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Carole Dufouil

Publications and source records attributed to Carole Dufouil.

17 recordsLinked to original sources
PubMed2026

APOE-stratified genome-wide association analyses provide insights into the genetic etiology of Alzheimers's disease.

Among the more than 90 identified genetic risk loci for late-onset Alzheimer's disease (AD) and related dementias, the apolipoprotein E (APOE) gene ɛ2/ɛ3/ɛ4 polymorphisms remain the longstanding benchmark for genetic disease risk with a consistently large effect across studies1-10. Despite this massive signal, the exact mechanisms by which ɛ4 increases and ɛ2 decreases dementia risk remain poorly understood. Notably, recent trials of anti-amyloid therapies suggest less efficacy and higher risks of severe side effects in ε4 carriers11-13, hampering the treatment of those with the highest unmet need. To improve our understanding of the genetic architecture of AD in the context of its main genetic driver, we performed genome-wide association studies (GWASs) stratified by ε4 and ε2 carrier status. HP1BP3, SLC50A1, PTPRC, NPAS3, DDHD1, CHST9, SMYD2, PRAMEF1 and GFRA1 emerged as new genomic signals for AD risk, appearing only when stratified by APOE carrier status. DDHD1 appeared especially promising, showing protective effects in ε4 carriers, being identified as an expression quantitative trait locus and being involved in rare neuronal diseases. Such APOE-stratified insights may help understand and overcome side effects, inform clinical trial enrollment strategies, and create the scientific basis for targeted, mechanism-driven therapies in neurodegenerative diseases.

Journal Article↗
PubMed2006

Cerebral changes on MRI and cognitive function: the CASCADE study.

The aging, non-demented brain undergoes several physiological changes, some of which may affect cognitive function. The goal of the present study was to examine the associations between subcortical and periventricular white matter hyperintensities (WMHs), cortical and subcortical atrophy, and cognitive function (episodic memory, word fluency, attention, and perceptual, cognitive, and motor speed). This was done within a European collaborative study, Cardiovascular Determinants of Dementia (CASCADE), in which magnetic resonance imaging (MRI) was performed on community-dwelling individuals. The study includes 1254 persons from eight European study centers, ranging between 64 and 76 years of age (M 69.4+/-3.3; 55% men). When demographics (age, education, and sex), study center, and concurrent brain changes had been adjusted for, periventricular WMHS predicted lower performance in word fluency and the Stroop test (time), and subcortical atrophy predicted lower performance in motor speed and the Stroop test (errors). The findings are consistent with findings from lesion and functional neuroimaging studies.

Age Distribution↗
PubMed2005

[Epidemiology of Alzheimer's disease].

Because of global ageing of the population, the occurrence of Alzheimer's disease (AD) cases is increasing dramatically and AD is becoming a major public health preoccupation. By the year 2020, the World Health Organisation predicts that there will be almost 29 millions demented people throughout the world, two third of them being AD cases. This dramatic perspective could only be modified with new curative treatments or prevention. These last years, there is increasing evidence from epidemiological studies for the role of vascular risk factors in the aetiology of AD among which hypertension, type 2 diabetes, or high cholesterol. These potentially modifiable risk factors raise hope for prevention of Alzheimer's disease.

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PubMed2005

Effects of blood pressure lowering on cerebral white matter hyperintensities in patients with stroke: the PROGRESS (Perindopril Protection Against Recurrent Stroke Study) Magnetic Resonance Imaging Substudy.

BACKGROUND: The prevalence of white matter hyperintensities (WMHs) detected on cerebral MRI is associated with hypertension, but it is not known whether blood pressure lowering can arrest their progression. We report here the results of an MRI substudy of PROGRESS (Perindopril Protection Against Recurrent Stroke Study), a randomized trial of blood pressure lowering in subjects with cerebrovascular disease. METHODS AND RESULTS: The substudy comprised 192 participants who had a cerebral MRI both at baseline and after a mean follow-up time of 36 months (SD=6.0 months). At the first MRI, WMHs were graded with a visual rating scale from A (no WMH) to D (severe WMH). Participants were assigned to a combination of perindopril plus indapamide (or their placebos; 58%) or to single therapy with perindopril (or placebo). At the time of the second MRI, the blood pressure reduction in the active arm compared with the placebo arm was 11.2 mm Hg for systolic blood pressure and 4.3 mm Hg for diastolic blood pressure. Twenty-four subjects (12.5%) developed new WMHs at follow-up. The risk of new WMH was reduced by 43% (95% CI -7% to 89%) in the active treatment group compared with the placebo group (P=0.17). The mean total volume of new WMHs was significantly reduced in the active treatment group (0.4 mm3 [SE=0.8]) compared with the placebo group (2.0 mm3 [SE=0.7]; P=0.012). This difference was greatest for patients with severe WMH at entry, 0.0 mm3 (SE=0) in the active treatment group versus 7.6 mm3 (SE=1.0) in the placebo group (P<0.0001). CONCLUSIONS: These results indicate that an active blood pressure-lowering regimen stopped or delayed the progression of WMHs in patients with cerebrovascular disease.

