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Biomedical subjects

G Binetti

Publications and source records attributed to G Binetti.

At least 37 records · Page 2Linked to original sources
PubMed2000

Genetic association of a cystatin C gene polymorphism with late-onset Alzheimer disease.

OBJECTIVE: To determine whether the cystatin C gene (CST3) is genetically associated with late-onset Alzheimer disease (AD). DESIGN: A case-control study with 2 independent study populations of patients with AD and age-matched, cognitively normal control subjects. SETTING: The Alzheimer's Disease Research Unit at the University Hospital Hamburg-Eppendorf, Hamburg, Germany, for the initial study (n = 260). For the independent multicenter study (n = 647), an international consortium that included the Massachusetts Alzheimer's Disease Research Center at the Massachusetts General Hospital, Boston; the Scientific Institute for Research and Patient Care, Brescia, Italy; and Alzheimer's research units at the Universities of Basel and Zurich, Switzerland, and Bonn, Goettingen, and Hamburg, Germany. PARTICIPANTS: Five hundred seventeen patients with AD and 390 control subjects. MEASURES: Molecular testing of the KspI polymorphisms in the 5' flanking region and exon 1 of CST3 and the apolipoprotein E (APOE) genotype. Mini-Mental State Examination scores for both patients with AD and control subjects. RESULTS: Homozygosity for haplotype B of CST3 was significantly associated with late-onset AD in both study populations, with an odds ratio of 3.8 (95% confidence interval, 1.56-9.25) in the combined data set; heterozygosity was not associated with an increased risk. The odds ratios for CST3 B/B increased from 2.6 in those younger than 75 years to 8.8 for those aged 75 years and older. The association of CST3 B/B with AD was independent of APOE epsilon4; both genotypes independently reduced disease-free survival. CONCLUSIONS: CST3 is a susceptibility gene for late-onset AD, especially in patients aged 75 years and older. To our knowledge, CST3 B is the first autosomal recessive risk allele in late-onset AD.

Age of Onset↗
PubMed2000

Differences between Pick disease and Alzheimer disease in clinical appearance and rate of cognitive decline.

OBJECTIVES: To define the cognitive characteristics of Pick disease (PcD), and to determine which features distinguish PcD from Alzheimer disease (AD), in a cross-sectional and longitudinal study. METHODS: The participants were 44 patients with PcD (10 pathologically verified), 121 patients with AD (14 pathologically verified), and 60 normal control subjects. We obtained information regarding the initial symptom of dementia from each patient's caregiver, estimated global dementia severity by the Blessed Dementia Scale and the Activities of Daily Living Scale, and assessed specific cognitive domains by administering 10 tests of memory, language, visuospatial, and reasoning abilities and selective attention. RESULTS: Among initial symptoms reported by caregivers, personality change and language impairment were significantly more common in PcD than AD; deficits in memory were common in both groups but more prevalent in AD (P<.001). At initial cognitive testing, the scores of patients with PcD were inferior to those of normal controls on all tests, except on a measure of visuospatial function; the scores of patients with AD were inferior to those of controls on all tests. Patients with PcD were superior to patients with AD on measures of explicit memory (P<.001) and visuospatial function (P = .001) but had greater impairments on the Activities of Daily Living Scale (P<.05). During the course of illness, patients with PcD declined significantly faster than those with AD on language tests and on global measures of dementia severity (P<.05), whereas measures of explicit memory and visuospatial and reasoning abilities worsened equally in both patient groups. CONCLUSIONS: There is a characteristic cognitive profile and course of dementia in PcD. Nonetheless, cognitive test performance does not clearly distinguish PcD from AD.

Activities of Daily Living↗
PubMed2000

High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes.

