated increasing cognitive support by increasing encoding time and offering cued recall, the investigators noted.

Statistical analysis of the study data “suggested recall performance of low-B12-epsilon4 carriers was less than that of the other groups, but only in the faster, two-second encoding condition; this group exhibited more marked improvement relative to other groups when encoding time was increased to five seconds,” the research team reported.

Increasing the level of support beyond provision of five seconds for encoding by organization into taxonomic groups or cued recall “produced parallel performance gains irrespective of APOE-vitamin group,” according to the researchers.

The investigators also found a trend in the data for folate that was similar to that for vitamin B12 but they were “unable to draw any firm conclusions concerning low folate levels and APOE in respect to episodic memory.”

The findings suggest that “brain reserve may vary as a function of APOE genotype and that epsilon4 carriers may be particularly vulnerable to cognitive impairment in the presence of an additional factor that deleteriously influences neuroanatomical structures and processes,” the investigators wrote. As their work suggests that vitamin B12 may be such a factor, they observed that “APOE epsilon4 carriers may derive relatively greater cognitive benefits from B12 and folate supplements,” which are “relatively inexpensive” and could become part of preventive health regimes for older persons.

NR

Bunce D, Kivipelto M, Wahlin A. Utilization of cognitive support in episodic free recall as a function of apolipoprotein E and vitamin B12 or folate among adults aged 75 years and older. Neuropsychology. 2004;18: 362-370.

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