• Can Vitamins Stave Off Vascular Dementia?
• Establishing an Optimal Dosage for Warfarin Therapy
• Positive Neurocognitive Outcomes After Febrile Seizures
• Parkinsonism Associated With Increased Mortality
• A Seminal Event in the Pathogenesis of Alzheimer's Disease

LONG-TERM USE OF VITAMINS E AND C MAY IMPROVE COGNITIVE FUNCTION

Long-term use of vitamin E and C supplements may reduce the risk of vascular dementia and improve cognitive function in later life, according to a report in the March 28 Neurology. Data from the Honolulu-Asia Aging Study (HAAS) indicated that a combination of vitamins E and C reduced the risk of vascular dementia by 88%. The study did not indicate, however, that the individual use of either vitamin reduced the risk of vascular dementia, nor did it indicate that the vitamins in combination reduced the incidence of Alzheimer's disease or stroke.

Initiated in 1965 for the study of heart disease and stroke, HAAS is a longitudinal study of Japanese-American men living in Hawaii. Data for this study were obtained from a subsample of the cohort interviewed in 1982, and from the entire cohort from a mailed questionnaire in 1988 and the dementia prevalence survey in 1991 to 1993. The subjects included 3,385 men, ages 71 to 93, whose use of vitamin E and C supplements had been previously ascertained. The men were interviewed or surveyed in 1982 and 1988 and were assessed for dementia and mental abilities during examinations in 1991 to 1993. Of the participants, 47 were diagnosed with Alzheimer's disease, 35 with vascular dementia, 50 with other or mixed types of dementia; 254 had low cognitive test scores without diagnosed dementia; and 2,999 men showed no cognitive difficulties.

Participants taking both vitamin E and C supplements regularly (at least once per week) in 1988 were 88% less likely to have vascular dementia four years later and 69% less likely to have forms of dementia other than vascular or Alzheimer's-related dementia or mixed-forms dementia. There was no significant reduction in the occurrence of Alzheimer's disease four years later.

Participants without dementia were evaluated for mental performance and function. Those who reported taking vitamin E and C supplements in 1988 had an approximately 20% greater chance of having better cognitive function during the 1991 to 1993 examination than those who did not take vitamin supplements. However, men taking the supplements in both 1982 and 1988 had an approximately 75% greater chance of having better cognitive function. This suggests that long-term use could significantly improve cognitive performance in late life.

"We originally thought that the beneficial impact antioxidant vitamin supplements had against vascular dementia was the prevention of stroke. However, to our surprise, we found there was not a significant association between vitamin supplement use and clinically recognized stroke," said study author Kamal Masaki, MD, of the University of Hawaii in Honolulu. As vitamin use did not reduce the incidence of stroke, the authors suggested that the vitamins may play a role in limiting the cellular and molecular oxidative injury provoked by an ischemic event, rather than decreasing the frequency with which such events occur. "The supplements may also play a role in providing protection against brain cell and membrane injury involved in many aging-related diseases, thus resulting in significantly higher scores on mental performance tests later in life."

As previous reports have shown that antioxidants may slow the progression of Alzheimer's disease, the researchers were also surprised that they did not find a protective effect against Alzheimer's disease.

"It is critically important for patients to practice preventive efforts shown to lower stroke risk and have broad ranging beneficial effects," commented Dr. Masaki. "More effective strategies for prevention also must be found. Therefore, a prevention trial of both vitamin E and C to further examine the potential protective effects on both vascular dementia and Alzheimer's disease is needed."

Masaki KH, Losonczy KG, Izmirlian G, et al. Association of vitamin E and C supplement use with cognitive function and dementia in elderly men. Neurology. 2000;54:1265-1272.

WHAT IS THE OPTIMAL WARFARIN DOSE FOR SECONDARY PREVENTION OF STROKE?

Low-intensity warfarin appears to be a safer preventive therapy than conventional-intensity warfarin for the secondary prevention of stroke in patients with nonvalvular atrial fibrillation, according to a report in the April Stroke.

