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S Sorbi

Publications and source records attributed to S Sorbi.

At least 19 recordsLinked to original sources
PubMed2003

Interleukin-1B polymorphism is associated with age at onset of Alzheimer's disease.

Interleukin-1alpha (IL-1alpha) and IL-1beta are two pro-inflammatory cytokines involved in the pathogenesis of Alzheimer's disease (AD). The genes coding for IL-1alpha (IL-1A) and for IL-1beta (IL-1B) are clustered in chromosome 2q14-2q14.2. In a previous work, we investigated the role of IL-1A promoter polymorphism (-889 position) in AD pathogenesis: IL-1A -889 TT genotype was associated with sporadic early onset AD. We now report the study on polymorphism of exon 5 IL-1B in position +3953, the nearest polymorphism to -889 IL-1A. We found that the genotype distribution of IL-1B +3953 varied significantly between patients with early and late onset of AD (P<0.0001). Patients carrying IL-1B +3953 CT or TT genotypes had 4 or 5 years anticipation of AD onset (P=0.0034; odds ratio for early onset, 3.01) and 7 years anticipation if they also carried the IL-1A -889 TT genotype (P<0.0001; odds ratio for early onset, 7.4). These data further support a role for inflammation-related genes in AD or indicate linkage disequilibrium with an unknown chromosome 2 locus.

Aged↗
PubMed2002

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. Age at onset and minimal BMI were also taken into consideration in order to detect clinical heterogeneity or a quantitative trait effect. The TDT approach showed that the A allele was transmitted 133 times and not transmitted 148 times (McNemar chi(2) = 0.29, df = 1, P = 0.59). Also, the haplotype-based haplotype relative risk method showed no evidence for association of the A allele, in samples from each centre (chi(2) < 2.15, df = 1, P > 0.14) and in the total sample (chi(2) = 0.55, df = 1; P = 0.46). Furthermore, we found no evidence for heterogeneity of the A allele frequency between samples (chi(2) = 2.54, df = 4, P = 0.64), either according to minimal-BMI (F1/242 = 2.14, P = 0.45) or age at onset (F1/224 = 2.39; P = 0.12). QTL-TDT analyses also showed no direct role of the A allele on these traits. We thus found no evidence for a significant role of the 5-HT(2A) gene in anorexia nervosa. Previous results may have been exposed to stratification bias (which we controlled by the TDT method) and/or the risk of type 1 error (from which we were less exposed because of the sample size).

Adolescent↗
PubMed2001

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. However, contrasting results on the distribution of the MTHFR C677T common polymorphism in AD have been published. We analyzed the distribution of the MTHFR and apolipoprotein E (APOE) polymorphisms in Italian patients with sporadic AD. The distribution of the C677T polymorphism did not differ in AD and controls. Our data suggest that the MTHFR polymorphism does not contribute to genetic susceptibility in Italian sporadic AD and does not mitigate the effect of ApoE epsilon4 allele on AD risk.

Adult↗
PubMed2001

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. RESULTS: Fifty-two percent of AD patients with psychotic symptoms were homozygous for the C102 allele, as compared with 6.9% of AD patients without psychosis. Similarly, the C102/C102 genotype was significantly more frequent in FAD patients with psychosis than in FAD patients without (46.5% vs. 7.8%). CONCLUSIONS: Our data strongly confirm and extend to FAD previous studies suggesting that the genetic variation at this locus is associated with prominent psychotic features in AD and that the 102C allele could play an important role in late-onset AD.

Aged↗
PubMed2001

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. Our data do not confirm these associations, in particular we found a significant decrease of the deletion allele in AD with respect to controls. Our data do not support a role for the A2M gene as genetic risk factor for AD.

Aged↗
PubMed2001

Cognitive dysfunction in early-onset multiple sclerosis: a reappraisal after 10 years.

