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Biomedical subjects

F Pasquier

Publications and source records attributed to F Pasquier.

At least 19 recordsLinked to original sources
PubMed2000

A FE65 polymorphism associated with risk of developing sporadic late-onset alzheimer's disease but not with Abeta loading in brains.

The FE65 protein was previously described interacting with amyloid protein precursor (APP) and mediating its internalization. Hu et al. (Hum. Genet., 103 (1998) 295) recently reported that a deletion polymorphism in intron 13 of the FE65 gene may be protective for sporadic Alzheimer's disease (AD) forms and suggested that this deletion may modify splicing between exon 13 and 14 (the two exons encoding the interaction domain of FE65 with APP). We tested the impact of this polymorphism in 646 controls and 639 sporadic AD cases. We were only able to detect a protective effect of the deletion in the population over 75 years (odds ratio = 0.53, 95% confidence interval (0.35-0.82), P= 0.002). Furthermore, no association of this polymorphism with Abeta40, Abeta42(43) and total Abeta loads were detected in 74 AD brains, although, we could expect that this deletion was associated with modifications of the APP metabolism. In conclusion, the FE65 gene may be a minor genetic determinant only for sporadic late-onset AD forms, although, we cannot conclude that this impact is mediated by a modulation of the APP process and/or Abeta peptide deposition.

Age of Onset↗
PubMed2000

The transcriptional factor LBP-1c/CP2/LSF gene on chromosome 12 is a genetic determinant of Alzheimer's disease.

Although the varepsilon4 allele of the apolipoprotein E gene appears as an important biological marker for Alzheimer's disease (AD) susceptibility, other genetic determinants are clearly implicated in the AD process. Here, we propose that a genetic variation in the transcriptional factor LBP-1c/CP2/LSF gene, located close to the LRP locus, is a genetic susceptibility factor for AD. We report an association between a non-coding polymorphism (G-->A) in the 3'-untranslated region of this gene and sporadic AD in French and British populations and a similar trend in a North American population. The combined analysis of these three independent populations provides evidence of a protective effect of the A allele (OR = 0.58, 95% CI 0.44-0.75). We describe a potential biologically relevant role for the A allele whereby it reduces binding to nuclear protein(s). The absence of the A allele was associated with a lower LBP-1c/CP2/LSF gene expression in lymphocytes from AD cases compared with controls. Our data suggest that polymorphic variation in the implication of the LBP-1c/CP2/LSF gene may be important for the pathogenesis of AD, particularly since LBP-1c/CP2/LSF interacts with proteins such as GSKbeta, Fe65 and certain factors involved in the inflammatory response.

3' Untranslated Regions↗
PubMed2000

How can cerebral infarcts and hemorrhages lead to dementia?

The incidence of new onset dementias is increased after stroke. The objective of this review is to investigate how cerebral infarcts and hemorrhages can lead to dementia. Stroke subtypes, total volume of cerebral lesion and functional tissue loss, and location of the lesions are the major determinant of dementia in stroke patients. The causal relationship between stroke and dementia is clear: (1) in young patients who are unlikely to have associated Alzheimer pathology; (2) when the cognitive functioning was normal before stroke, impaired immediately after, and does not worsen over time; (3) when the lesions are located in strategic areas; and (4) when a well-defined vasculopathy known to be associated with dementia is proven. However, white matter changes and associated Alzheimer pathology may also contribute to the dementia syndrome in stroke patients.

Brain↗
PubMed2000

Relevance of white matter changes to pre- and poststroke dementia.

White matter changes are often associated with stroke, risk factors for stroke, and dementia. From a theoretical point of view, they may be associated with an increased risk of pre- or poststroke dementia because (i) they are linked with subtle cognitive decline, which may add to the consequences of the stroke lesions and of associated Alzheimer pathology; and (ii) they indicate an increased risk of stroke recurrence. The aim of this study was to evaluate the contribution of white matter changes to pre- and poststroke dementia. The relationship between preexisting dementia and white matter changes was evaluated in the Lille stroke-dementia cohort. We assessed the cognitive functioning prior to stroke in 202 consecutive patients with ischemic or hemorrhagic stroke, by means of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). We classified in the dementia group patients with IQCODE scores of 104 or more. White matter changes were rated on CT with the Blennow's rating scale. Thirty-three of 202 patients were demented before stroke (16.3%; 95% confidence interval: 11.2-21.4); the logistic regression analysis found that female sex, family dementia, white matter changes, and cerebral atrophy were independently associated with prestroke dementia. White matter changes were also associated with an increased risk of poststroke dementia, 2 years after stroke onset. Thus, white matter changes contribute to dementia occurring in stroke patients.