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PubMed2005

Subjective cognitive complaints and cognitive decline: consequence or predictor? The epidemiology of vascular aging study.

OBJECTIVES: To explore whether more cognitive complaints are associated with previous or future cognitive decline. DESIGN: Longitudinal; epidemiology vascular aging study. SETTING: Community in Nantes, France. PARTICIPANTS: Seven hundred thirty-three subjects, aged 59 to 71. MEASUREMENTS: Subjective cognitive complaints were recorded at 4-year follow-up examination in a prospective study of people aged 59 to 71 at study entry. Participants' cognitive performances were assessed repeatedly at each wave (baseline, 4 years, and 6 years) of the study using a series of neuropsychological tests including the Mini-Mental State Examination. Depressive symptoms were evaluated using the Center for Epidemiological Studies Depression Scale. Subjects also had a cerebral magnetic resonance imaging scan at 4-year follow-up to evaluate presence and severity of white matter hyperintensities (WMHs). RESULTS: Subjects with more cognitive complaints had greater cognitive decline. This significant relationship persisted after adjusting for potential confounders, including depressive symptoms. Multivariate analysis also showed that, in subjects without measured cognitive decline between study entry and 4-year follow-up, those with more cognitive complaints at 4-year follow-up had significantly greater measured cognitive decline during the subsequent 2 years. In the presence of severe WMH, more cognitive complaints were an even stronger predictor of future cognitive decline. CONCLUSION: Cognitive complaints reflect measured cognitive decline, but they also predict cognitive decline at an earlier stage than objective tests that are not able to detect cognitive deficits. They need to be taken into account in clinical practice.

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PubMed2005

The prevalence and correlates of major and minor depression in older medical inpatients.

OBJECTIVES: To describe the prevalence of and characteristics associated with major and minor depression in older medical inpatients and to compare associated characteristics by sex and history of depression. DESIGN: Cross-sectional study of two patient samples, with and without a screening diagnosis of major or minor depression. SETTING: The medical services of two acute care hospitals. PARTICIPANTS: Medical admissions of people aged 65 and older with at most mild cognitive impairment (N=380). MEASUREMENTS: Diagnoses of major and minor depression (Diagnostic Interview Schedule), cognitive impairment (Mini-Mental State Examination), premorbid disability, sociodemographic variables (including social networks and support), comorbidity, severity of illness, history of depression. RESULTS: The prevalence of major depression differed by hospital, ranging from 14.2% (95% confidence interval (CI)=11.7-17.1) in Hospital A to 44.5% (95% CI=33.1-56.4) in Hospital B. The prevalence of minor depression was similar in the two hospitals, ranging from 9.4% (95% CI=7.4-11.9) in Hospital A to 7.9% (95% CI=2.9-16.3) in Hospital B. After adjustment for hospital, the same characteristics (history of depression, premorbid disability, cognitive impairment, perceived adequacy of support, and visits from friends) were associated with major and minor depression, although most of these associations tended to be weaker for minor depression. Most of these factors were also associated with depression in multivariate analyses. The most important characteristics in women were premorbid disability, history of depression, and adequacy of emotional support; in men they were history of depression, cognitive impairment, and adequacy of emotional support. A cerebrovascular or other cardiovascular diagnosis did not explain the association between depression and cognitive impairment. CONCLUSION: Major and minor depression occur frequently in older medical inpatients and are associated with similar patient characteristics. A history of depression and the patient's sex should be considered in the identification and interpretation of these associated factors.

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PubMed2004

No epsilon4 gene dose effect on hippocampal atrophy in a large MRI database of healthy elderly subjects.