The only previously conducted study on the efficacy of warfarin for secondary prevention of stroke in patients with nonvalvular atrial fibrillation was the European Atrial Fibrillation Trial (EAFT). Results from that trial indicated that warfarin at an international normalized ratio (INR) of 2.5 to 4.0 reduced the annual risk of stroke from 12% to 4% and was associated with a low incidence of major hemorrhagic events (2.8% per year). Hemorrhagic complications were, however, more common in the anticoagulation group than in the control group (risk ratio, 3.4). The investigators noted that no treatment effect was apparent with anticoagulation below an INR of 2.0. They did not evaluate the efficacy of various doses of warfarin within the INR 1.0 to 1.9 group. However, according to data from the third Stroke Prevention in Atrial Fibrillation (SPAF III) trial, a lower risk of ischemic stroke or systemic embolism was associated with an INR between 1.5 and 1.9 than with an INR lower than 1.5.

To clarify the dosage discrepancy, Takenori Yamaguchi, MD, and colleagues in the Japanese Nonvalvular Atrial Fibrillation-Embolism Secondary Prevention Cooperative Study Group studied the safety and efficacy of low and conventional warfarin dosages in a cohort of 115 patients younger than 80 who had had definite or possible cardioembolic stroke or transient ischemic attack (TIA) due to nonvalvular atrial fibrillation between one and six months before inclusion in the study. Subjects were randomly assigned to conventional-intensity (target INR, 2.5; n = 55) or low-intensity warfarin (target INR, 1.9; n = 60).

Monthly examinations were conducted by stroke specialists for two years or until an end point was reached. Primary end points included brain infarction, embolism to other parts of the body, TIA, amaurosis fugax, or asymptomatic brain infarction confirmed with CT scanning or MRI. Secondary end points were brain hemorrhage, retinal hemorrhage, or other severe hemorrhagic complications that were fatal; hospital admission for emergency treatment; or blood transfusion.

Due to a higher-than-expected rate of hemorrhagic complications in the conventional-intensity warfarin group, the trial was stopped early. Dr. Yamaguchi reported that the rate of hemorrhagic complications was 6.6% in the conventional intensity group and 0.0% in the low-intensity group. The rate of ischemic stroke was low in both groups: 1.1% in the conventional-intensity group and 1.7% in the low-intensity group. During the follow-up period, the INR was 2.3 ± 0.4 for the conventional-intensity group and 1.9 ± 0.3 for the low-intensity group. The six patients who experienced hemorrhagic complications were all elderly. Complications included gastrointestinal bleeding, hemoptysis, massive subcutaneous bleeding from an accidental fall, and cerebellar hemorrhage. A post hoc analysis of 46 patients at least age 70 indicated that anticoagulation with low-intensity warfarin (INR, 1.75 to 2.25) appears to be effective and safe in the prevention of stroke in elderly patients with nonvalvular atrial fibrillation, the author added.

Dr. Yamaguchi noted that size and ethnic characteristics of the study population could have affected the study results. The study population was smaller than that of the EAFT. There may also have been ethnic differences; a higher rate of intracerebral hemorrhage is reported in Japan than in Western countries.

Yamaguchi T. Optimal intensity of warfarin therapy for secondary prevention of stroke in patients with nonvalvular atrial fibrillation: a multicenter, prospective, randomized trial. Stroke. 2000;31:817-821.

ARE FEBRILE CONVULSIONS LINKED TO ATTENTION DEFICIT?

Children with a history of early febrile convulsions do not show adverse effects on behavior, scholastic performance, or neurocognitive attention outcomes when they reach school age, according to the results of a population-based study conducted in China. Reporting in the April Epilepsia, the researchers noted that the results of the study should "reassure parents about the favorable prognosis of [febrile convulsions]."

