Carbohydrate craving in obese people: Suppression by treatments affecting serotoninergic transmission

We examined the existence of carbohydrate cravings, and the effects on such cravings of treatments that enhance serotonin release, among 24 obese subjects who claimed to have excessive appetites for carbohydrates. Subjects living in a college dormitory for four weeks were given three fixed meals daily and allowed to choose at will among five protein‐rich or five carbohydrate‐rich isocaloric snack foods, provided via a vending machine. For two weeks, they received no treatment (study 1) or a placebo (study 2); for the next two weeks, they received placebo, d‐1 fenfluramine or 1‐tryptophan. All but one of the subjects exhibited a marked preference for carbohydrate‐rich over protein‐rich snacks during the first two weeks of the study. The average daily intake of carbohydrate‐rich snacks was 4.1 ± 0.4 and of protein‐rich snacks 0.8 ± 0.3. Seventeen of the subjects failed to consume any protein snacks on most days during the baseline or test periods, thus it was not possible for us to examine the effect of test treatments on protein snack intake. Fenfluramine administration significantly reduced carbohydrate snacking in six of nine test subjects, as well as in the group as a whole (2.4 ± 0.6 snacks/day vs 4.2 ± 0.6 during the two‐week baseline period). Tryptophan significantly diminished carbohydrate intake in three of the eight treated subjects, and increased it in one subject; it did not significantly modify snacking patterns in the group as a whole. Placebo administration did not affect carbohydrate intake in any of the seven test subjects. These observations show that some obese people do consume carbohydrate‐rich snacks frequently and preferentially, and that this behavior can sometimes be diminished by treatments thought to enhance serotonin's release (fenfluramine) or synthesis (tryptophan)

Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson's disease

A key driver of patients' well-being and clinical trials for Parkinson's disease (PD) is the course that the disease takes over time (progression and prognosis). To assess how genetic variation influences the progression of PD over time to dementia, a major determinant for quality of life, we performed a longitudinal genome-wide survival study of 11.2 million variants in 3,821 patients with PD over 31,053 visits. We discover RIMS2 as a progression locus and confirm this in a replicate population (hazard ratio (HR) = 4.77, P = 2.78 x 10(-11)), identify suggestive evidence for TMEM108 (HR = 2.86, P = 2.09 x 10(-8)) and WWOX (HR = 2.12, P = 2.37 x 10(-8)) as progression loci, and confirm associations for GBA (HR = 1.93, P = 0.0002) and APOE (HR = 1.48, P = 0.001). Polygenic progression scores exhibit a substantial aggregate association with dementia risk, while polygenic susceptibility scores are not predictive. This study identifies a novel synaptic locus and polygenic score for cognitive disease progression in PD and proposes diverging genetic architectures of progression and susceptibility.A genome-wide survival study identifies variants at RIMS2 associated with progression of Parkinson's disease to dementia and highlights divergence in the genetic architecture of disease onset and progression.Neurological Motor Disorder

Effects of proximal and distal muscles' groups contraction and mental stress on the amplitude and frequency of physiological finger tremor. An accelerometric study.

Physiological finger tremor was assessed by two-dimensional solid accelerometry in 40 healthy normal subjects at rest (R) with the hand hanging over the armrest of a chair, in posture (P) with the arm rested on the armrest but the hand extended from the wrist, and finally adding proximal muscles contraction in extension (E) with the arm extended in front of the patient, each time with and without mental stress. The mean amplitude for physiological tremor, about 30 microns, was almost doubled by hand extension and increased by 4 to 5-fold by arm extension with further increase by mental stress in each position, which gives a good estimation of the contribution of proximal and distal muscles into the amplitude of physiological tremor. There was no significant effect of age between 20 and 60 years on tremor amplitude, but mean tremor frequency decreased significantly between 40 to 60 years. Mental stress increased amplitude but decreased tremor frequency of both across all position, possibly by increasing the synchronization of motor unit firing and by modifying the gain of the motoneurones and the stretch reflex as shown by electrophysiological studies

Multiple etiologies for Alzheimer disease are revealed by segregation analysis.

We have evaluated several transmission models for Alzheimer disease (AD), using the logistic regressive approach in 401 nuclear families of consecutively ascertained and rigorously diagnosed probands. Models postulating no major gene effect, random environmental transmission, recessive inheritance, and sporadic occurrence were rejected under varied assumptions regarding the associations among sex, age, and major gene susceptibility. Transmission of the disorder was not fully explained by a single Mendelian model for all families. Stratification of families as early- and late-onset by using the median of family mean onset ages showed that, regardless of the model studied, two groups of families fit better than a single group. AD in early-onset families is transmitted as an autosomal dominant trait with full penetrance in both sexes and has a gene frequency of 1.5%. Dominant inheritance also gave the best fit of the data in late-onset families, but this hypothesis was rejected, suggesting the presence of heterogeneity within this subset. Our study also revealed that genetically nonsusceptible males and females develop AD, indicating the presence of phenocopies within early-onset and late-onset groups. Moreover, our results suggest that the higher risk to females is not solely due to their increased longevity

Rate of progression of Alzheimer's disease is associated with genetic risk.

OBJECTIVE: To determine whether differences in genetic origin affect the clinical course of Alzheimer's disease (AD). The limited number of cases of AD linked to a known genetic abnormality is a major obstacle in determining whether the disorder is expressed differently in patients with familial AD and those with sporadic AD. DESIGN: Cross-sectional study. SETTING: Memory Disorders Unit of the Alzheimer's Disease Research Center at Massachusetts General Hospital, Boston. PARTICIPANTS: A total of 186 patients who had a clinical diagnosis of probable AD, family history information available for all first-degree relatives, and three or more outpatient visits were identified from a consecutive case series. MAIN OUTCOME MEASURES: Rate of decline on the Blessed Dementia Scale and the Activities of Daily Living Scale. RESULTS: We calculated the probability that an individual patient has a major genetic locus for AD (MGAD) using an algorithm that incorporates information from a genetic model and the individual's family. We measured cognitive and functional changes by the average annual rate of increase (slope) in scores for the Blessed Dementia Scale and Activities of Daily Living Scale, respectively. Multivariate analysis adjusted for age at onset, duration of illness at entry into the study, and education level indicated that scores on the Activities of Daily Living Scale worsened significantly faster in men with MGAD than in men with non-MGAD. No differences in Activities of Daily Living Scale slopes were observed among women with MGAD and non-MGAD. The slopes for Blessed Dementia Scale scores were similar in men and women regardless of the MGAD probability. CONCLUSIONS: Genetic factors may account for heterogeneity in rates of functional decline in AD. This study also illustrates the practical application of a probabilistic method that characterizes the genetic status of AD in an individual patient

No Genetic Effect of α1-Antichymotrypsin in Alzheimer Disease

Alzheimer disease (AD) is the most common neurodegenerative disorder for individuals over the age of 40. AD has a complex etiology, and it is likely that multiple genes, acting independently and/or interacting, affect the risk of developing AD. Several genes involved with AD have been described already, but only the APOE gene on chromosome 19q has been shown to affect the risk of the common late onset form of AD. α1-Antichymotrypsin (AACT) is a major component of the amyloid plaques found in the brains of AD patients, and an allele in its gene has been proposed to increase the risk of developing AD when also associated with the APOE-4 allele. We have examined the role of this AACT polymorphism in a large set of families and sporadic cases, and do not see any effect, either alone or in combination with the APOE-4 allele