Clinical differential diagnosis of early-onset dementia (EOD) includes familial Alzheimer disease (FAD) and hereditary prion disease. In both disease entities, postmortem brain histopathological examination is essential for unambiguous diagnosis. Mutations in the genes encoding the presenilins (PS1 and PS2) and amyloid precursor protein (APP) are associated with FAD, whereas mutations in the prion protein (PrP) gene are associated with prion disease. To investigate the proportion of EOD attributable to known genes, we prospectively (i.e., antemortem) screened these four genes for mutations by sequencing genomic PCR products from patients with EOD before age 60 years. Family history for dementia was positive (PFH) in 16 patients, negative (NFH) in 17 patients, and unknown (UFH) in 3 patients. In 12 patients, we found five novel mutations (in PS1, F105L; in PS2, T122P and M239I; and in PrP, Q160X and T188K) and five previously reported mutations (in APP, in three patients who were most likely unrelated, V717I; in PS1, A79V and M139V; and in PrP, P102L and T183A) that are all considered to be disease causing. Of these 12 patients, 9 had PFH. This indicates a detection rate of 56% (9/16) in patients with PFH. We found two mutations (APP V717I) in two of the three UFH patients, and only one mutation (PrP T188K) in 1 of the 17 patients with NFH. We conclude that because of the lack of specific antemortem diagnostic markers for FAD and hereditary prion disease, all four genes should be included in a molecular diagnostic program in patients with EOD who had PFH.

Adult↗
PubMed2000

High frequency of mutations in four different disease genes in early-onset dementia.

Heterozygous mutations in the genes for amyloid precursor protein (APP), the presenilins (PS1, PS2), prion protein (PrP), neuroserpin, and tau are associated with early-onset dementia (EOD) with or without neurological signs in the early disease stage. To investigate the proportion of EOD without early neurological signs attributable to known genes we prospectively (i.e., ante mortem) screened these six genes for mutations in 36 patients with EOD before age 60. Family history for dementia was positive (PFH) in 16, negative (NFH) in 17, and unknown (UFH) in 3 patients. In 12 patients, we found 5 novel mutations (PS1: F105L; PS2: T122P, M239I; PrP: Q160X, T188K) and 5 previously reported mutations (APP: in three most likely unrelated patients V717I; PS1: A79V, M139V; PrP: P102L, T183A) that all are considered disease causing. Of these 12 patients, 9 had PFH. This indicates a detection rate of 56% (9/16) in patients with PFH. We found 2 mutations (APP V717I) in 2 of the 3 the UFH-patients, and only 1 mutation (PrP T188K) in 1 of the 17 patients with NFH. No mutation was found in tau and neuroserpin genes. To date, three patients died and FAD, predicted by PS mutations in two patients, and prion disease, predicted by a PrP mutation in the third one, were histopathologically confirmed at autopsy. Up to now, mutation findings may be the most specific biomarkers for an ante mortem diagnosis of FAD or hereditary prion disease.

Age of Onset↗
PubMed2000

Temporal lobe asymmetry in patients with Alzheimer's disease with delusions.

OBJECTIVE: To test the hypothesis that delusions are associated with asymmetric involvement of the temporal lobe regions in Alzheimer's disease. METHODS: Temporal lobe atrophy was assessed with a linear measure of width of the temporal horn (WTH) taken from CT films. Temporal asymmetry was computed as the right/left (R/L) ratio of the WTH in 22 non-delusional and 19 delusional patients with Alzheimer's disease. Delusional patients had paranoid delusions (of theft, jealousy, persecution). None of the patients had misidentifications or other delusions of non-paranoid content. RESULTS: The R/L ratio indicated symmetric temporal horn size in the non-delusional (mean 1. 05 (SD 0.20), and right greater than left temporal horn in the delusional patients (mean 1.30, (SD 0.46); t=2.27, df=39, p=0.03). When patients were stratified into three groups according to the R/L ratio, 47% of the delusional (9/19) and 14% of the non-delusional patients (3/21; chi(2)=5.6, df=1, p=0.02) showed right markedly greater than left WTH. CONCLUSIONS: Predominantly right involvement of the medial temporal lobe might be a determinant of paranoid delusions in the mild stages of Alzheimer's disease.