Febrile convulsion affects between 2% and 4% of children before age 5, they wrote. Most previously published hospital-based studies have shown fairly high rates of mental retardation (8% to 22%), behavioral disturbance (30%), and academic difficulties in children with febrile convulsion. The authors suggested that these rates may not be representative of the general febrile convulsive population, as such cohorts may include more severe and possibly atypical cases.

To assess whether febrile convulsions in early childhood are associated with neurocognitive attention deficits in school age, a total of 103 children confirmed to have had febrile convulsions before age 3 were followed until at least age 6. Among this group, 21.3 months was the average age of febrile seizure onset; 35.6% had recurrent febrile convulsions, and 4.5% had subsequent unprovoked seizures. Eighty-seven children from the initial cohort completed scholastic achievement, behavior, and attention tests. These children did not have epilepsy or take antiepileptic drugs, and they attended regular classes. Eighty-seven randomly selected, population-matched controls also underwent similar testing.

Compared with the control group, subjects with a history of febrile convulsions did not have scholastic performance or behavioral outcome disadvantage. Overall performance among subjects with a history of febrile convulsions was distinguished by significantly higher scores in the achievement test and fewer missing errors and commission errors, less variability in reaction time, and a nonsignificant trend of impulsivity. Attention performance was similar between the two groups. Among the subjects with a history of febrile convulsions, neither the development of unprovoked seizures nor prior use of phenobarbital had an adverse effect on neurocognitive attention outcome.

"Although there is a high rate of febrile convulsion recurrence, the long-term outlook for [children with febrile convulsions] is favorable and optimistic," the researchers wrote. "This study found that febrile convulsion is not associated with a decrement in neurocognitive attention, early academic performance, or behavioral outcome. Surprisingly, and in contrast with previous studies that showed no difference, this study found that [children with a history of febrile convulsions] demonstrated significantly better control of distractibility and attention," the researchers concluded.

Chang YC, Guo NW, Huang CC, et al. Neurocognitive attention and behavior outcome of school-age children with a history of febrile convulsions: a population study. Epilepsia. 2000;41:412-420.

ASSOCIATION BETWEEN PARKINSONISM, DEMENTIA, AND MORTALITY

Parkinsonism is linked to an increased risk of mortality in older people, whether or not they have dementia, according to a report in the April Journal of the American Geriatrics Society.

In their study of the impact of parkinsonism (exclusive of drug-induced extrapyramidalism) on individuals with Alzheimer's disease and dementia, the researchers compiled data on 721 subjects with Alzheimer's disease and 1,705 subjects without dementia. Susan L. Mitchell, MD, MPH, from the University of Ottawa, Ontario, and Kenneth Rockwood, MD, MPA, from Dalhousie University, Halifax, Nova Scotia used data gathered by the Canadian Study of Health and Aging, a multicenter study of cognitive impairment in older people, which includes 10,263 Canadians age 65 and older in its study population.

Parkinsonism was detected in 5% of the combined cohort, 9% of the Alzheimer's group, and 4% of the group without dementia. Parkinsonism was associated with a 1.51 risk of mortality; Alzheimer's disease was associated with a 1.34 risk; and no dementia was associated with a 1.54 risk. The researchers noted that a diagnosis of Alzheimer's disease was a significant risk factor for parkinsonism. Alzheimer's disease was also a predictor for mortality during the five-year follow-up; 75% of subjects with Alzheimer's disease died, while only 39% of those without dementia died during follow-up.

Subgroups were based on age (65 to 74, 75 to 84, and older than 85), residence (community or institution), and severity of cognitive impairment (based on criteria from the third revision of the Diagnostic and Statistical Manual of Mental Disorders, the National Institute of Neurological and Communicative Disorders and Stroke, and the Alzheimer's Disease and Related Disorders Association at baseline). The researchers noted that after adjustment for age, residence, and severity of cognitive impairment, the association between parkinsonism and poorer survival (risk ratio, 1.33) remained significant.

