Alexis Elbaz

Timing of onset of cognitive decline: results from Whitehall II prospective cohort study.

Objectives To estimate 10 year decline in cognitive function from longitudinal data in a middle aged cohort and to examine whether age cohorts can be compared with cross sectional data to infer the effect of age on cognitive decline. Design Prospective cohort study. At study inception in 1985-8, there were 10 308 participants, representing a recruitment rate of 73%. Setting Civil service departments in London, United Kingdom. Participants 5198 men and 2192 women, aged 45-70 at the beginning of cognitive testing in 1997-9. Main outcome measure Tests of memory, reasoning, vocabulary, and phonemic and semantic fluency, assessed three times over 10 years. Results All cognitive scores, except vocabulary, declined in all five age categories (age 45-49, 50-54, 55-59, 60-64, and 65-70 at baseline), with evidence of faster decline in older people. In men, the 10 year decline, shown as change/range of test×100, in reasoning was −3.6% (95% confidence interval −4.1% to −3.0%) in those aged 45-49 at baseline and −9.6% (−10.6% to −8.6%) in those aged 65-70. In women, the corresponding decline was −3.6% (−4.6% to −2.7%) and −7.4% (−9.1% to −5.7%). Comparisons of longitudinal and cross sectional effects of age suggest that the latter overestimate decline in women because of cohort differences in education. For example, in women aged 45-49 the longitudinal analysis showed reasoning to have declined by −3.6% (−4.5% to −2.8%) but the cross sectional effects suggested a decline of −11.4% (−14.0% to −8.9%). Conclusions Cognitive decline is already evident in middle age (age 45-49).

UCHL1 Is a Parkinson's Disease Susceptibility Gene

An Erratum has been published for this article in Ann Neurol 2004;55:899.

Common Carotid Artery Intima-Media Thickness and Brain Infarction The Étude du Profil Génétique de l’Infarctus Cérébral (GÉNIC) Case-Control Study

Background-The use of intima-media thickness (IMT) as an outcome measure in observational studies and intervention trials relies on the view that it reflects early stages of atherosclerosis and cardiovascular risk. There is little knowledge concerning the relation between IMT and brain infarction (BI). Methods and Results-We investigated the relation of IMT with BI and its subtypes in 470 cases and 463 controls. Cases with BI proven by MRI were consecutively recruited and classified into subtypes by cause of BI. Controls were recruited among individuals hospitalized at the same institutions and matched for age, sex, and center. IMT was measured at the far wall of both common carotid arteries (CCA) using an automatic detection system. Adventitia-to-adventitia diameters and CCA-IMT were measured on transverse views; lumen diameter was computed using these measures. Mean (±SEM) CCA-IMT was higher in cases (0.797±0.006 mm) than in controls (0.735±0.006 mm; P<0.0001). This difference remained after adjustment for lumen diameter and when analyses were restricted to subjects free of previous cardiovascular or cerebrovascular history. The difference in CCA-IMT between cases and controls was significant in the main subtypes. The risk of BI increased continuously with increasing CCA-IMT. The odds ratio per SD increase (0.150 mm) was 1.82 (95% confidence interval, 1.54 to 2.15); adjustment for cardiovascular risk factors slightly attenuated this relation (odds ratio, 1.73; 95% confidence interval, 1.45 to 2.07). Conclusions-An increased CCA-IMT was associated with BI, both overall and in the main subtypes. An increased IMT may help select patients at high risk for BI.

Risk tables for parkinsonism and Parkinson's disease

We applied the incidence rates of parkinsonism and Parkinsons disease (PD) from Olmsted County, MN (1976-1990) to a hypothetical cohort undergoing the mortality rates observed in Minnesota, and computed the lifetime risk and the remaining lifetime risk of developing parkinsonism and PD. These risks were compared to cumulative incidences that do not take competing risks of death into account. The lifetime risk of developing parkinsonism from birth was 4.4% for men and 3.7% for women (ratio = 1.2). The corresponding risk of developing PD was 2.0% for men and 1.3% for women (ratio = 1.5). Because of the opposite effect of higher incidence and higher mortality rates in men, the lifetime risks were only slightly higher in men than in women. Lifetime cumulative incidences were consistently higher than lifetime risks; this difference was more pronounced in men and in older subjects. Lifetime risk estimates are useful in clinical practice, epidemiologic research, and public health.

Slow walking speed and cardiovascular death in well functioning older adults: prospective cohort study.