OBJECTIVE: To reassess, in a cohort of patients with early-onset multiple sclerosis, the long-term evolution of cognitive deficits, their relationship to the disease's clinical progression, and their effects on daily life. DESIGN: Ten years after our baseline assessment, we again compared the cognitive performance of patients and control subjects on a neuropsychological test battery. Clinical and demographic correlates of cognitive impairment and their effects on everyday functioning were determined by multiple linear regression analysis. SETTING: The research clinic of a university department of neurology. PARTICIPANTS: Forty-five inpatients and outpatients with multiple sclerosis and 65 demographically matched healthy controls from the original sample. MAIN OUTCOME MEASURES: Mean scores of both groups on the neuropsychological test battery in initial and 2 follow-up evaluations (about 4 and 10 years, respectively); number of cognitively impaired subjects, defined by the number of subtests failed; regression coefficients measuring the relationship between clinical variables and cognitive outcome and between mental decline and everyday functioning assessed by the Environmental and the Incapacity Status Scales. RESULTS: Previously detected cognitive defects in verbal memory, abstract reasoning, and linguistic processes were confirmed on the third testing, at which time deficits in attention/short-term spatial memory also emerged. Only 20 of 37 patients who were cognitively unimpaired on initial testing remained so by the end of the follow-up, when the proportion of subjects who were cognitively impaired reached 56%. Degree of physical disability, progressive disease course, and increasing age predicted the extent of cognitive decline. Disability level and degree of cognitive impairment were independent predictors of a patient's handicap in the workplace and in social settings. CONCLUSIONS: In the course of a sufficiently long follow-up, cognitive dysfunction is likely to emerge and progress in a sizable proportion of patients. As multiple sclerosis advances, neurological and cognitive involvement tend to converge. Limitations in a patient's work and social activities are correlated with the extent of cognitive decline, independent of degree of physical disability.

Activities of Daily Living↗
PubMed2001

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. PATIENTS: One hundred sixty-seven patients affected by sporadic, autosomal dominant and recessive hereditary ataxia were clinically examined and analyzed for SCA8 expansion. We further studied 161 control subjects and 125 patients with psychiatric disorders. RESULTS: We found abnormally expanded CTA/CTG repeats in 5 ataxic patients, 3 of them characterized by pure cerebellar ataxia. One patient had vitamin E deficiency and 1 patient with a sporadic case was affected by gluten ataxia. No evidence of expanded alleles was found in healthy control subjects and in patients with psychiatric disorders. CONCLUSIONS: Our data support the evidence that CTG expansions may be linked to SCA8, since the pathogenic expansions have been found only among patients with genetically unidentified forms of hereditary and sporadic ataxia. Patients carrying expanded alleles present peculiar phenotypic features, thus suggesting that unknown additional factors could probably predispose to the disease.

Adult↗
PubMed2001

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. We have explored this hypothesis by analyzing mtDNA germline variants (mtDNA haplogroups) in a sample of AD patients (213 subjects) genotyped for APOE and classified as APOE epsilon4 carriers and non-carriers. We found that the frequency distribution of mtDNA haplogroups is different between epsilon4 carriers and non-carriers (P=0.018), thus showing non-random association between APOE and mtDNA polymorphisms. The same analysis, carried out in two samples of healthy subjects (179 age-matched and 210 individuals aged more than 100 years), showed independence between epsilon4 allele and mtDNA haplogroups. Therefore, the APOE/mtDNA interaction is restricted to AD and may affect susceptibility to the disease. In particular, some mtDNA haplogroups (K and U) seem to neutralize the harmful effect of the APOE epsilon4 allele, lowering the epsilon4 odds ratio from statistically significant to non-significant values.

Aged↗
PubMed2001

Mutations in the open reading frame of the beta-site APP cleaving enzyme (BACE) locus are not a common cause of Alzheimer's disease.

Amyloid beta-peptide (Abeta) plays a central role in the pathogenesis of Alzheimer's disease (AD). The gene encoding the beta-site APP cleaving enzyme (BACE), one of two enzymes that sequentially cleave the beta-amyloid precursor protein to generate Abeta, has recently been cloned. We tested the hypothesis that BACE might be genetically associated with AD by linkage analysis (56 pedigrees), by direct nucleotide sequencing of the entire open reading frame (20 subjects with familial AD, and 10 subjects with sporadic AD) and by allelic association analysis (155 AD cases and 173 non-demented controls). Our results revealed no evidence for either genetic linkage or allelic association between BACE and AD, and no coding sequence mutations were detected in the open reading frame of the BACE gene. These data suggest that while BACE protein plays an important role in the pathogenesis of AD, and may be a robust therapeutic target, it is unlikely to be a major AD susceptibility locus.

Aged↗
PubMed2001

Which target for DBS in Parkinson's disease? Subthalamic nucleus versus globus pallidus internus.

