Jean-Sébastien Vidal

Midlife Blood Pressure, Plasma β-Amyloid, and the Risk for Alzheimer Disease: The Honolulu Asia Aging Study

&bgr;-Amyloid (A&bgr;), a vasoactive protein, and elevated blood pressure (BP) levels are associated with Alzheimer disease (AD) and possibly vascular dementia. We investigated the joint association of midlife BP and A&bgr; peptide levels with the risk for late-life AD and vascular dementia. Subjects were 667 Japanese-American men (including 73 with a brain autopsy), from the prospective Honolulu Heart Program/Honolulu Asia Aging Study (1965–2000). Midlife BP was measured starting in 1971 in participants with a mean age of 58 years; A&bgr; was measured in specimens collected in 1980–1982, and assessment of dementia and autopsy collection started in 1991–1993. The outcome measures were prevalent (present in 1991–1993) and incident AD (n=53, including 38 with no contributing cardiovascular disease) and vascular dementia (n=24). Cerebral amyloid angiopathy, &bgr;-amyloid neuritic plaques, and neurofibrillary tangles were evaluated in postmortem tissue. The risk for AD significantly increased with lower levels of plasma A&bgr; (A&bgr;1-40 hazard ratio: 2.1 [95% CI: 1.4 to 3.1]; A&bgr;1-42 hazard ratio: 1.6 [95% CI: 1.1 to 2.3]). Evidence of interaction between diastolic BP and plasma A&bgr; (1-40 P interaction<0.05; 1-42 P interaction<0.07) levels indicated that the A&bgr;-related risk for AD was higher when BP was higher. Low plasma A&bgr; was associated with the presence of cerebral amyloid angiopathy (P trend<0.05) but not the other neuropathologies. A&bgr; plasma levels start decreasing ≥15 years before AD is diagnosed, and the association of A&bgr; to AD is modulated by midlife diastolic BP. Elevated BP may compromise vascular integrity leading to cerebral amyloid angiopathy and impaired A&bgr; clearance from the brain.

Coronary Artery Calcium, Brain Function and Structure The AGES-Reykjavik Study

Background and Purpose— Several cardiovascular risk factors are associated with cognitive disorders in older persons. Little is known about the association of the burden of coronary atherosclerosis with brain structure and function. Methods— This is a cross-sectional analysis of data from the Age, Gene, Environment Susceptibility (AGES)-Reykjavik Study cohort of men and women born 1907 to 1935. Coronary artery calcification (CAC), a marker of atherosclerotic burden, was measured with CT. Memory, speed of processing, and executive function composites were calculated from a cognitive test battery. Dementia was assessed in a multistep procedure and diagnosed according to international guidelines. Quantitative data on total intracranial and tissue volumes (total, gray matter volume, white matter volume, and white matter lesion volume), cerebral infarcts, and cerebral microbleeds were obtained with brain MRI. The association of CAC with dementia (n=165 cases) and cognitive function in nondemented subjects (n=4085), and separately with MRI outcomes, was examined in multivariate models adjusting for demographic and vascular risk factors. Analyses tested whether brain structure mediated the associations of CAC to cognitive function. Results— Subjects with higher CAC were more likely to have dementia and lower cognitive scores, more likely to have lower white matter volume, gray matter volume, and total brain tissue, and to have more cerebral infarcts, cerebral microbleeds, and white matter lesions. The relations of cognitive performance and dementia to CAC were significantly attenuated when the models were adjusted for brain lesions and volumes. Conclusions— In a population-based sample, increasing atherosclerotic load assessed by CAC is associated with poorer cognitive performance and dementia, and these relations are mediated by evidence of brain pathology.

S18Y polymorphism in the UCH-L1 gene and Parkinson's disease: evidence for an age-dependent relationship.

We studied the relationship between Parkinsons disease (PD) and the S18Y polymorphism in the UCH‐L1 gene and the effect on this relationship of age at onset, smoking, and pesticides. Patients requested free health coverage for PD to the Mutualité Sociale Agricole (MSA), the French health insurance organization for people whose work is related to agriculture. Controls requested reimbursement of health expenses to the MSA. A maximum of three controls were matched to each case. Analyses included participants with both parents born in Europe. There were no differences in S18Y genotypes between patients (n = 209; 67% SS, 32% SY, 1% YY) and controls (n = 488; 66% SS, 30% SY, 4% YY). The relationship between PD and S18Y was modified by age at onset (P = 0.03). The Y allele was inversely associated with PD for patients with onset before 61 years (odds ratio [OR] = 0.53; 95% confidence interval [CI], 0.29–0.99); there was no association for older patients (62–68 years: OR = 1.21; 95% CI, 0.67–2.20; >68 years: OR = 1.24; 95% CI, 0.67–2.31). Among patients, Y carriers had a later onset than noncarriers (P = 0.04). These findings were not modified or confounded by smoking and pesticides. In this community‐based case‐control study, carriers of the Y allele were at decreased risk of developing PD at a young age, independently of pesticides and smoking.