The effect of ApoE genotype on grey matter (GM) atrophy was studied on a cohort of 750 healthy elderly volunteers (age range 63-75 years). High-resolution T1-weighted MR images were processed using both voxel-based morphometry and region of interest analysis for hippocampal volume estimation. Significant decrease of grey matter in epsilon(4) homozygous subjects (n = 12), as compared both to epsilon(4) heterozygous subjects (n = 175) and to noncarrier (n = 563) subjects, was found bilaterally in the medial temporal lobe, including the hippocampus, and extending over the superior temporal gyrus. By contrast, no significant difference was observed between epsilon(4) heterozygous subjects and noncarriers at the level of the medial temporal lobe. Follow-up of the cohort cognitive performances over 4 years after their MRI exam revealed that, as compared to noncarrier subjects, the relative risk of cognitive impairment was 5.9 for epsilon(4) homozygous subjects (P = 0.03), while it was not different from 1 for epsilon(4) heterozygous subjects (P = 0.92). These findings indicate that, in the age range of this cohort, ApoE-4 effects on cortical atrophy and cognitive performances of healthy elderly are limited to epsilon(4) homozygous subjects.

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PubMed2004

The association between blood pressure, hypertension, and cerebral white matter lesions: cardiovascular determinants of dementia study.

Cerebral white matter lesions are frequently observed on magnetic resonance imaging (MRI) scans in elderly people and are associated with stroke and dementia. Elevated blood pressure is presumed one of the main risk factors, although data are almost exclusively derived from cross-sectional studies. We assessed in 10 European cohorts the relation between concurrently and previously measured blood pressure levels, hypertension, its treatment, and severe cerebral white matter lesions. In total, 1805 nondemented subjects aged 65 to 75 years were sampled from ongoing community-based studies that were initiated 5 to 20 years before the MRI. White matter lesions in the periventricular and subcortical region were rated separately using semiquantitative measures. We performed logistic regression analyses adjusted for potential confounders in 1625 people with complete data. Concurrently and formerly assessed diastolic and systolic blood pressure levels were positively associated with severe white matter lesions. Both increases and decreases in diastolic blood pressure were associated with more severe periventricular white matter lesions. Increase in systolic blood pressure levels was associated with more severe periventricular and subcortical white matter lesions. People with poorly controlled hypertension had a higher risk of severe white matter lesions than those without hypertension, or those with controlled or untreated hypertension. Higher blood pressure was associated with an increased risk of severe white matter lesions. Successful treatment of hypertension may reduce this risk; however, a potential negative effect of decreasing diastolic blood pressure level on the occurrence of severe periventricular white matter lesions should be taken into account.

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PubMed2004

Analysis of longitudinal studies with death and drop-out: a case study.

The analysis of longitudinal data has recently been an active area of biostatistical research. Two main approaches to analysis have emerged, the first concentrating on modelling evolution of marginal distributions of the main response variable of interest and the other on subject-specific trajectories. In epidemiology the analysis is usually complicated by missing data and by death of study participants. Motivated by a study of cognitive decline in the elderly, this paper argues that these two types of incomplete follow-up may need to be treated differently in the analysis, and proposes an extension to the marginal modelling approach. The problem of informative drop-out is also discussed. The methods are implemented in the 'Stata' statistical package.

Age Factors↗
PubMed2004

Magnetic resonance imaging of the brain in diabetes: the Cardiovascular Determinants of Dementia (CASCADE) Study.

Diabetic patients are at increased risk for stroke, but little is known about the presence of other brain lesions. We studied the association of magnetic resonance imaging-detected brain lesions to diabetes in 1,252 individuals aged 65-75 years who were randomly selected from eight European population registries or defined working populations. All scans were centrally read for brain abnormalities, including infarcts, white matter lesions, and atrophy. We used a three-point scale to rate periventricular white matter lesions, and the volume of subcortical lesions was calculated according to their number and size. Subjective grading of cortical atrophy by lobe and summation of the lobar grades resulted in a total cortical atrophy score. The mean of three linear measurements of the ventricular diameter relative to the intracranial cavity defined the severity of subcortical atrophy. After adjustment for possible confounders, diabetes was associated with cortical brain atrophy but not with any focal brain lesions or subcortical atrophy. There was a strong interaction of diabetes and hypertension, such that the association between diabetes and cortical atrophy existed only in hypertensive but not in normotensive participants. Cognitive and pathological data are needed to determine the clinical significance of these findings as well as to understand the mechanisms underlying these associations.

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PubMed2003

Homocysteine, white matter hyperintensities, and cognition in healthy elderly people.

