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Florence Pasquier

Publications and source records attributed to Florence Pasquier.

At least 19 recordsLinked to original sources
PubMed2025

Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer's disease.

BACKGROUND: Protein truncating variants (PTVs) in SORL1 are observed almost exclusively in Alzheimer’s Disease (AD) cases, but the effect of rare SORL1 missense variants is unclear. METHODS: To identify high-priority missense variants (HPVs), we applied ‘domain mapping of disease mutations’ for the 637 unique coding SORL1 variants detected in 18,959 AD-cases and 21,893 non-demented controls. RESULTS: In this sample, PTVs and HPVs associated with respectively a 35- and 10-fold increased risk of early onset AD and 17- and 6-fold increased risk of overall AD. The median age at onset (AAO) of PTV- and HPV-carriers was 62 and 64 years, and APOE-genotype contributed to AAO-variability. The median AAO of PTV- and HPV-carriers is ~8–10 years earlier than wild-type SORL1 carriers, matched for APOE-genotype. Specific HPVs are highly penetrant and lead to earlier AAOs than PTVs, suggesting possible dominant negative effects. CONCLUSION: Our results justify a debate on whether HPV carriers should be considered for clinical counseling.

Humans↗
PubMed2025

Proteomic analysis reveals distinct cerebrospinal fluid signatures across genetic frontotemporal dementia subtypes.

We used an untargeted mass spectrometric approach, tandem mass tag proteomics, for the identification of proteomic signatures in genetic frontotemporal dementia (FTD). A total of 238 cerebrospinal fluid (CSF) samples from the Genetic FTD Initiative were analyzed, including samples from 107 presymptomatic (44 C9orf72, 38 GRN, and 25 MAPT) and 55 symptomatic (27 C9orf72, 17 GRN, and 11 MAPT) mutation carriers as well as 76 mutation-negative controls ("noncarriers"). We found shared and distinct proteomic alterations in each genetic form of FTD. Among the proteins significantly altered in symptomatic mutation carriers compared with noncarriers, we found that a set of proteins including neuronal pentraxin 2 and fatty acid binding protein 3 changed across all three genetic forms of FTD and patients with Alzheimer's disease from previously published datasets. We observed differential changes in lysosomal proteins among symptomatic mutation carriers with marked abundance decreases in MAPT carriers but not other carriers. Further, we identified mutation-associated proteomic changes already evident in presymptomatic mutation carriers. Weighted gene coexpression network analysis combined with gene ontology annotation revealed clusters of proteins enriched in neurodegeneration and glial responses as well as synapse- or lysosome-related proteins indicating that these are the central biological processes affected in genetic FTD. These clusters correlated with measures of disease severity and were associated with cognitive decline. This study revealed distinct proteomic changes in the CSF of patients with genetic FTD, providing insights into the pathological processes involved in the disease. In addition, we identified proteins that warrant further exploration as diagnostic and prognostic biomarker candidates.

Humans↗
PubMed2006

Phenotype associated with APP duplication in five families.

Different duplications of the APP locus have been identified in five families with autosomal dominant early onset Alzheimer's disease (ADEOAD) and Abeta-related cerebral amyloid angiopathy (CAA). This study describes the phenotype of this new entity. Clinical, neuropsychological, imagery and neuropathological data were reviewed. The phenotype was not dependent on the size of the duplication and there was no clinical feature of Down's syndrome. Dementia was observed in all cases; intracerebral haemorrhage (ICH) was reported in 6 (26%) and seizures occurred in 12 (57%) of 21 patients. Age of onset of dementia ranged from 42 to 59 years, ICH from 53 to 64 years and age at death from 46 to 75 years. The neuropathological findings in five cases demonstrated Alzheimer's disease and severe CAA lesions that were reminiscent from those reported in brains of Down's syndrome patients. A striking feature consisted in intraneuronal Abetax-40 accumulation located in the granular cell layer of the dentate gyrus and in the pyramidal cell layer of the Ammon's horn.

Adult↗
PubMed2006

Influence of dementia on antithrombotic therapy prescribed before stroke in patients with atrial fibrillation.