Aged↗
PubMed1999

Presenilin 1 protein directly interacts with Bcl-2.

Presenilin proteins are involved in familial Alzheimer's disease, a neurodegenerative disorder characterized by massive death of neurons. We describe a direct interaction between presenilin 1 (PS1) and Bcl-2, a key factor in the regulation of apoptosis, by yeast two-hybrid interaction system, by co-immunoprecipitation, and by cross-linking experiments. Our data show that PS1 and Bcl-2 assemble into a macromolecular complex, and that they are released from this complex in response to an apoptotic stimulus induced by staurosporine. The results support the idea of cross-talk between these two proteins during apoptosis.

Alzheimer Disease↗
PubMed1999

Energy metabolism inhibition impairs amyloid precursor protein secretion from Alzheimer's fibroblasts.

The present study investigates the influence of aglycemia and sodium azide (a Cytochrome c Oxidase inhibitor) on sAPP secretion from skin fibroblasts derived from sporadic AD patients and control subjects. Aglycemia reduced sAPP release in the medium of both AD and control fibroblasts to a similar extent after 2 h incubation. Treatment for 2 h with increasing azide concentrations (1 microM-100 mM) under glucose deprivation did not significantly affect sAPP secretion from control fibroblasts, but was able to significantly inhibit sAPP secretion from AD fibroblasts (maximal inhibition 51%). The failure of antioxidants like glutathione (GSH) or N-acetylcysteine (NAC) to antagonize the azide effect on AD fibroblasts and lipoperoxidation data seemed to rule out the possibility that oxidative stress could mediate the sodium azide effect on sAPP release from AD fibroblasts.

Acetylcysteine↗
PubMed1999

Risperidone treatment of behavioral disturbances in outpatients with dementia.

The authors retrospectively assessed the effectiveness and side effects of risperidone used to treat behavioral disturbances in elderly outpatients with dementia. In 41 patients treated with risperidone 1.8 +/- 1.4 mg/day, there was complete suppression of the target symptom in 15%, partial response in 41%, and no response in 44%. Risperidone appeared equally effective in treating agitation and psychosis. New or worsening extrapyramidal side effects (EPS) occurred in 32%, associated with longer duration of treatment and possibly with concomitant use of serotonergic anti-depressants. Risperidone was a useful adjunct in the treatment of agitation and psychosis in outpatients with dementia but was limited by EPS in about one-third of patients.

Age Factors↗
PubMed1998

Bradykinin-induced amyloid precursor protein secretion: a protein kinase C-independent mechanism that is not altered in fibroblasts from patients with sporadic Alzheimer's disease.

We treated human skin fibroblasts with bradykinin (BK) and observed a concentration-dependent increase in the release of soluble amyloid precursor protein (sAPP). The estimated EC50 for the observed effect is 2.8 nM, which is of the same order of magnitude as the reported Kd of BK binding in human skin fibroblasts. The effect of BK on sAPP secretion appears to be dependent on interaction of the ligand with the B2 type of BK receptors but independent of activation of protein kinase C. We also show that sAPP release after BK treatment in fibroblasts from patients with sporadic Alzheimer's disease is not different from control cells and is paralleled by equivalent levels of inositol trisphosphate production. A discussion of the differences from previously published work focuses on the possible divergent alterations in transduction systems in fibroblasts from patients with familial and sporadic Alzheimer's disease. Our results are the first example of receptor-mediated sAPP release in human skin fibroblasts and the first demonstration of the co-existence of protein kinase C-dependent and -independent mechanisms in these cells.

Adult↗
PubMed1998

Specific role for protein kinase C alpha in the constitutive and regulated secretion of amyloid precursor protein in human skin fibroblasts.