Adult↗
PubMed2000

Alzheimer's disease and frontotemporal dementia are differentiated by discriminant analysis applied to (99m)Tc HmPAO SPECT data.

OBJECTIVE: Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the most frequent neurodegenerative cognitive disorders. However, FTD remains poorly recognised clinically. The use of (99m)HmPAO-single photon emission computed tomography (SPECT) has been demonstrated in the differentiation of AD and FTD. Nethertheless, there are very few comparative studies designed to assess its precise value in this differential diagnosis. The aim was to determine a simple decision rule, deduced from statistical analysis, which, if applied to regions of interest (ROIs) and mini mental state examination (MMSE), could improve the predictive value of SPECT in differential diagnosis between AD and FTD. METHODS: Forty patients, 20 with probable AD and 20 with probable FTD were included. All patients underwent brain SPECT imaging, after an intravenous injection of (99m)Tc HmPAO-(555mBq). For each patient, 20 ROIs were determined on the Fleishig's slice and their activity was normalised to the mean cerebellar activity. Bivariate analysis (Wilcoxon rank tests) and multivariate analysis (stepwise discriminant analysis) were performed to determine the subgroup of variables able to give the highest predictive value for this differential diagnosis. A simple decision rule was built from a predictive score derived by factorial discriminant analysis. RESULTS: As previously described, the fixation defect was found in frontal regions of interest (ROIs) in FTD and in the left temporoparietal-occipital ROIs in AD. Among the 21 variables, five were finally selected: right median frontal, left lateral frontal, left tempoparietal, left temporoparietal-occipital areas, and MMSE. One hundred per cent of patients with FTD were correctly classified by the decision rule (20/20 patients) and 90% of patients with AD (18/20). CONCLUSION: AD and FTD are differentiated by SPECT. Automatic classification based on a decision rule deduced from factorial discriminant analysis could enhance its performance.

Alzheimer Disease↗
PubMed1999

The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer's disease.

OBJECTIVE: To determine the spatiotemporal mapping of neurofibrillary degeneration (NFD) in normal aging and the different stages of AD. BACKGROUND: The pathophysiologic significance of AD lesions, namely amyloid plaques and neurofibrillary tangles, is still unclear, especially their interrelationship and their link with cognitive impairment. METHODS: The study included 130 patients of various ages and different cognitive statuses, from nondemented control subjects (n = 60, prospective study) to patients with severe definite AD. Paired helical filaments (PHF)-tau and Abeta were used as biochemical and histologic markers of NFD and amyloid plaques, respectively. RESULTS: NFD with PHF-tau was systematically present in variable amounts in the hippocampal region of nondemented patients age >75 years. When NFD was found in other brain areas, it was always along a stereotyped, sequential, hierarchical pathway. The progression was categorized into 10 stages according to the brain regions affected: transentorhinal cortex (S1), entorhinal (S2), hippocampus (S3), anterior temporal cortex (S4), inferior temporal cortex (S5), medium temporal cortex (S6), polymodal association areas (prefrontal, parietal inferior, temporal superior) (S7), unimodal areas (S8), primary motor (S9a) or sensory (S9b, S9c) areas, and all neocortical areas (S10). Up to stage 6, the disease could be asymptomatic. In all cases studied here, stage 7 individuals with two polymodal association areas affected by tau pathologic states were cognitively impaired. CONCLUSIONS: The relationship between NFD and Alzheimer-type dementia, and the criteria for a biochemical diagnosis of AD, are documented, and an association between AD and the extent of NFD in defined brain areas is shown.

Aged↗
PubMed1999

Early diagnosis of dementia: neuropsychology.

Neuropsychology contributes greatly to the diagnosis of dementia. Cognitive deficits can be detected several years before the clinical diagnosis of dementia. The neuropsychological profile may indicate the underlying neuropathology. Neuropsychological assessment at an early stage of dementia has two goals: (a) to determine a memory disorder, not always associated with a memory complaint, and (b) to characterize the memory disorder in light of the cognitive neuropsychology and to assess other cognitive (and noncognitive) functions toward integrating the memory disorder in a syndrome. We review the global tools, the memory tests that describe the memory profile and indicate the underlying pathology, the assessment of other cognitive functions, and the neuropsychological patterns of typical Alzheimer's disease, frontotemporal dementia, primary progressive aphasia, semantic dementia, Lewy body dementia, subcortical dementia, and vascular dementia. These patterns must be interpreted in the light of the history, rate of progression, imaging results, and nature of existing behavioral disturbances. Moreover, there may be overlap between two or more pathologies, which complicates the diagnostic process. Follow-up of patients is necessary to improve diagnostic accuracy.

Alzheimer Disease↗
PubMed1999

Association between coding variability in the LRP gene and the risk of late-onset Alzheimer's disease.

