Association of BDNF with anorexia, bulimia and age of onset of weight loss in six European populations.

Several genes with an essential role in the regulation of eating behavior and body weight are considered candidates involved in the etiology of eating disorders (ED), but no relevant susceptibility genes with a major effect on anorexia nervosa (AN) or bulimia nervosa (BN) have been identified. Brain-derived neurotrophic factor (BDNF) has been implicated in the regulation of food intake and body weight in rodents. We previously reported a strong association of the Met66 allele of the Val66Met BDNF variant with restricting AN (ANR) and low minimum body mass index in Spanish patients.

Influence of apolipoprotein E epsilon4 genotype on brain tissue integrity in relapsing-remitting multiple sclerosis.

Background: Recent clinical and imaging studies have raised the hypothesis that patients with multiple sclerosis (MS) and the apolipoprotein E (ApoE) epsilon4 allele may have a more severe disease course than those without the ApoE epsilon4 allele. This seems to be related to more extensive tissue destruction and less efficient neuronal maintenance and repair in ApoE epsilon4 carriers.

Objective: To evaluate the influence of different ApoE genotypes on brain tissue integrity in patients with relapsing-remitting MS (RRMS).

Age and ApoE genotype interaction in Alzheimer's disease: an FDG-PET study.

Previous positron emission tomography (PET) studies with fluorodeoxglucose (FDG) as tracer in healthy elders showed that the epsilon4 allele of the apolipoprotein E (ApoE) gene is disruptive to cerebral glucose metabolism (rCMRglu), possibly through the interaction with the aging process. The present study was aimed at assessing whether this interaction occurs in patients with Alzheimer's disease (AD). Eight-six AD patients, including 40 ApoE4 carriers and 46 non-carriers, underwent (18)F-FDG PET scanning at rest.

Fibroblasts from FAD-linked presenilin 1 mutations display a normal unfolded protein response but overproduce Abeta42 in response to tunicamycin.

Many patients affected by early onset familial Alzheimer's disease (FAD), carry mutations in the presenilin 1 (PS1) gene. Since it has been suggested that FAD-linked PS1 mutations impair the unfolded protein response (UPR) due to endoplasmic reticulum (ER) stress, we analyzed the UPR and amyloid beta-protein processing in fibroblasts bearing various PS1 mutations. Neither in normal conditions nor after induction of ER stress with DTT or tunicamycin were the mRNA levels of UPR-responsive genes (BiP and PDI) significantly different in control and FAD fibroblasts.

Brain metabolic decreases related to the dose of the ApoE e4 allele in Alzheimer's disease.

Objectives: Declines in brain glucose metabolism have been described early in Alzheimer's disease (AD), and there is evidence that a genetic predisposition to AD contributes to accelerate this process. The epsilon 4 (e4) allele of the apolipoprotein E (ApoE) gene has been implicated as a major risk factor in this process. The aim of this FDG-PET study was to assess the ApoE e4 dose related effect on regional cerebral glucose metabolism (METglc) in clinical AD patients, with statistical voxel based methods.

Combined family trio and case-control analysis of the COMT Val158Met polymorphism in European patients with anorexia nervosa.

The high activity Val158 (H) allele of the dopamine-metabolizing enzyme catechol-O-methyltransferase (COMT) was associated with anorexia nervosa (AN) in a recent family trio-based study of patients from Israel. In an attempt to replicate this finding, we performed a combined family trio and case-control study in an European population from seven centers in six different countries (Austria, Germany, Great Britain, Italy [Milan], Italy [Florence], Slovenia, and Spain), together contributing a total of 372 family trios, 684 controls and 266 cases. TDT analyses of high (H) and low (L) alleles in family trios showed that H allele and L allele were each transmitted 101 times (chi(2) = 0, ns).

Identification of new presenilin gene mutations in early-onset familial Alzheimer disease.

Background: Mutations in the presenilin 1 (PS1) and presenilin 2 (PS2) genes, and more rarely in beta-amyloid precursor protein (betaAPP), underlie the pathogenesis of most cases of familial Alzheimer disease (FAD).

