Roberta F. White

Neurobehavioral deficits associated with PCB in 7-year-old children prenatally exposed to seafood neurotoxicants.

Prenatal exposure to polychlorinated biphenyls (PCBs) was examined by analysis of cord tissue from 435 children from a Faroese birth cohort. Analysis of 50 paired cord blood samples showed excellent correlation with the cord tissue concentration (r=.90). Among 17 neuropsychological outcomes determined at age 7 years, the cord PCB concentration was associated with deficits on the Boston Naming Test (without cues, two-tailed P=.09 not adjusted for mercury; with cues, P=.03), the Continuous Performance Test reaction time (P=.03), and, possibly, on long-term recall on the California Verbal Learning Test (P=.15). The association between cord PCB and cord-blood mercury (r=.42) suggested possible confounding. While no PCB effects were apparent in children with low mercury exposure, PCB-associated deficits within the highest tertile of mercury exposure indicated a possible interaction between the two neurotoxicants. PCB-associated increased thresholds were seen at two of eight frequencies on audiometry, but only on the left side, and no deficits occurred on evoked potentials or contrast sensitivity. The limited PCB-related neurotoxicity in this cohort appears to be affected by concomitant methylmercury exposure.

Apolipoprotein E element 4 association with dementia in a population-based study: The Framingham Study

Apolipoprotein E type 4 allele (apoE epsilon4) is associated with Alzheimers disease (AD) in the late-onset familial form and in sporadic cases, but the age-associated risk in a randomly sampled elderly population is not established. We examined the association of apoE epsilon4 with AD and other dementias (mainly multi-infarct or dementia following stroke) in 1,030 persons aged 71 to 100 years in the population-based Framingham Study cohort. Kaplan-Meier survival analysis revealed that 55% of the apoE epsilon4/epsilon4 homozygotes developed AD by age 80, whereas 27% of apoE epsilon3/epsilon4 heterozygotes developed AD by age 85, and 9% of those without a 4 allele developed AD by age 85 years. In comparison with persons without a 4 allele, the risk ration for AD was 3.7 (95% CI = 1.9 to 7.5) for apoE epsilon3/epsilon4 heterozygotes and 30.1 (95% CI = 10.7 to 84.4) for apoE epsilon4 homozygotes. ApoE epsilon2 (2/2, 2/3, or 2/4 genotypes) was associated with an absence of AD. One-half (n=21) of the 43 AD patients were either homozygous or heterozygous for apoE epsilon4. We found evidence for an association of apoE epsilon4 with other dementia, primarily multi-infarct dementia and stroke. The risk ratio was 2.3 (95% CI = 0.9 to 6.1) for non-AD dementias among persons with apoE epsilon3/epsilon4. Although the apoE epsilon4 allele is a potent risk factor for AD and may be associated with other forms of dementia, most apoE epsilon4 carriers do not develop dementia, and about one-half of AD is not apoE epsilon4 associated. The low positive predictive value of this marker (0.10) suggest that use of apoE genotyping as a screening test for AD is not supported.

Lifetime risk of dementia and Alzheimer's disease The impact of mortality on risk estimates in the Framingham Study

We estimated the remaining lifetime risks of developing Alzheimers disease (AD) and dementia from all causes, based on data from longitudinal population studies. The risk of developing AD during ones lifetime depends on both disease incidence and life expectancy. Conventional estimates of cumulative incidence overestimate the risk when there is a substantial probability of mortality due to competing causes. A total of 2,611 cognitively intact subjects (1,061 men, 1,550 women; mean age, 66± 7 years) were prospectively evaluated for the development of AD or other dementia. A modified survival analysis was used to estimate both cumulative incidence and the sex-specific remaining lifetime risk estimates for quinquennial age groups above age 65 years. Over a 20-year follow-up period, 198 subjects developed dementia (120 with AD). The remaining lifetime risk of AD or other dementia depended on sex, being higher in women, but varied little with age between 65 and 80 years. In a 65-year-old man, the remaining lifetime risk of AD was 6.3% (95% CI, 3.9 to 8.7) and the remaining lifetime risk of developing any dementing illness was 10.9% (95% CI, 8.0 to 13.8); corresponding risks for a 65-year-old woman were 12% (95% CI, 9.2 to 14.8) and 19% (95% CI, 17.2 to 22.5). The cumulative incidence between age 65 and 100 years was much higher: for AD, 25.5% in men and 28.1% in women; for dementia, 32.8% in men and 45% in women. The actual remaining lifetime risk of AD or dementia varies with age, sex, and life expectancy and is lower than the hypothetical risk estimated by a cumulative incidence in the same population.