Factors predicting improvement in motor disability in writer’s cramp treated with botulinum toxin

Objective: To identify factors predicting improvement in motor disability in writer’s cramp treated with botulinum toxin (BTX). Methods: 47 patients with writer’s cramp were treated with BTX and were evaluated by the same neurologists at initial referral, after each BTX injection, and when the effect of BTX was maximal at the time of the study. Patients and examiners simultaneously and independently rated the efficacy of BTX injections. Self assessment was a global clinical impression of the impact of treatment on writing quality, writing speed, writing errors, and legibility of handwriting; for objective assessment, the examiners used the Burke-Fahn-Marsden (BFM) scale. Results: On the BFM scale, there was a significant improvement (p<0.0001) in both severity and disability scores. Patients with a pronation/flexion pattern of dystonia showed the best and the most sustained improvement. Primary writing tremor was little improved. There was a correlation between the self assessment score and the Burke-Fahn-Marsden score. Benefit was maintained over time Conclusions: These results have implications for the identification of patients most likely to benefit from BTX injections.

Cigarette smoking and Parkinson's disease: A case–control study in a population characterized by a high prevalence of pesticide exposure

Epidemiological studies have been consistent in showing that cigarette smoking is inversely associated with Parkinsons disease (PD), whereas pesticide use is positively associated with PD. However, the relationship between PD and cigarette smoking remains poorly understood. Our objective was to study the relationship between cigarette smoking and PD in a population characterized by a high prevalence of pesticide exposure. This case–control study was carried out among subjects enrolled in the Mutualité Sociale Agricole, the French health insurance organization for workers connected to the agricultural world. We included 247 cases and 676 controls matched on age, sex, and region of residency. Information on smoking was obtained through in‐person interviews. Pesticide exposure was assessed using a case‐by‐case expert evaluation procedure. We found an inverse relationship between ever cigarette smoking and PD (odds ratio [OR] = 0.6; 95% confidence interval [CI] = 0.4–0.9). The strength of this association increased with the number of pack‐years. This relationship was present even when smoking was considered as long as 40 years before PD onset. An inverse association was also present among subjects professionally exposed to pesticides (OR = 0.5; 95% CI = 0.3–0.8) and was independent of the duration of exposure among men. We confirm the inverse association between cigarette smoking and PD in a population characterized by a high prevalence of professional pesticide exposure. The relationship between PD and cigarette smoking was not significantly modified or confounded by exposure to pesticides.

Association of polymorphisms in the Tau and Saitohin genes with Parkinson's disease

Background: The Saitohin gene has recently been identified in intron 9 of the Tau gene. Because an association between Parkinson’s disease and Tau has been described, Saitohin represents a candidate gene for Parkinson’s disease. Objective: To test these two genes for their association with Parkinson’s disease in a large community based case–control study. Results: Cases (n = 208) were more often homozygotes for the Tau H1 haplotype than controls (n = 483; odds ratio (OR) = 1.71 (95% confidence interval, 1.20 to 2.43); p = 0.003), and the saitohin Q allele was in complete linkage disequilibrium with the H1 haplotype. This association was stronger among cases with Parkinson’s disease onset below 65 years (⩽65 years: OR = 2.52 (1.49 to 4.25); p<0.001) than among those with older onset (>65 years: OR = 1.20 (0.73 to 1.98); p<0.47). Conclusions: The data suggest that there is a functional polymorphism at this locus involved in Parkinson’s disease.

Memantine therapy for Alzheimer disease in real-world practice: an observational study in a large representative sample of French patients.

Clinical trials have shown modest effects of memantine, an N-methyl-D aspartate receptor antagonist, in Alzheimer disease patients and memantine effectiveness in routine clinical practice needs to be established further. In 2003, memantine was recommended in France for Alzheimer disease patients with disease severity ranging from 15 to 3 on the mini-mental state examination at the first prescription. Our study aimed at describing memantine use in real-world practice in a cohort of 5283 memantine-treated patients (mean age: 80.1 y; women: 69.4%) randomly selected from the database of the national healthcare insurance, which covers 70% of the French elderly population. Mean follow-up after starting memantine prescription was 10.4 months (range: 1 to 20 mo). Patients were older and had a less severe cognitive impairment than patients included in the first controlled clinical trials. Memantine was prescribed with a cholinesterase inhibitor in 53.3% of cases. At 6 months, 26% of the patients had stopped memantine therapy (36% at 12 mo); conversely, patients who continued treatment were highly compliant. The 1-year mortality rate (12.5%) was similar for a comparative cohort of untreated demented patients and the memantine-treated ones. Approximately one-third of the memantine-treated patients did not strictly fit with the French summary of product characteristic recommendations for the first memantine prescription.