Objective: To screen the entire coding region of the PS1 and PS2 genes and exons 16 and 17 of the betaAPP to find pathogenetic mutations in FAD. Patients Patients with FAD were consecutively enrolled from among the outpatients from the neurology departments at the Universities of Florence and Parma and the Santa Maria Nuova Hospital in Reggio Emilia, Italy.

Brain metabolic differences between sporadic and familial Alzheimer's disease.

This FDG-PET study with SPM99 compared 46 patients with sporadic Alzheimer disease (SAD) to 40 patients with familial AD (FAD) and to 35 matched controls. AD groups had equivalent metabolic (METglu) reductions in several cortical and limbic areas with respect to the controls. Patients with FAD showed decreased METglu in the posterior cingulate, parahippocampal, and occipital cortex as compared to the patients with SAD (p < 0.

Absence of association between Alzheimer disease and the regulatory region polymorphism of the PS2 gene in an Italian population.

Alzheimer disease (AD) is the most common neurodegenerative disorder of aging. Identifying novel AD genetic risk factors is important for understanding its pathogenesis. A recent study demonstrated that the deletion of adenosine in the promoter region of the presenilin 2 gene (PS2) is a susceptibility factor for early-onset AD.

A family with spinocerebellar ataxia type 8 expansion and vitamin E deficiency ataxia.

Background: Ataxia with vitamin E deficiency is a recessive autosomal neurodegenerative disorder resembling the Friedreich ataxia phenotype but is due to mutations in the alpha-tocopherol transfer protein (TTPA) gene. In a recent article, we described a patient with ataxia carrying reduced serum vitamin E levels and showing CTA/CTG expansions of 320 triplet repeats in the SCA8 gene.

Objectives: To perform a screening of the TTPA gene in the patient and to evaluate the effects of treatment with vitamin E on the patient's neurologic disturbances.

Oxidative stress and reduced antioxidant defenses in peripheral cells from familial Alzheimer's patients.

We have measured the levels of typical end products of the processes of lipid peroxidation, protein oxidation, and total antioxidant capacity (TAC) in skin fibroblasts and lymphoblasts taken from patients with familial Alzheimer's disease (FAD), sporadic Alzheimer's disease (AD), and age-matched healthy controls. Compared to controls, the fibroblasts and lymphoblasts carrying amyloid precursor protein (APP) and presenilin-1 (PS-1) gene mutations showed a clear increase in lipoperoxidation products, malondialdehyde (MDA), and 4-hydroxynonenal (4-HNE). In contrast, the antioxidant defenses of cells from FAD patients were lower than those from normal subjects.

Cathepsin D polymorphism in Italian sporadic and familial Alzheimer's disease.

A recent study has shown that a genetic variation in the Cathepsin D (catD) gene is a major risk factor for the development of Alzheimer's disease (AD). CatD is an intracellular aspartyl protease involved in neurodegeneration. A C-->T (Ala-->Val) transition at position 224 has been associated with altered intracellular maturation.

5-HT2A receptor gene polymorphism and eating disorders.

Recent studies have reported a genetic association between the -1438 G/A polymorphism within the promoter region of the 5-HT(2A) receptor gene and eating disorders (ED), with conflicting results. To clarify the role of the -1438 G/A polymorphism in different ED categories we have analyzed the genotype and allele frequency distribution in 54 Italian patients with Binge ED (BED) compared to 132 obese non-BED subjects. No significant differences were found between obese BED and obese non-BED individuals, suggesting that this polymorphism does not genetically distinguish these two phenotypes.

The 5-HT(2A) -1438G/A polymorphism in anorexia nervosa: a combined analysis of 316 trios from six European centres.

Several case-control association studies have raised the possibility that the A allele of a -1438 G/A polymorphism in the type 2A serotonin receptor (HTR2A) gene may be a risk factor for anorexia nervosa. However the absence of linkage and the existence of negative association studies raise the possibility of false positive findings, resulting from population stratification or lack of statistical power. To address this controversy we recruited a sample of 316 patients with anorexia nervosa from six European centres, and utilised a family-based transmission disequilibrium (TDT) approach to analyse the HTR2A-1438 G/A polymorphism.