Reduced levels of protein kinase C alpha (PKC alpha) seems to be related to an altered amyloid precursor protein (APP) secretion in fibroblasts from Alzheimer's disease (AD) patients. In this report we used a specific inhibitor of PKC alpha (Gö-6976), to investigate the role of PKC alpha in the basal and phorbol esters regulated secretion of soluble APP (sAPP) in human fibroblasts derived from healthy aged volunteers. Treatment with Gö-6976 alone reduced basal secretion by a maximum of 39%, compared to untreated cells, suggesting the partial dependence of constitutive APP secretory pathway on PKC alpha enzyme. Moreover Gö-6976 treatment completely abolished the effect of phorbol-esters mediated PKC stimulation on sAPP release, suggesting that PKC alpha is the only PKC isoform involved in controlling the secretion of sAPP in human fibroblasts.

Aged↗
PubMed1998

Behavioral disorders in Alzheimer disease: a transcultural perspective.

OBJECTIVES: To compare 2 samples of patients with Alzheimer disease (AD), from Italy and the United States, in order to determine transcultural differences in the manifestation of noncognitive symptoms. To analyze the concurrent validity, internal consistency reliability, between-rater reliability, and test-retest reliability of the Neuropsychiatric Inventory Scale (NPI). METHODS: The NPI was given to 50 Italian and 50 US patients with AD. To demonstrate the validity and reliability of the Italian version of the instrument, several different methods of analysis were used. The total score on the NPI and the score of single items in the different stages of the disease were compared in the 2 samples of patients. RESULTS: A high level of internal consistency reliability was confirmed, the between-rater reliability was very high, and the test-retest reliability was significantly correlated. Apathy was the most frequently recorded behavior in the Italian sample. Five of 10 NPI item scores showed a significant relation with the Mini-Mental State Examination scores in both samples. The Italian patients showed an increasing and significantly higher mean NPI total score at all levels of dementia severity when compared with the US patients. The scores on some NPI subscales, such as apathy, aberrant motor behavior, disinhibition, and agitation, were significant higher in Italian patients at different levels of severity covarying with educational level. CONCLUSIONS: These results indicate that NPI is a reliable instrument with which to study transcultural differences in the presentation of neuropsychiatric disturbances in patients with AD. The described similar pattern of behaviors between Italians and US patients with AD suggests a biological origin of the disorders. However, cultural influences must be taken in account when the focus of the study is on psychopathological aspects of dementia.

Aged↗
PubMed1998

Visual and spatial perception in the early phase of Alzheimer's disease.

A battery of visuospatial perception tests was administered to 27 mild probable Alzheimer's disease (AD) patients; 21 were reassessed after 8 months. At the first evaluation, AD patients were impaired only in an object-naming task. After 8 months, the performance in the subtests of object perception was unchanged, while there was a significant decline in the total score of the items tapping space perception. A significant worsening was also observed in the Rey's figure copy score and was correlated with the decrease in the spatial perception score. This study confirms that an impairment in visual perceptual tests requiring access to semantic and lexical knowledge is present in the earliest phase of AD, whereas visuospatial and constructional impairments became evident only later. This pattern of progression may represent the clinical correlate of increasing pathological involvement of posterior associative cortex.

Aged↗
PubMed1998

Genetic association of an alpha2-macroglobulin (Val1000lle) polymorphism and Alzheimer's disease.

alpha2-Macroglobulin (A2M) is a proteinase inhibitor found in association with senile plaques (SP) in Alzheimer's disease (AD). A2M has been implicated biochemically in binding and degradation of the amyloid beta (Abeta) protein which accumulates in SP. We studied the relationship between Alzheimer's disease and a common A2M polymorphism, Val1000 (GTC)/Ile1000 (ATC), which occurs near the thiolester active site of the molecule. In an initial exploratory data set (90 controls and 171 Alzheimer's disease) we noted an increased frequency of the G/G genotype from 0.07 to 0.12. We therefore tested the hypothesis that the G/G genotype is over-represented in Alzheimer's disease in an additional independent data set: a group of 359 controls and 566 Alzheimer's disease patients. In the hypothesis testing cohort, the G/G genotype increased from 0.07 in controls to 0.12 in Alzheimer's disease (P < 0.05, Fisher's exact test). The odds ratio for Alzheimer's disease associated with the G/G genotype was 1.77 (1.16-2.70, P < 0.01) and in combination with APOE4 was 9.68 (95% CI 3.91-24.0, P < 0.001). The presence of the G allele was associated with an increase in Abeta burden in a small series. The A2M receptor, A2M-r/LRP, is a multifunctional receptor whose ligands include apolipoprotein E and the amyloid precursor protein. These four proteins have each been genetically linked to Alzheimer's disease, suggesting that they may participate in a common disease pathway.