Hyperhomocysteinemia is associated with an increased risk of vascular disease, and recent results suggest that it also could increase the risk of dementia. We examined the relationship between homocysteine and cognitive decline in 1,241 subjects aged 61 to 73 years, followed up over 4 years. Plasma homocysteine levels were determined in all participants as well as cardiovascular risk factors, apolipoprotein E genotype, plasma levels of folate, and vitamin B12. Cognitive performances were assessed repeatedly by using Mini-Mental State Examination, Trail Making Test, Digit Symbol Substitution Test, and Finger Tapping Test. At 2-year follow-up, 841 subjects underwent cerebral magnetic resonance imaging, and white matter hyperintensities were rated visually. Analyses were adjusted for all cardiovascular risk factors. Cross-sectional analyses showed that higher concentrations of homocysteine were significantly related to poorer performances at all neuropsychological tests. Longitudinal analyses confirmed this finding. The odds of cognitive decline was 2.8-fold (p < 0.05) higher in subjects with homocysteine levels above 15 micromol/L compared with those with homocysteine levels below 10 micromol/L. In participants who underwent magnetic resonance imaging, the relationship between homocysteine and cognition was unchanged after taking into account white matter hyperintensities suggesting that white matter hyperintensities do not mediate the association between homocysteine and cognition.

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PubMed2003

Exploring sex differences in the relationship between depressive symptoms and dementia incidence: prospective results from the PAQUID Study.

OBJECTIVES: To estimate the predictive relationship between depressive symptoms and 8-year dementia incidence in a large prospective community sample of French older adults and to compare the effect magnitude for men and women. DESIGN: Prospective population-based cohort with four interview waves and complete vital status ascertainment. SETTING: Urban and rural communities in the Aquitaine Region (Gironde and Dordogne), southwest France. PARTICIPANTS: Three thousand seven hundred seventy-seven adults aged 65 and older residing in noninstitutional settings at study baseline. MEASUREMENTS: Each participant was interviewed by a neuropsychologist and screened for dementia with the Mini-Mental State Examination, a cognitive test battery, and a standardized questionnaire designed to ascertain the presence of the criteria for dementia according to the Diagnostic and Statistical Manual for Mental Disorders, Third Edition, Revised (DSM-III-R). Dementia status and subtype were confirmed using neurological examination and categorized according to DSM-III-R criteria for dementia and the National Institute of Neurological Disorders and Stroke/Alzheimer's and Related Disorders Association criteria. The Hachinski score was calculated to specify the etiology: possible or probable Alzheimer's disease, vascular dementia, and other types of dementia. Depressive symptomatology was evaluated using the Center for Epidemiologic Studies-Depression scale. Statistical analyses were weighted to correct for attrition not due to mortality. RESULTS: Ninety-seven men (incidence rate: 14.4/1,000) and 183 women (Incidence rate: 19.0/1,000) developed dementia during 8 years of follow-up. Baseline prevalence of depressive symptomatology was 12.9% for men and 14.7% for women. Depressive symptoms increased risk of dementia at subsequent interview wave, but only for men (odds ratio (OR) (men) = 3.5, 95% confidence interval (CI) = 1.9-6.5; OR (women) = 1.2, 95% CI = 0.7-2.0, P-value for sex difference = 0.03). The hypothesis that vascular depression might explain the observed sex difference was studied, and it was found that risk was 50% higher for men with hypertension who were depressed than for normotensive men. For women, hypertension status did not modify the absence of an association. CONCLUSION: This study supports the hypothesis of a relationship between proximal depressive symptomatology and dementia in men, but distant depression did not increase dementia risk in this sample. The results suggest that depression in older men might reflect a form of vascular depression associated with cerebral vascular pathology or multiinfarct disease that may amplify the dementing or declining process, hence accelerating the onset of manifest symptoms of dementia.

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PubMed2002

Long-term benzodiazepine use and cognitive decline in the elderly: the Epidemiology of Vascular Aging Study.

Several cross-sectional studies have found cognitive impairment in subjects taking benzodiazepines for long periods. However, it is not known whether long-term use of benzodiazepines accelerates cognitive decline in the elderly. The authors addressed this issue in a follow-up study of 1,389 people aged 60 to 70 years recruited from the electoral rolls of the city of Nantes (Epidemiology of Vascular Aging study). Data on cognitive functioning (five cognitive tests), depressive symptoms (Center for Epidemiologic Studies-Depression Scale), anxiety symptoms (Spielberger Inventory Scale), use of psychotropics and other drugs, and tobacco and alcohol consumption were collected at baseline, 2-year, and 4-year examinations. People reporting to take benzodiazepines at one, two and three examinations were classified as episodic, recurrent, and chronic users, respectively. Among the 1,176 subjects (85%) who participated in the three examinations, the proportions of episodic, recurrent, and chronic users were 10%, 6%, and 7%, respectively. Chronic users of benzodiazepines had a significantly higher risk of cognitive decline in the global cognitive test (Mini Mental State Examination) and the two attention tests than nonusers (Mini Mental State Examination: odds ratio [OR] [95% confidence interval (CI)] = 1.9 [1.0-3.5]; Digit Symbol Substitution test: OR [95% CI] = 2.7 [1.6-4.7]; Trail Making test, part B: OR [95% CI] = 2.1 [1.2-3.7]). Overall, episodic and recurrent users had lower cognitive scores than nonusers, but differences were not statistically significant. These results were independent of age, sex, education, alcohol and tobacco use, anxiety and depression scores, and use of psychotropic drugs other than benzodiazepines. The findings suggest that long-term use of benzodiazepines is risk factor of increased cognitive decline in the elderly.