Evaluation of the impact of memantine treatment initiation on psychotropics use: a study from the French national health care database.

Background: Clinical studies reported that treatments for Alzheimer’s disease may have an impact on behavioral and psychiatric disorders. We tested the hypothesis that memantine treatment initiation modifies psychotropic medication in real-life practice patients. Methods: A 2-year follow-up cohort study was performed. A sample of patients treated in the general population, extracted from the database of the French national healthcare system (CNAM-TS), was examined. The sample included 4,600 memantine-treated patients (mean age 79.8 years, 69% women) randomly selected from the database of the CNAM-TS covering 69% of the French population aged 65 years and over. The follow-up rate was 95.0%. This database includes exhaustive data on drug consumption. We used interrupted time series analysis of the proportion of psychotropics users (all psychotropic drugs and specific categories) before and after onset of memantine. Results: There was a 39–50% regular increase in patients treated with psychotropic drugs before memantine initiation This increasing trend stopped after memantine initiation, the proportion of psychotropic users remaining stable around 53% up to the end. The trends before and after memantine onset were significantly different (p < 0.001). Conclusions: Our results suggest a temporal relationship between the onset of memantine and the stabilization of psychotropic drugs use in this large sample of elderly patients.

Mirror movements of the non-affected hand in hemiparkinsonian patients: a reflection of ipsilateral motor overactivity?

Mirror movements may result from a primary motor efferent system dysfunction with secondary motor reorganisation. A profound dysfunction of the motor pathways has been reported in Parkinson’s disease (PD) during execution of motor tasks.1,2 Recent PET studies have demonstrated overactivation of ipsilateral motor areas in hemiparkinsonian patients.3,4 However, the clinical expression of ipsilateral cortical activation was not specifically investigated in previous reports. In this study, we explored the presence of mirror movements (MM) during standardised unilateral hand tasks in a series of 21 hemiparkinsonian patients. Patients were divided into two groups: de novo patients (n=11), age 53.2 (7.5) years (mean (SD)), duration of evolution 1.8 years (range: 1–5 years), UPDRS III motor score 12 (5.7), affected side: left n=5, right n=6; and treated patients (n=10), age 59.8 (7.6) years, duration of evolution 3.7 (1.8) years (range: 2–7 years), UPDRS III motor score 14 (7.5), affected side: left n=4, right n=6, mean daily dose …

Determination of Angptl4 mRNA as a Diagnostic Marker of Primary and Metastatic Clear Cell Renal-Cell Carcinoma

Background We have previously shown that angiopoietin-like 4 (angptl4) mRNA, a hypoxia-inducible gene, is highly expressed in clear cell renal-cell carcinoma (ccRCC), the most common subtype of RCC for which no specific marker is available. We here investigated whether angptl4 mRNA 1) could be a useful diagnostic and/or prognostic marker of ccRCC in a large and comprehensive retrospective series, 2) induction is dependent on the VHL status of tumors. Methodology/Principal Findings Using in situ hybridization, we report that angptl4 mRNA is expressed in 100% of both sporadic (n = 102) and inherited (n = 6) primary ccRCCs, without any statistical association with nuclear grade (p = 0.39), tumor size (p = 0.09), stage grouping (p = 0.17), progression-free survival (p = 0.94), and overall survival (p = 0.80). Angptl4 mRNA was also expressed in 26 (87%) of 30 secondary ccRCCs but neither in any other secondary RCCs (n = 7). In contrast, angptl4 mRNA was neither expressed in 94% non-ccRCC renal tumors (papillary RCCs (n = 46), chromophobe RCCs (n = 28), and oncocytomas (n = 9)), nor in non-renal clear cell carcinomas (n = 39). Angptl4 expression was also examined in tumors associated (n = 23) or not associated (n = 66) with VHL disease. 40 (98%) hemangioblastomas expressed angptl4 whereas all pheochromocytomas (n = 23) and pancreatic tumors (n = 25) were angptl4-negative, whatever their VHL status. Conclusions/Significance Angptl4 mRNA expression was highly associated with ccRCC (p = 1.5 10−49, Chi square test) allowing to define its expression as a diagnosis marker for primary ccRCC. Moreover, angptl4 mRNA allows to discriminate the renal origin of metastases of clear-cell carcinomas arising from various organs. Finally, inactivation of VHL gene is neither necessary nor sufficient for angptl4 mRNA induction.