The effect of education on the incidence of dementia and Alzheimer's disease in the Framingham Study

Objective: To evaluate whether low educational attainment is a risk factor for the incidence of dementia and Alzheimers disease (AD) in the Framingham Study and to determine whether age at onset of dementia is earlier in persons with low educational levels. Design: A community-based cohort was studied longitudinally for the development of dementia. Diagnosis was made according to strict criteria by two neurologists and a neuropsychologist. Subtype of dementia and year at onset were determined. Incidence rates were compared in three education groups: less than grade school, less than high school, and more than equals high school. Participants: A total of 3,330 men and women aged 55 to 88 years. Results: During 17 years of follow-up, 258 incident cases of dementia, including 149 AD cases, were identified. Unadjusted incidence rates were significantly elevated (p less than 0.05) for dementia and non-AD dementia among the least educated. The age-adjusted relative risk for subjects with a grade school education or less compared with those who earned a high school diploma was 1.31 (95% confidence interval [CI], 0.90 to 1.90) for dementia generally, 1.04 (95% CI, 0.62 to 1.74) for AD, and 1.75 (95% CI, 1.03 to 2.98) for non-AD dementia. Age at onset of dementia did not vary by educational attainment. Conclusions: After age adjustment, low educational attainment was not a significant risk factor for the incidence of dementia generally or of AD. Low educational attainment was associated with increased risk of non-AD dementia, perhaps because of deleterious smoking habits and other risk factors for stroke in the least-educated individuals. Adequately adjusting for age and examining subtypes of dementia are important in assessing the influence of education on dementia incidence. NEUROLOGY 1995;45: 1707-1712

Solvents and neurotoxicity

We describe the clinical evaluation of the nervous-system effects of solvent exposure. We review the current evidence in the epidemiological literature on neurotoxicological effects of solvents, and outline methods and issues to be taken into account in assessment of the patient whose symptoms may be related to solvent toxicity. Primary prevention of these disorders is essential, because treatment options are limited.

Health implications for Faroe Islanders of heavy metals and PCBs from pilot whales

In the Faroe Islands marine food constitutes a considerable part of the diet. In addition to fish, both meat and blubber from pilot whales are included in the diet. Muscle tissue of pilot whales caught in the Faroe Islands contains an average mercury concentration of 3.3 micrograms/g (16 nmol/g), about half of which is methylmercury. In some years an evenly distributed annual catch of pilot whales would make the average dietary intake of mercury close to an excess of the Provisional Temporary Weekly Intake of 0.3 mg recommended by WHO. In one out of eight consecutive births, the mercury concentration in maternal hair exceeded a limit of 10 micrograms/g where a risk of neurobehavioral dysfunction in the child may occur; the maximum was 39.1 micrograms/g. Mercury concentrations in umbilical cord blood showed a similar distribution with a maximum of 351 micrograms/l. The large variation in mercury exposure is associated with differences in the frequency of whale dinners. The average PCB concentration in pilot whale blubber is very high, i.e. about 30 micrograms/g. With an estimated daily consumption of 7 g of blubber, the average daily PCB intake could therefore exceed 200 micrograms, i.e. close to the Acceptable Daily Intake. In Scandinavia, the average daily PCB intake is about 15-20 micrograms. To obtain an improved scientific basis for public health action, two major prospective studies have been initiated. A birth cohort of 1000 children has been examined at approximately 7 years of age for neurobehavioral dysfunctions associated with prenatal exposure to mercury and PCB. Preliminary analyses of the data show that several neurobehavioral tests are associated with mercury exposure parameters. With emphasis on prenatal exposures to PCB, another cohort has been generated during 1994-95, and this cohort will be followed closely during the next years.