BACKGROUND AND PURPOSE: Oral anticoagulation (OAC) decreases the risk of stroke in patients with nonvalvular atrial fibrillation (NVAF), but remains underused in practice. The aim of this study was to test the hypothesis that prestroke dementia influenced the nonprescription of OAC before stroke. METHODS: This is an ancillary study of Stroke in Atrial Fibrillation Ensemble II, an observational study conducted in patients with a previously known NVAF, consecutively admitted for an acute stroke to French and Italian centers. Prestroke dementia was evaluated by the clinical physician and validated by an Informant Questionnaire for Cognitive Decline in the Elderly score of >or=104 in patients with a reliable informant. RESULTS: Of 204 patients, 24 patients met criteria for prestroke dementia according to GP's opinion. The only variables independently associated with OAC before stroke were follow-up by a cardiologist (adjusted OR: 3.33; 95% CI: 1.47-7.53) and a younger age of patients (adjusted OR: 0.94; 95% CI: 0.89-0.99). Variables independently associated with any antithrombotic drug therapy before stroke were follow-up by a general practitioner (adjusted OR: 2.78; 95% CI: 1.09-7.11), and by a cardiologist (adjusted OR: 3.15; 95% CI: 1.48-6.69). CONCLUSION: In daily practice, the under-prescription of OAC in patients with NVAF mainly depends on co-morbidity and on characteristics of the physician, not on prestroke dementia.

Administration, Oral↗
PubMed2006

[Epidemiology of Alzheimer disease and related disorders].

Alzheimer's disease and related disorders (dementia) are a major public health problem due to the number of cases in the general population, the projections for the future, and the consequences of these diseases. We can estimate that about 850 000 cases of dementia were present in France in 2005 and this number will increase to 1,200,000 in 2020 and 2,100,000 in 2040 if the incidence and the duration of the disease did not change. The development of prevention is therefore necessary. Four ways of prevention are credible. The most important is the treatment of vascular risk factors and particularly hypertension. Other ways are nutritional factors, stimulating leisure activities and depression.

Aged↗
PubMed2005

[Treatment of Alzheimer's disease].

Alzheimer's disease (AD) is a neurodegenerative disorder with a decline in memory and cognitive abilities. During the past 20 years, research on AD has increased the knowledge of the physiopathological mechanisms leading to the disease. The major hallmarks of AD are amyloid plaques and neurofibrillary tangles, associated with a prevalent and early cholinergic deficit and an excitotoxicity with inflammation. These pathological mechanisms represent current and future therapeutic targets. cholinesterase inhibitors were the first therapeutic class that has consistently shown a clinical efficacy and safety in patients with mild to moderate ad. more recently glutamate receptor antagonists have been shown effective in the management of patients with moderate to severe AD. These two therapeutic classes could improve cognitive functions, slow the progression of the cognitive decline, prevent some behavioural changes and delay institutionalisation. However, AD represents a problem of public health and preventive and curative strategies have to be proposed.

Aged↗
PubMed2005

Natural history of primary progressive aphasia.

OBJECTIVE: To characterize the natural history of primary progressive aphasia (PPA). METHODS: Forty-nine patients (28 women) with newly diagnosed with PPA presenting to a memory disorders clinic between 1992 and 2001 were prospectively evaluated. RESULTS: Median age at onset was 62 years (range 49 to 73 years) and at first visit was 66 years (52 to 80 years). The median duration of follow-up was 4 years (1 to 11 years). Impairments in activities of daily living developed a median of 6 to 7 (2 to 12) years post onset. Seventy-five percent of patients eventually met clinical diagnostic criteria for frontotemporal dementia (FTD), 14% met diagnostic criteria for dementia with Lewy bodies, and 8% developed signs of corticobasal degeneration; 60% of the patients died after a median course of 7 years (3 to 17 years) at a median age of 71 years (56 to 81 years). Patients showing high Mini-Mental State Examination scores, moderate aphasia, and fluent language at first visit subsequently retained greater autonomy in daily life. CONCLUSIONS: Although activities of daily living are well maintained during the first years of the disease, patients with primary progressive aphasia (PPA) may lose autonomy 6 to 7 years after onset. The majority of patients with PPA in the current study developed frontotemporal dementia.

