Complex Genetic Disease: Can Genetic Strategies in Alzheimer's Disease and New Genetic Mechanisms Be Applied to Epilepsy?

Summary: Strategies used in molecular genetics have changed modern neurology. The gene or genes responsible for several major neurologic diseases have now been identified using "reverse" or positional genetics. Unexpected new genetic mechanisms have been discovered in human neurologic diseases, including (a) identical mutations of the prion protein gene in Creutzfeldt-Jakob disease and fatal familial insomnia with the phenotypic expression directed by an accompanying polymorphism; (b) stable duplications of chromosome 17 in Charcot-Marie-Tooth disease (type 1 A) that involve many genes, only one of which appears to cause neuropathy; and (c) highly variable, dynamic mutations in myotonic dystrophy, fragile X syndrome, and Kennedy's syndrome that modulate variable expressivity in multiple tissues. There is growing recognition that neurologic diseases are often complex genetic diseases with multifactorial rather than simple modes of inheritance. For example, genetic association/linkage strategies have interacted with biochemistry and immunopathology studies to produce new insights into the disease mechanism of late-onset Alzheimer's disease. The role of apolipoprotein E in late-onset Alzheimer's disease is an example of how new analytical techniques of genetic disease can be applied to dissect multiple genes. Similar research strategies are suggested for the study of epilepsy as a complex disease.     

Alexithymia in Holocaust Survivors with and Without PTSD

Alexithymia was measured in non-treatment seeking, community-dwelling Holocaust survivors using the Toronto Alexithymia Scale—Twenty Item Version (TAS-20). Scores of survivors with (n = 30) and without (n = 26) posttraumatic stress disorder (PTSD) were compared, and associations among alexithymia, severity of trauma, and severity of PTSD symptoms were determined. Survivors with PTSD had significantly higher scores on the TAS-20 compared to survivors without PTSD. TAS-20 scores were significantly associated with severity of PTSD symptoms, but not with severity of trauma. This study adds to our knowledge of the relationship between alexithymia and trauma by demonstrating that this characteristic is related to the presence of posttraumatic symptoms and not simply exposure to trauma.     

Prevalence of vitamin B12 deficiency among geriatric outpatients.

BACKGROUND. Healthy people can have low levels of cobalamin (vitamin B12) without symptoms or signs of cobalamin deficiency. Early detection of deficiency is imperative for treatment to be effective. Development of radioimmunoassay tests has greatly improved accurate determination of cobalamin (Cbl) levels. Nevertheless, results of studies of Cbl deficiency vary widely because of the variety of populations studied. METHODS. In a prospective study, we tested 100 consecutive, unselected geriatric outpatients in a primary care setting to determine the prevalence of cobalamin deficiency. All patients, 65 years of age or older, who visited the office of one of the authors during a period of 11 consecutive working days, had their serum Cbl level checked. If the level was 299 pg/mL or lower, serum intrinsic factor and parietal cell antibodies, serum gastrin, part 1 Schilling test, serum methylmalonic acid, and total homocysteine were done, when possible, for the diagnosis of type A gastritis and intracellular Cbl deficiency. RESULTS. Sixteen percent of geriatric outpatients had serum Cbl levels of 200 pg/mL or below, and 21% had levels between 201 and 299 pg/mL. Among the 16 patients with levels < or = 200 pg/mL, 2 patients had macrocytic anemia, 3 patients had peripheral neuropathy, and 8 patients had type A gastritis. Among the 21 patients with levels of 201 to 299 pg/mL, 2 patients had peripheral neuropathy, 9 patients had type A gastritis, and none of the patients had macrocytic anemia. Among the patients whose methylmalonic acid and total homocysteine levels were determined, the results were high in 80% of those with Cbl levels < or = 200 pg/mL and in 33% of those with levels from 201 to 299 pg/mL. CONCLUSIONS. The prevalence of Cbl deficiency in geriatric outpatients was found to be higher than in any recent report. The lower limit of the normal range for Cbl level should be increased to 300 pg/mL.     

Psychiatric morbidity among people aged 85+ in 1987. A follow-up study at two and a half years: Associations with changes in psychiatric morbidity

This article reports findings from a longitudinal survey of very elderly people living at home in London. The research aimed to identify social, psychological and physical characteristics associated with positive ageing and successful survival in the community in later life and its converse—negative ageing—as well as the associated policy implications. Associations with psychiatric morbidity, measured using the General Health Questionnaire, among sample members without cognitive impairment between the baseline interviews in 1987 and at follow-up, two and a half years later in 1990, are reported. Twenty-five per cent of survivors scored over the threshold of the GHQ in 1987 and 30% scored over the threshold in 1990. Half of those with a score over the threshold in 1990 also scored over the threshold in 1987. Hierarchical regression (using residualized change analysis) was used to estimate the effects of the independent variables on changes in psychiatric morbidity. The most significant predictor of psychiatric morbidity (GHQ score) in 1990 was baseline GHQ score, followed by health and functional status scores. Health and functional status were also the strongest predictors of baseline (1987) GHQ scores. The uniqueness of the study lies in the collection of follow-up data on a sample of very elderly people, given that most surveys are corss-sectional and contain too few people aged 85+ to merit separate analysis. It contributes to the small body of literature on outcome of depression. The lack of consistent associations with recovery from psychiatric morbidity in the literature enhances the importance of studies aiming to identify factors associated with different outcomes.     

Pathology of falciparum malaria in Vietnam.

Autopsy samples from the brains of 20 patients who died of falciparum malaria were examined by light microscopy and by an immunohistologic method. Particular attention was paid to a comparison of the pathologic features of the white matter and the cortex. In the high-sequestration (greater than 50%) group (n = 8), the mean +/- SD percentage of cerebral microvessels that showed parasitized red blood cell (PRBC) sequestration was 71.2 +/- 8.1% in the cortex and 84.0 +/- 6.7% in the white matter. The difference in the PRBC sequestration rate between cortex and white matter was statistically significant (P less than 0.01). Perivascular and ring hemorrhages were seen more frequently in the white matter than in the cortex. Deposition of IgG and Plasmodium falciparum antigen in the cerebral microvessels was more highly significant in the white matter than in the cortex (P less than 0.01). Our study demonstrated that the localized concentration of PRBC sequestration in the brain correlated with the marked immunohistologic differences in the microvessels of cortex and white matter.