Alleles↗
PubMed1998

Peripheral markers in testing pathophysiological hypotheses and diagnosing Alzheimer's disease.

Alterations in amyloid precursor protein (APP) metabolism, calcium regulation, oxidative metabolism, and transduction systems have been implicated in Alzheimer's disease (AD). Limitations to the use of postmortem brain for examining molecular mechanisms underscore the need to develop a human tissue model representative of the pathophysiological processes that characterize AD. The use of peripheral tissues, particularly of cultured skin fibroblasts derived from AD patients, could complement studies of autopsy samples and provide a useful tool with which to investigate such dynamic processes as signal transduction systems, ionic homeostasis, oxidative metabolism, and APP processing. Peripheral cells as well as body fluids (i.e., plasma and CSF) could also provide peripheral biological markers for the diagnosis of AD. The criteria required for a definite diagnosis of AD presently include clinical criteria in association with histopathologic evidence obtained from biopsy or autopsy. Thus, the use of peripheral markers as a diagnostic tool, either to predict or at least to confirm a diagnosis, may be of great importance.

Alzheimer Disease↗
PubMed1998

The prevalence of apoE-epsilon4 in Alzheimer's disease is age dependent.

The epsilon4 allele of apolipoprotein E is a risk factor for Alzheimer's disease. However, other yet unidentified factors might be involved. It has been suggested that the epsilon4 allele might be relatively less relevant in Alzheimer's disease with onset before age 60 and after age 80. The aim was to evaluate the association of the epsilon4 allele with Alzheimer's disease across a wide range of ages at onset. 156 patients with age at onset between 46 and 89 and 120 cognitively unimpaired subjects aged 53 to 89 as controls were studied. Age at onset in the cases and age in the controls were stratified into six groups (60 and younger, 60 to 64, 65 to 69, 70 to 74, 75 to 79, and 80 and older). Multivariable sex adjusted probit regression analysis was used to model epsilon4 prevalences in cases and controls across age. The sex adjusted relation of epsilon4 with age in controls was slightly negative with prevalence of 0.16 in the youngest and 0.09 in the oldest age groups. The sex adjusted relation in cases with Alzheimer's disease had a bell shaped curve with prevalence of 0.23 in the youngest age group, rising to 0.54 and 0.51 in the age groups 65 to 69 and 70 to 74, and decreasing to 0.12 in the oldest age group. It is concluded that the relation of the epsilon4 allele with Alzheimer's disease is age dependent, indicating that other risk factors might be relevant in the younger and older ages.

Age Factors↗
PubMed1998

Object and action naming in Alzheimer's disease and frontotemporal dementia [see comment].

To assess noun and verb processing in different dementia types, we tested object and action naming in three groups of subjects: probable Alzheimer's disease (AD) with mild to moderate dementia; age- and education-matched normal subjects; and a group of frontotemporal dementia (FTD) patients. AD and FTD patients were impaired in naming compared with control subjects; action naming was more severely impaired. However, the discrepancy between object and action naming was significantly greater in FTD than in AD patients, independent of the severity of dementia or of overall language impairment. The latter finding is compatible with the hypothesis that the frontal lobe plays a crucial role in action naming. A relatively selective impairment in action naming might be a characteristic neuropsychological feature of FTD.

Aged↗