Neurotoxic Risk Caused by Stable and Variable Exposure to Methylmercury From Seafood

OBJECTIVES To examine whether the dose-effect relationship for developmental mercury neurotoxicity is affected by variable mercury exposure during pregnancy. METHODS The study was based on a birth cohort of 1022 children born in the Faroe Islands between March 1986 and December 1987. Neurobehavioral performance of 917 children (90%) was assessed at age 7. Intrauterine methylmercury exposure was determined from mercury concentrations in cord blood and 2 sets of maternal hair. Complete exposure information was available for 614 children (67%). RESULTS In children with complete exposure data, 8 of 16 neuropsychological tests showed deficits significantly associated with the cord-blood mercury concentration after confounder adjustment. Variable intrauterine exposure was suggested by disagreement between mercury concentrations in the 2 maternal hair samples. Removal of the 61 children (10%) with the greatest degree of variable exposure had a minimal effect on most exposure-effect relationships. However, the effect of the cord-blood concentration on verbal learning and memory was greater after this exclusion. CONCLUSION The study supports previous findings from this cohort study that maternal mercury exposure during pregnancy is associated with neuropsychological deficits detectable at age 7 years and that this association is evident in women with stable exposures throughout pregnancy. Thus the association is not the result of variable exposures.

Asymptomatic sequelae to acute sarin poisoning in the central and autonomic nervous system 6 months after the Tokyo subway attack

Abstract Six to eight months after the Tokyo subway attack in March 1995, the neurophysiological effects of acute sarin poisoning were investigated in 18 passengers exposed to sarin (sarin cases) in the subways to ascertain the focal or functional brain deficits induced by sarin. The event-related and visual evoked potentials (P300 and VEP), brainstem auditory evoked potential, and electrocardiographic R-R interval variability (CVRR), together with the score on the posttraumatic stress disorder (PTSD) checklist, were measured in the sarin cases and the same number of control subjects matched for sex and age. None of the sarin cases had any obvious clinical abnormalities at the time of testing. The P300 and VEP (P100) latencies in the sarin cases were significantly prolonged compared with the matched controls. In the sarin cases, the CVRR was significantly related to serum cholinesterase (ChE) levels determined immediately after exposure; the PTSD score was not significantly associated with any neurophysiological data despite the high PTSD score in the sarin cases. These findings suggest that asymptomatic sequelae to sarin exposure, rather than PTSD, persist in the higher and visual nervous systems beyond the turnover period of ChE; sarin may have neurotoxic actions in addition to the inhibitory action on brain ChE.

Late onset of Huntington's disease.

Twenty-five patients with late-onset Huntingtons disease were studied; motor impairment appeared at age 50 years or later. The average age at onset of chorea was 57.5 years, with an average age at diagnosis of 63.1 years. Approximately 25% of persons affected by Huntingtons disease exhibit late onset. A preponderance of maternal transmission was noted in late-onset Huntingtons disease. The clinical features resembled those of mid-life onset Huntingtons disease but progressed more slowly. Neuropathological evaluation of two cases reveal less severe neuronal atrophy than for mid-life onset disease.

Relationship of psychiatric status to Gulf War veterans' health problems.

OBJECTIVE A growing body of research has shown that there are important links between certain psychiatric disorders and health symptom reporting. Two disorders in particular (posttraumatic stress disorder (PTSD) and major depression) have been the most widely implicated to date, and this association has sometimes been used to explain the occurrence of ill-defined medical problems and increased somatic symptoms in certain groups, most recently Gulf War veterans. METHODS Structured psychiatric diagnostic interviews were used to examine the presence of major psychiatric (axis I) disorders and their relation to health symptom reporting in a well-characterized, stratified subset of Gulf War veterans and a non-Gulf-deployed veteran comparison group. RESULTS Rates of most psychiatric disorders were substantially lower than national comorbidity estimates, consistent with prior studies showing heightened physical and emotional well-being among active-duty military personnel. Rates of PTSD and major depression, however, were significantly elevated relative to the veteran comparison group. The diagnosis of PTSD showed a small but significant association with increased health symptom reports. However, nearly two-thirds of Gulf participants reporting moderate to high health symptoms had no axis I psychiatric diagnosis. CONCLUSIONS Results suggest that rates of psychiatric illness were generally low with the exception of PTSD and major depression. Although PTSD was associated with higher rates of reported health problems, this disorder did not entirely account for symptoms reported by participants. Factors other than psychiatric status may play a role in Gulf War health problems.