According to previously published research by Bennett and colleagues, posture and gait disturbances are particularly important in the association between parkinsonism and mortality. Postural dyscontrol, in particular, was found to be highly associated with mortality, noted the researchers. They added that one of the limitations of their own study is that rigidity, gait, and postural disturbance were not precisely defined during collection of clinical examination data. However, as gait abnormalities have been linked to mortality in other studies, they suggested that physical therapy and exercise programs could be tested as preventive therapy in older patients with parkinsonism.

Mitchell S, Rockwood K. The association between parkinsonism, Alzheimer's disease, and mortality: a comprehensive approach. J Am Geriatr Soc. 2000;48:422-425.

AMYLOID ß-PEPTIDE LEVELS—A TARGET FOR ALZHEIMER'S DISEASE PREVENTION?

Levels of amyloid ß-peptide (Aß) correlated with cognitive decline and predated tau pathology in a study described in the March 22 JAMA. These findings suggest that treatment strategies for dementia could target the formation, accumulation, or cytotoxic effects of Aß, suggested lead author Jan Näslund, PhD, and colleagues.

The study cohort was selected from 278 consecutively autopsied nursing home residents from the Jewish Home and Hospital in Manhattan and the Bronx, New York. Only subjects with neuropathological lesions associated with Alzheimer's disease were included in the cohort. The 79 selected subjects (16 men, 63 women) were assigned Clinical Dementia Rating (CDR) scale scores no more than six months after their death. On the basis of the CDR scores, the subjects were classified as cognitively intact (CDR, 0.0 [n = 16]), questionably demented (CDR, 0.5 [n = 11]), mildly demented (CDR, 1.0 [n = 22]), moderately impaired (CDR, 2.0 [n = 15]), or severely demented (CDR, 4 to 5 [n = 15]).Total Aß peptide levels—soluble Aß, aggregate Aß, and Aß deposits—were evaluated. Enzyme-linked immunosorbent assays showed that levels of both Aßx-42 and Aßx-40 were elevated even in patients classified as having questionable dementia. Peptide levels increased with severity of dementia in all cortical regions except the primary visual cortex. The authors also reported that Aß accumulation preceded the formation of neurofibrillary tangles, both of which occurred before the criteria for clinical Alzheimer's disease were met.

In this study, the development of neurofibrillary tangles followed Aß deposition; however, neurofibrillary tangles may develop in the absence of Aß deposition. Although Aß deposits do not necessarily precede the development of neurofibrillary tangles, soluble Aß may be linked to the process. According to the report, Aß may lower neuronal thresholds to cellular insults such as excitatory amino acids, glucose deprivation, and oxidative stress. Such insults are key features of the "pathological spectrum of Alzheimer's disease." The authors proposed that prevention and treatment strategies for Alzheimer's disease "should focus on inhibiting the cellular production of Aß and/or slowing the pathogenic assembly of Aß into aggregates."

In an accompanying editorial, Dennis J. Selkoe, MD, of the Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, noted that this study confirms that Aß is a rational therapeutic target for Alzheimer's disease. Dr. Selkoe predicted that formal Alzheimer's disease risk assessment in an individual's fifth or sixth decade will become part of routine health maintenance. "This assessment most likely will include a careful exploration of family history for [Alzheimer's disease] or other dementias, a blood screen for relevant gene defects underlying [Alzheimer's disease], measurement of plasma Aß levels and, when indicated, determination of cerebrospinal fluid levels of AWF, tau, and other markers of the neuropathology." A regimen of anti-inflammatory agents or antioxidants for high risk patients could prevent the onset of Alzheimer's disease, suggested Dr. Selkoe.

Näslund J, Haroutunian V, Mohs R, et al. Correlation between elevated levels of amyloid ß-peptide in the brain and cognitive decline. JAMA. 2000;283:1571-1577.
Selkoe D. The origins of Alzheimer disease: A is for Amyloid. JAMA. 2000;283:1615-1617.

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