Activities of Daily Living↗
PubMed2005

Poststroke dementia.

Dementia is one of the major causes of dependency after stroke. The prevalence of poststroke dementia (PSD)-defined as any dementia occurring after stroke-is likely to increase in the future. In community-based studies, the prevalence of PSD in stroke survivors is about 30% and the incidence of new onset dementia after stroke increases from 7% after 1 year 48% after 25 years. Having a stroke doubles the risk of dementia. Patient-related variables associated with an increased risk of PSD are increasing age, low education level, dependency before stroke, prestroke cognitive decline without dementia, diabetes mellitus, atrial fibrillation, myocardial infarction, epileptic seizures, sepsis, cardiac arrhythmias, congestive heart failure, silent cerebral infarcts, global and medial-temporal-lobe atrophy, and white-matter changes. Stroke-related variables associated with an increased risk of PSD are stroke severity, cause, location, and recurrence. PSD might be the result of vascular lesions, Alzheimer pathology, white-matter changes, or combinations of these. The cause of PSD differs among studies in relation to the mean age of patients, ethnicity, criteria used, and time after stroke. In developed countries, the proportion of patients with presumed Alzheimer's disease among those with PSD is between 19% and 61%. Patients with PSD have high mortality rates and are likely to be functionally impaired. These patients should be treated according to the current guidelines for stroke prevention.

Dementia↗
PubMed2005

Telling the difference between frontotemporal dementia and Alzheimer's disease.

PURPOSE OF REVIEW: A precise diagnosis of the cause of dementia during life is needed for proper management, in order to explain the symptoms to the patient and to the close relatives, and to give appropriate indications on the prognosis and possibly on the genetic risk. Frontotemporal dementia remains under-diagnosed and often misdiagnosed for Alzheimer's disease, the most common cause of dementia. More and more studies explore the differences between the two syndromes. RECENT FINDINGS: Progress in neuropsychological testing improves the ability to distinguish between syndromes and knowledge on brain functioning. More attention has been paid over these last months--or years--on emotion, insight, behavior, artistic creativity and quality of responses. Yet, biomarkers do not improve the diagnostic accuracy of trained clinicians, and do not help to distinguish between histological subtypes of frontotemporal dementia. SUMMARY: Improvement in knowledge on cognitive and emotional impairment in frontotemporal dementia and Alzheimer's disease is essential for the management of the patient--information can be given to the patients and the families that helps them to understand and to behave in consequence.

Journal Article↗
PubMed2005

Poststroke dementia in the elderly.

Risk of dementia increases after stroke, and poststroke dementia (PSD) is an important cause of disability in the elderly. The prevalence rates of PSD vary from 12.2% to 31.8% within 3 months to 1 year after stroke, depending on patient populations and the diagnostic criteria used in the numerous studies. Incidence rates of PSD increase with time after the stroke. Although vascular lesions and white matter changes can explain the cognitive disorders seen in stroke patients, an underlying neurodegenerative disorder may contribute to the development of PSD. Cognitive decline may pre-date the stroke and follow a progressive course after the stroke. The vascular and degenerative processes involved share common environmental and genetic risk factors. This review explains the mechanisms of dementia in stroke patients and identifies predictive factors for PSD. The following points are successively considered: (i) demographic characteristics of the patients, including age and level of education; (ii) prestroke cognitive decline; (iii) vascular risk factors, including diabetes mellitus and prior strokes; (iv) stroke characteristics, including severity and location of the vascular lesion; (v) co-morbid disorders; and (vi) abnormalities on brain imaging, including location, size and number of vascular lesions, white matter changes and cerebral atrophy. Older age, prestroke cognitive decline, stroke recurrence, hypoxic-ischaemic disorders, left-side infarcts, strategic infarcts and white matter lesions appear to be the main predictive factors of PSD. Prevention of stroke should reduce the morbidity and mortality associated with PSD. In addition, management of PSD with secondary prevention treatments could reduce occurrence of further strokes. Cholinesterase inhibitors may be beneficial not only in Alzheimer's disease associated with cerebrovascular lesions, but also for the treatment of cholinergic dysfunction arising from pure vascular dementia. Better knowledge of the risk factors for PSD, including environmental and genetic factors, should increase the effectiveness of preventive strategies in patients with this condition.