We have sequenced the entire (89 exons) open reading frame of the LRP gene in 12 cases of Alzheimer's disease (AD) from Northern France. We have found no novel changes but confirm the occurrence of a polymorphism in exon 6 of the gene (A216V). This polymorphism is rare (2.8% of controls) and is in linkage equilibrium with previously reported polymorphisms. The V216 allele is negatively associated with the disease in a large case-controlled series. These data suggest that the LRP receptor may be involved in the pathobiology of AD, but the association that we report here cannot explain the previously reported genetic data implicating the LRP gene in AD. If the LRP gene is a major site of genetic variability leading to AD, there must be other biologically relevant variability in promoter or other regulatory elements of this large gene.

Aged↗
PubMed1999

The clinical picture of frontotemporal dementia: diagnosis and follow-up.

Frontotemporal dementia (FTD) was diagnosed in 74 outpatients with a standardized assessment including neuropsychological tests, behavioural scale, structural and functional imaging. Clinical characteristics were consistent with the literature data. The cohort was followed for 2-6 years to determine the reliable variable for evaluating the progression of FTD. Every fourth patient died after a mean duration of 7 years. At first, FTD manifests itself in behavioural changes with relatively stable global cognition although language, verbal fluency and memory tests were reliable tools to follow the progression of the disease. Below 18 of Mini-Mental State Examination, mutism and apathy prevented from neuropsychological testing within the next 6 months. Behavioural disorders evolved with time but restlessness and hyperorality were long-lasting. Imaging showed the progression of a consistent pattern of anterior abnormalities with frequent leukoaraiosis.

Activities of Daily Living↗
PubMed1999

Confusional state in stroke: relation to preexisting dementia, patient characteristics, and outcome.

BACKGROUND AND PURPOSE: Acute confusional state (ACS) is frequent in hospitalized stroke patients. We previously showed that 16% of patients admitted for a stroke have preexisting dementia. The extent to which preexisting cognitive decline is associated with a risk of ACS at the acute stage of stroke remains to be systematically examined. The aim of this study was to evaluate the prevalence of ACS in acute stroke patients, to study the influence of preexisting cognitive decline and other patient characteristics, and to evaluate the influence of ACS on outcome. METHODS: We diagnosed ACS using DSM-IV criteria and the Delirium Rating Scale with a cutoff of 10 in 202 consecutive stroke patients aged 40 years or older (median age, 75 years; range, 42 to 101 years). Cognitive functioning before stroke was assessed with the Informant Questionnaire on Cognitive Decline in the Elderly. RESULTS: Forty-nine stroke patients (24.3%; 95% CI, 18.3% to 30.2%) had an ACS during hospitalization. Using logistic regression analysis, we found preexisting cognitive decline (P=0.006) and metabolic or infectious disorders (P=0.008) to be independent predictors of ACS. Functional, but not vital, prognosis was worse in patients with ACS at discharge and 6 months after stroke. CONCLUSIONS: ACS occurs in one fourth of stroke patients older than 40 years. Its occurrence requires inquiry for a preexisting cognitive decline, which usually remains unrecognized in the absence of a systematic evaluation.

Acute Disease↗
PubMed1999

Technetium HMPAO SPECT study in dementia with Lewy bodies, Alzheimer's disease and idiopathic Parkinson's disease.

UNLABELLED: The aim of this study was to compare the regional cerebral blood flow measurements studied by SPECT in dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) to determine the contribution of SPECT to the differential diagnosis of these two diseases. METHODS: SPECT analysis with 99mTc-hexamethyl propyleneamine oxime (HMPAO) was performed in 20 patients with probable DLB, 20 patients with probable AD and 20 patients with idiopathic Parkinson's disease (IPD). Ten pairs of regions of interest were analyzed. Tracer uptake was expressed as a corticocerebellar activity ratio. RESULTS: Compared with IPD, in the DLB group there was a global decrease of HMPAO uptake in cortical regions of interest except in the posterior frontal and occipital regions; in the AD group there was limited left temporal and parietal hypoperfusion. In the DLB group, frontal HMPAO uptake was significantly lower than in the AD group. Two predictive scores were established by a factorial discriminant analysis from six left cortical indices (medial frontal, lateral frontal, posterior frontal, temporoparietal, parietal and parietooccipital) and the Mini-Mental State Examination, which correctly classified 53 of 60 patients (88%) (DLB, 18 of 20; AD, 16 of 20; IPD, 19 of 20). CONCLUSION: These findings indicate the presence of diffuse cortical abnormalities in DLB and suggest that SPECT may be useful in discriminating in vivo DLB from AD, revealing mainly frontal hypoperfusion in the former group. We estimate that SPECT study increases the possibility of separating DLB and AD because both disorders share different patterns of cerebral blood flow abnormality.