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PubMed2002

Longitudinal study of carotid atherosclerosis and white matter hyperintensities: the EVA-MRI cohort.

BACKGROUND AND PURPOSE: White matter hyperintensities (WMHs) are often observed on cerebral magnetic resonance imaging (MRI) of elderly individuals. Epidemiological studies have shown that age and hypertension are associated with WMHs, suggesting a vascular mechanism in WMH pathogenesis. In a population-based prospective study, we examined the association of carotid atherosclerosis measured at baseline and 4-year follow-up with severity of WMHs assessed at 4-year follow-up. METHODS: The sample consisted of 640 healthy subjects aged 59-71 years at entry enrolled in the prospective EVA Study. Systolic and diastolic blood pressures were measured at each wave. Ultrasonographic measures of intima-media thickness (IMT) of the common carotid arteries and plaques were made at baseline and at 4-year follow-up examination. An MRI examination was performed at 4-year follow-up. The presence and severity of WMHs were evaluated by a single radiologist. RESULTS: After adjusting for age, gender, and hypertension, the presence of carotid plaques at baseline was significantly associated with the presence of severe WMHs 4 years later [odds ratio (OR) = 1.70; 95% confidence interval (CI): 1.05-2.74]. The association was stronger in men than in women. A 0.1-mm increase of baseline IMT was associated with an increased risk of severe WMHs in both sexes (adjusted OR = 1.17; 95% CI: 0.96-1.41), but the association was not significant (p = 0.12). Cross-sectional relationships between carotid plaques and severe WMHs at 4-year follow-up showed that the risk of having severe WMHs was stronger in the group of subjects who had already plaques at study entry compared to the group of subjects whose plaques occurred during 4-year follow-up. CONCLUSION: This study confirmed an association between carotid atherosclerosis and WMHs independently of age and hypertension. It also suggested that the older the carotid plaques, the higher the risk of having severe WMHs.

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PubMed2002

Depressive symptoms and cognitive decline in elderly people. Longitudinal study.

BACKGROUND: Depressive symptoms are associated with cognitive decline in elderly people, but the nature of their temporal relationship remains equivocal. AIMS: To test whether depressive symptoms predict cognitive decline in elderly people with normal cognition. METHOD: The Center for Epidemiologic Study depression scale (CES-D) and the Mini-Mental State Examination (MMSE) were used to evaluate depressive symptomatology and cognitive functioning, respectively. A sample of 1003 persons aged 59-71 years and with a MMSE score of 26 or over was selected. Cognitive decline was defined as a drop of at least 3 points on the MMSE at 4-year follow-up. RESULTS: Baseline high levels of depressive symptoms predicted a higher risk of cognitive decline at 4-year follow-up. The MMSE score of participants with depression was more likely to fall below 26 at 2-year follow-up and to remain below at 4-year follow-up than the MMSE score of those without depressive symptoms. Persistent but not episodic depressive episodes were associated with cognitive decline. CONCLUSIONS: High levels of depressive symptoms, when persistent, are associated with cognitive decline in a sample of elderly people.

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PubMedDate not supplied

Short-term stability of diagnoses of major and minor depression in older medical inpatients.

The authors sought to determine the short-term stability of diagnoses of major and minor depression in older medical inpatients. The investigation was a test-retest design involving comparisons between different pairs of interviewers who assessed patients independently on medical wards of two acute-care, university-affiliated hospitals by use of the Diagnostic Interview Schedule (DIS) at intervals between 1 and 51 days. Patients were 380 cognitively-intact patients age > or =65, assessed twice with the DIS. Core depressive symptoms (depressed mood, loss of interest or pleasure) were more stable than the other depressive symptoms. The presence of moderate-to-severe depressive symptoms, moderate-to-severe disability, and depression symptoms of > or =6 months' duration were associated with a higher short-term stability of diagnosis. Age, gender, language, education, rater, interval between assessments, baseline number of medications, medical comorbidity, severity of medical illness, acute physiology score, and cognitive functioning were not associated with short-term depression stability. Stability of diagnosis may be improved by emphasis on core depressive symptoms or the presence of more severe depressive symptoms, moderate-to-severe disability, and duration of symptoms > or =6 months.

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