Clinical and genetic analysis of hereditary and sporadic ataxia in central Italy.

We have clinically and genetically evaluated 24 affected patients belonging to 22 Italian Friedreich ataxia (FA) families, 52 patients from 32 kindreds with proven autosomal dominant cerebellar ataxia (ADCA), 9 patients belonging to 5 families with autosomal recessive hereditary ataxia (ARCA) and 103 sporadic cases, 89 of which affected by idiopathic late onset cerebellar ataxia (ILOCA). Genotype-phenotype correlation analyses in FA patients have evidenced an inverse relationship between GAA repeat expansion length and age of onset, disease duration, and presence of cardiomyopathy. Among autosomal dominant types, spinocerebellar ataxia 2 (SCA2) genotype has been found in 31% of our ADCA families, resulting the most frequent form of ataxia.

The C677T methylenetetrahydrofolate reductase mutation is not associated with Alzheimer's disease.

The methylenetetrahydrofolate reductase (MTHFR) gene has been recently considered as a candidate gene for Alzheimer's disease (AD). MTHFR is a key enzyme in the metabolism of homocysteine and elevated levels of that amino acid have been associated to Vascular Dementia and AD. A T-->C transition at codon 677 produces a thermolabile type of the enzyme.

Genetic and clinical analysis of spinocerebellar ataxia type 8 repeat expansion in Italy.

Background: The spinocerebellar ataxias (SCAs) are clinically heterogeneous disorders caused by triplet repeat expansions in the sequence of specific disease genes. Spinocerebellar ataxia type 8 (SCA8), originally described in a family characterized by pure cerebellar ataxia with slow disease progression, presents with expansion of combined CTA/CTG repeats.

Objective: To perform SCA8 repeat expansion analysis in a heterogeneous group of ataxic patients, to determine the prevalence of this mutation in our patients and establish the frequency of expanded CTA/CTG repeats in a large group of control subjects.

Genetic risk factors in familial Alzheimer's disease.

In the last 10 years significant progress has been made to describe and identify the underlying biological mechanisms that cause the different manifestation of Alzheimer's disease. Since the first report of a possible locus on chromosome 21 in a small group of families with early onset familial Alzheimer's disease (FAD), considerable progress has been made. Results from linkage analysis and gene sequencing has provided evidence that a minority of early onset FAD families develops the disease as a result of mutations in the gene coding for the Abeta-amyloid precursor protein, and that mutations in presenilin 1 and 2 genes account for a larger subgroup of early onset families.

Association between 5-HT(2A) receptor polymorphism and psychotic symptoms in Alzheimer's disease.

Background: The aim of this study is to analyze the segregation of the 102T/C polymorphism in the serotonin 2A receptor gene in patients affected by sporadic and familial Alzheimer's disease (FAD) with and without psychotic symptoms.

Methods: The polymorphism was analyzed in 275 subjects. A semistructured interview was used to obtain information about delusions, hallucinations, and other specific behavioral signs occurring during the disease.

Mitochondrial DNA haplogroups and APOE4 allele are non-independent variables in sporadic Alzheimer's disease.

Allele epsilon4 of the nuclear APOE gene is a leading genetic risk factor for sporadic Alzheimer's disease (AD). Moreover, an allele-specific effect of APOE isoforms on neuronal cell oxidative death is known. Because of the role of the mitochondrial genome (mtDNA) in oxidative phosphorylation and oxidative stress, an interaction between APOE polymorphism and mtDNA inherited variability in the genetic susceptibility to sporadic AD can be hypothesized.

Alpha2-macroglobulin polymorphisms in Italian sporadic and familial Alzheimer's disease.

A 5-bp deletion and a Val1000 polymorphism at the alpha(2)-macroglobulin (A2M) gene have recently been reported to be associated with late onset Alzheimer's disease (AD). As recently it has been suggested that the effect of the A2M gene on AD susceptibility may be limited to certain populations or families, we analyzed the segregation of A2M and apolipoprotein E polymorphisms in Italian sporadic and familial AD. We analyzed the two polymorphisms in a total of 346 subjects including 98 controls by polymerase chain reaction-restriction fragment length polymorphism method.