Aged↗
PubMed2004

Association study of three polymorphisms of kinesin light-chain 1 gene with Alzheimer's disease.

The transport of amyloid precursor protein is mediated through its interaction with kinesin light-chain 1 (KNS2). We hypothesized that kinesin light-chain dysfunction might be involved in the pathogenesis of Alzheimer's disease (AD). To assess the physiological relevance of an allelic variation in the KNS2 gene, the association analysis of three single nucleotide polymorphisms (SNPs) in the 5'UTR or in intronic sequences of KNS2 gene were performed in 100 AD brain patients and in 103 controls. For one of these polymorphisms (G58836C in intron 13), the association between AD and the C allele was found to be significant (odds ratio = 1.73, 95% CI: 1.12-2.67, P = 0.012). No synergistic effects were found between the APOE epsilon 4 allele and KNS2 gene polymorphisms.

Aged↗
PubMed2004

Comparison of secondary vascular prevention in practice after cerebral ischemia and coronary heart disease.

BACKGROUND: Secondary prevention measures in patients with cerebral ischemia or coronary heart disease (CHD) consist of vascular risk factors management and antithrombotic therapy. The aim of this study was to compare how secondary prevention measures are applied in practice between patients with a history of CHD or cerebral ischemia. METHOD: We compared vascular risk factors management and antithrombotic therapy between patients with a history of CHD and patients with a history of cerebral ischemia that occurred 2 months to 6 years earlier. Whether patients were properly treated or not was determined by a comparison between their current treatments and European guidelines for stroke and CHD management. RESULTS: We included 107 consecutive patients with a history of cerebral ischemia and 85 consecutive patients with a history of CHD. We found that: (i). most patients did not receive an appropriate secondary prevention in both groups: 76 of 107 patients with previous cerebral ischemia (71 %) and 73 of 85 patients with CHD (85.9 %); (ii). identification of risk factors, such as hypercholesterolemia, diabetes mellitus and smoking, did not differ between both groups, but arterial hypertension was more frequent in CHD patients; (iii). an inappropriate management of risk factors was more frequent in patients with TIA vs. ischemic stroke, and angina pectoris vs. myocardial infarction; (iv). arterial hypertension and hypercholesterolemia were the 2 more frequent risk factors that were not properly treated; (v). more than half diabetic patients had hyperglycemia > or= 126 mg/dl in both groups; (vi). patients with previous CHD had twice more frequently stopped smoking than those with cerebral ischemia. CONCLUSION: Many patients were not properly treated in both groups, and differences between practice and guidelines were more frequent in the CHD group, where guidelines are more strict.

Aged↗
PubMed2004

Natural history of frontotemporal dementia: comparison with Alzheimer's disease.

INTRODUCTION: Frontotemporal dementia (FTD) is a more common cause of dementia than previously recognised. Few data are available regarding the natural course of FTD in terms of survival, nursing home admission and causes of death. METHODS: An observational study of all consecutive patients referred to the memory centre of Lille, France, between 1995 and 1999, and examined at least twice in this centre, with a diagnosis of FTD (frontal or behavioural variant) or of Alzheimer's disease (AD) was performed. Kaplan-Meyer analysis allowing for delayed entry was used to compare the survival functions in FTD and AD. RESULTS: 552 patients were included, of whom 49 (8.9%) were lost to follow-up at 3 years. FTD patients were younger (mean age at onset 59 years), had more often a family history of psychiatric disorders (20%), had a longer delay between first symptoms and first visit (5.9 years) and a higher Mini-Mental State Examination (MMSE) score at first visit (24.5) than patients with AD (19.9). The mean annual MMSE score decline was 0.9 point in FTD vs. 2.0 points in AD (p < 0.0004). Fewer patients with FTD than with AD entered an institution (RR: 0.20, 95% CI 0.05-0.81). After adjustment for sex, age at first visit, level of education and MMSE score at first visit, survival rates in FTD and AD did not differ significantly. Patients with FTD often had a sudden death, the cause of which could not be found. The earlier the first visit after onset, the longer the survival rate, whatever the diagnosis (RR: 0.76, 95% CI 0.67-0.86, p < 0.0001 per year of earlier first visit). CONCLUSION: This large study showed that the mean duration of FTD was 2 years longer than that of AD, but the risk of death after adjustment for age and sex was similar in FTD and in AD. Sudden and unexplained causes of death were frequent and need further study. Early management increases the life span of demented patients.