We selected 14 patients with advanced idiopathic Parkinson's disease (PD) and examined the clinical effects of STN DBS versus GPi DBS. Nine patients underwent bilateral STN DBS and five underwent bilateral GPi patients. All patients were followed for at least 12 months. The evaluation was performed on and off drug before surgery; on-drug/on-DBS and off-drug/on-DBS at 1, 3, 6 and 12 months after stereotactic surgery. At 1 and 3 months after surgery in off-drug/on-DBS condition, both groups showed an improvement in motor score (UPDRS III). Nevertheless, the results changed after long-term stimulation in the two groups. Chronic STN DBS is superior to GPi DBS in the amelioration of the clinical features and in the decrease of time spent in the off state. The efficacy in reduction of LID was comparable at 1 and 3 months after surgery, but the results were better in STN DBS after chronic stimulation. The L-dopa dose was reduced only in the STN group.

Electric Stimulation Therapy↗
PubMed2001

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. Several other early onset FAD families are clearly not linked to any of these loci, suggesting that other genetic risk factors may exist. Recent genome-wide scanning studies have revealed the existence of a new locus on chromosome 12, which, together with inheritance of the epsilon4 allele of apolipoprotein E gene, on chromosome 19, represent the most important genetic factors associated with an increased risk of developing the disease in late onset FAD families.

Alzheimer Disease↗
PubMed2001

Spontaneous and induced chromosome damage in somatic cells of sporadic and familial Alzheimer's disease patients.

Alzheimer's disease (AD) is a neurodegenerative disorder of the elderly with a complex etiology due to the interaction between genetic and environmental factors. At least 15% of cases are inherited as an autosomal dominant mutation, but the majority are sporadic. We evaluated cytogenetic alterations, both spontaneous and chemical-induced [aluminium (Al) and griseofulvin (GF)], by means of the micronucleus (MN) test in lymphocytes or skin fibroblasts of 14 patients with sporadic and eight with familial Alzheimer's disease (FAD), respectively. The spontaneous MN frequencies of sporadic (20.8 +/- 9.2) and familial (20.7 +/- 4.6) AD patients are significantly higher than those of the respective control groups (9.0 +/- 6.8 and 6.7 +/- 3.4). In all AD patients, GF significantly increased the spontaneous MN frequency of somatic cells to a lesser extent (P < 0.05) as compared with the control group. Al treatment did not induce MN in AD patients. The results of the present study indicate that different types of somatic cells from sporadic and familial AD patients show comparable levels of spontaneous cytogenetic anomalies, and MN induction is partially reduced or lacking according to the type of chemical treatments.

Adult↗
PubMed2000

Association of apolipoprotein E polymorphism to clinical heterogeneity of multiple sclerosis.

In this study we investigated the distribution of apolipoprotein E (APO E) genotypes in sporadic multiple sclerosis (MS) cases and in normal controls. Later onset of chronic progressive MS was observed in patients carrying the epsilon2 allele, whereas APO E alleles were found at similar frequency in MS and in the control population. These findings indicate that clinical heterogeneity, but probably not susceptibility to the disease, is associated to APO E genotypes.

Adult↗
PubMed2000

Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing.

Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2. Suppression of nicastrin expression in Caenorhabditis elegans embryos induces a subset of notch/glp-1 phenotypes similar to those induced by simultaneous null mutations in both presenilin homologues of C. elegans (sel-12 and hop-1). Nicastrin also binds carboxy-terminal derivatives of beta-amyloid precursor protein (betaAPP), and modulates the production of the amyloid beta-peptide (A beta) from these derivatives. Missense mutations in a conserved hydrophilic domain of nicastrin increase A beta42 and A beta40 peptide secretion. Deletions in this domain inhibit A beta production. Nicastrin and presenilins are therefore likely to be functional components of a multimeric complex necessary for the intramembranous proteolysis of proteins such as Notch/GLP-1 and betaAPP.

Amino Acid Sequence↗
PubMed2000

Lack of SOD1 gene mutations and activity alterations in two Italian families with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive fatal disorder, which results from the degeneration of motor neurons in the brain and spinal cord. Approximately 20% of the inherited autosomal dominant cases are due to mutations within the gene coding for Cu/Zn superoxide dismutase 1 (SOD1), a cytosolic homodimeric enzyme that catalyzes the dismutation of toxic superoxide anion. We investigated the presence of SOD1 gene mutations and activity alterations in two unrelated families of ALS patients from Elba, an island of central Italy. No mutation in SOD1 exon 1 to 5 and no activity alteration were observed in all members of the two analyzed ALS families (FALS). These data show an apparent heterogeneous distribution of ALS patients with SOD1 gene mutations among different populations and suggest that another genetic locus could be involved in the disease.

Amyotrophic Lateral Sclerosis↗