Aged↗
PubMed1999

[Arterial hypertension and cognitive decline].

Arterial hypertension is the leading risk factor for all stroke subtypes. However, its relationship with cognitive decline and dementia is more complex than a simple causal relationship. Cognitive functions are worse in patients with arterial hypertension, especially when the level of education is lower, age higher and arterial hypertension more severe. Arterial hypertension is an independent factor of cognitive decline. It also leads to white matter changes which contribute to the cognitive decline. Longitudinal studies have shown that a higher blood pressure at the age of 70 years is associated with an increased risk of dementia (vascular or Alzheimer) 10 to 15 years later, but blood pressure spontaneously decreases as dementia occurs. Treatments of arterial hypertension decrease the incidence of stroke, but clinical trials are still necessary to determine if they also decrease the incidence of dementia. Preliminary results obtained in elderly subjects with systolic arterial hypertension, support this hypothesis.

Alzheimer Disease↗
PubMed1999

[Risk factors and mechanisms of post-stroke dementia].

Stroke significantly increases the risk of dementia in subjects aged 55 years or more. Twenty to 25 p. 100 of patients are demented 5 years after a stroke. Age and supratentorial location of the vascular lesion are risk factors for post-stroke dementia. Volume, left side of the lesion, large middle cerebral artery infarction, lesions of the frontal lobe, second stroke, diabetes, aphasia, clinical features expressing the severity of the stroke event in the acute phase, mitral valve prolapse, atrial fibrillation, depression, concomitant hypoxic/ischemic disorders, and white matter changes have also been found as predictors of dementia. There are many different mechanisms of vascular pathology that may lead to dementia: ischemic or hemorrhagic lesions, large vessel disease including multi-infarct and strategic single infarct, small-vessel disease including lacunes and white matter changes, hypoperfusion.... Post-stroke dementia may not be due only to vascular lesion. Some post-stroke dementias have a progressive onset and course. The cognitive decline may pre-exist to the stroke, even when a dementia is not diagnosed. This suggests a degenerative process. Alzheimer's disease is frequent in ages when the majority of strokes occur. Alzheimer's and vascular diseases share common risk factors such as age, APOE4, hypertension, and smoking. Patients with low MMS scores and AD patients are at risk for stroke. Moreover, white matter changes are associated with stroke and Alzheimer's disease and may contribute to the cognitive decline. Many post-stroke dementias could be multifactorial. Even when vascular lesions and degenerative changes (mainly Alzheimer changes) are not severe enough, no their own, to be the cause of dementia, their summation may reduce the preclinical stage of the degenerative process.

Aged↗
PubMed1999

[Organization of memory centers and prospects].

The concept of memory centers is based on a multidisciplinary approach to memory disorders and dementia, especially Alzheimer's disease, a public health challenge. The first memory centers were established in the 80s in the US and the British Isles. The aims of these centers are to make a diagnosis (and to reassure the 'worried well'), to detect dementia, to provide a service for their management, to educate care takers, to evaluate new therapies, and to contribute to clinical and basic research. Follow-up is crucial. The first memory centers all experienced long delay to diagnosis of dementia and found that Alzheimer's disease was the first cause of consultation. These observations led to the creation of such centers in many countries. A survey of 20 French memory centers defined the "ideal memory center": an identified structure with a clinic and a day-care unit for diagnosis and follow-up, with neurological, psychological, psychiatric, and geriatric skills. It must be part of a medical and social network for the management of dementia and participate in a network of memory centers at the regional and national level. Relationships between dementia and somatic diseases, frequent in demented patients, are still poorly known. Dementia interferes with the clinical expression, the management, and the prognosis of somatic diseases, some of which, such as cardiovascular conditions, are possibly linked with dementia. Conversely, somatic diseases may rapidly worsen the cognitive state and induce delirium, leading to hospitalization. Medical wards are not all appropriate. Memory centers must also be involved in these care, educational and research issues.

Academic Medical Centers↗
PubMed1998

[Differential diagnosis of Alzheimer's disease].

The differential diagnosis of Alzheimer's disease has dramatically changed since the evolution of the diagnostic strategies (with definition of neuropsychological, behavioural, and imaging patterns) and disposal of cholinergic drugs indicated in Alzheimer's disease. The question is no more centred on exclusion of the traditional reversible dementias or depression. It is centred on the distinction between Alzheimer's disease and other degenerative diseases still often misdiagnosed with Alzheimer's disease such as frontotemporal dementias, dementia with Lewy bodies, and some focal atrophies that do not have the same physiopathology and should not be treated with anticholinesterase drugs. Besides, better knowledge on the links between cerebrovascular pathology and Alzheimer's disease, remind us that both pathologies may coexist and should be taken into account.

Alzheimer Disease↗