Adult↗
PubMed2004

Frontotemporal dementia: a randomised, controlled trial with trazodone.

Behavioural troubles due to frontotemporal dementia (FTD) are difficult to treat. The serotonergic system is associated with frontal lobes, the degeneration of which contributes to FTD. Trazodone increases the extracellular 5-HT levels in the frontal cortex. In a randomised, double-blind, placebo-controlled cross-over study, we investigated the effect of trazodone. There was a significant decrease in the Neuropsychiatry Inventory (NPI) total score with trazodone (p = 0.028) in the 26 evaluable patients. A decrease of more than 50% in the NPI score was observed in 10 patients with trazodone. This improvement was mainly based on the improvement of 4 items of the scale (irritability, agitation, depressive symptoms and eating disorders). The Mini-Mental State Examination was not modified and trazodone was well tolerated. Results of this first placebo-controlled trial suggest that trazodone is an effective treatment for the behavioural symptoms of FTD.

Adult↗
PubMed2003

Diffuse form of argyrophilic grain disease: a new variant of four-repeat tauopathy different from limbic argyrophilic grain disease.

Argyrophilic grain disease (AGD) is characterized by the occurrence of argyrophilic grains and coiled bodies in brain tissue, mainly in limbic areas located in the temporal lobe. Recent biochemical data have shown that inclusions in AGD consist of aggregates of pathological microtubule-associated tau protein isoforms of 64/69 kDa. We report here a study on two AGD patients, belonging to a series of demented patients affected by several tauopathies, prospectively followed until death. In both patients, clinical, neuropathological and biochemical investigations clearly demonstrated AGD. Diffuse tau pathology was shown by Gallyas' silver stain, tau immunohistochemistry and tau protein variant biochemical analysis, not only in temporal lobes but also in all cortical and subcortical areas that were assessed. Primary motor, primary sensory, and associative brain cortices were involved, as well as brain stem, but not cerebellum. We suggest that "diffuse" AGD might be a subgroup of AGD, the specific profile of which is different from that of "limbic" AGD.

Aged↗
PubMed2003

Poststroke dementia: influence of hippocampal atrophy.

BACKGROUND: The prevalence of dementia is increased after stroke. Medial temporal lobe atrophy (MTLA) is associated with Alzheimer disease, and with prestroke dementia in patients who have had a stroke. OBJECTIVE: To determine the influence of MTLA on the long-term risk of dementia after stroke, after excluding the patients who had prestroke dementia. METHODS: The study was conducted in 144 consecutive patients who had a stroke, who were aged 40 years or older (66 women and 78 men; median age, 72 years), and who had an Informant Questionnaire on Cognitive Decline in the Elderly score lower than 104. On admission to the hospital all patients underwent a noncontrast computed tomographic scan including temporal lobe-positioned slices. A cut-off of 11.5 mm was used to differentiate patients with MTLA from those without MTLA. Patients were followed up with clinical and cognitive assessments over a 3-year period. RESULTS: Three years after stroke, 34 patients (23.6%) had developed new-onset dementia. The cumulative proportion of survivors without dementia was 57.6% in patients with MTLA and 80.8% in patients without MTLA (P =.02). The unadjusted relative risk of poststroke dementia associated with MTLA was 2.3 (95% confidence interval, 1.1-4.7). However, using the Cox proportional hazards model, MTLA did not seem to be an independent predictor of poststroke dementia. Independent predictors of poststroke dementia were increasing age, diabetes mellitus, severity of the clinical deficit at admission, and severity of leukoaraiosis on computed tomography. CONCLUSIONS: Patients who had a stroke and MTLA more frequently develop dementia than patients without MTLA, but our study does not suggest that MTLA independently contributes to dementia. A longer follow-up may be necessary to reevaluate the influence of MTLA.

Adult↗