Objective To study the relation between low walking speed and the risk of death in older people, both overall and with regard to the main causes of death. Design Prospective cohort study. Setting Dijon centre (France) of the Three-City study. Participants 3208 men and women aged ≥65 living in the community, recruited from 1999 to 2001, and followed for an average of 5.1 years. Main outcome measures Mortality, overall and according to the main causes of death, by thirds of baseline walking speed (measured at maximum speed over six metres), adjusted for several potential confounders; Kaplan-Meier survival curves by thirds of baseline walking speed. Vital status during follow-up. Causes of death. Results During 16 414 person years of follow-up, 209 participants died (99 from cancer, 59 from cardiovascular disease, 51 from other causes). Participants in the lowest third of baseline walking speed had an increased risk of death (hazard ratio 1.44, 95% confidence interval 1.03 to 1.99) compared with the upper thirds. Analyses for specific causes of death showed that participants with low walking speed had about a threefold increased risk of cardiovascular death (2.92, 1.46 to 5.84) compared with participants who walked faster. There was no relation with cancer mortality (1.03, 0.65 to 1.70). In stratified analyses, cardiovascular mortality was increased across various strata defined by sex, median age, median body mass index (BMI), and level of physical activity. Conclusion Slow walking speed in older people is strongly associated with an increased risk of cardiovascular mortality.

Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: A case-control study

BACKGROUND Background The leucine-rich repeat kinase 2 gene (LRRK2) harbours highly penetrant mutations that are linked to familial parkinsonism. However, the extent of its polymorphic variability in relation to risk of Parkinsons disease (PD) has not been assessed systematically. We therefore assessed the frequency of LRRK2 exonic variants in individuals with and without PD, to investigate the role of the variants in PD susceptibility. METHODS LRRK2 was genotyped in patients with PD and controls from three series (white, Asian, and Arab-Berber) from sites participating in the Genetic Epidemiology of Parkinsons Disease Consortium. Genotyping was done for exonic variants of LRRK2 that were identified through searches of literature and the personal communications of consortium members. Associations with PD were assessed by use of logistic regression models. For variants that had a minor allele frequency of 0·5% or greater, single variant associations were assessed, whereas for rarer variants information was collapsed across variants. FINDINGS 121 exonic LRRK2 variants were assessed in 15 540 individuals: 6995 white patients with PD and 5595 controls, 1376 Asian patients and 962 controls, and 240 Arab-Berber patients and 372 controls. After exclusion of carriers of known pathogenic mutations, new independent risk associations were identified for polymorphic variants in white individuals (M1646T, odds ratio 1·43, 95% CI 1·15-1·78; p=0·0012) and Asian individuals (A419V, 2·27, 1·35-3·83; p=0·0011). A protective haplotype (N551K-R1398H-K1423K) was noted at a frequency greater than 5% in the white and Asian series, with a similar finding in the Arab-Berber series (combined odds ratio 0·82, 0·72-0·94; p=0·0043). Of the two previously reported Asian risk variants, G2385R was associated with disease (1·73, 1·20-2·49; p=0·0026), but no association was noted for R1628P (0·62, 0·36-1·07; p=0·087). In the Arab-Berber series, Y2189C showed potential evidence of risk association with PD (4·48, 1·33-15·09; p=0·012). INTERPRETATION The results for LRRK2 show that several rare and common genetic variants in the same gene can have independent effects on disease risk. LRRK2, and the pathway in which it functions, is important in the cause and pathogenesis of PD in a greater proportion of patients with this disease than previously believed. These results will help discriminate those patients who will benefit most from therapies targeted at LRRK2 pathogenic activity. FUNDING Michael J Fox Foundation and National Institutes of Health.

Possible relation of atypical parkinsonism in the French West Indies with consumption of tropical plants: a case-control study

BACKGROUND In Europe and North America, Parkinsons disease is the major form of parkinsonism; less than 4% of cases are progressive supranuclear palsy (PSP) and about 20% are atypical parkinsonism. The distribution of these subgroups is different in the French West Indies. We aimed to define the clinical and demographic specificity of these disorders in Guadeloupe and to investigate a postulated link with consumption of herbal tea and fruits from the Annonaceae family (Annona muricata and Annona squamosa), which contain neurotoxic benzyltetrahydroisoquinoline alkaloids. METHODS Between September, 1996, and August, 1998, 87 consecutive patients with parkinsonism were referred to the single neurological department in Guadeloupe. After detailed clinical, neurophysiological, cognitive, and neuroradiological assessment, they were classified by generally accepted criteria as having Parkinsons disease, PSP, or atypical parkinsonism. We compared the amount of tropical fruits and herbal tea consumed by the various parkinsonian subgroups and by frequency-matched controls (patients with benign symptoms and no neurodegenerative disease). FINDINGS Of the 87 patients, 22 had Parkinsons disease, 31 had PSP, 30 had atypical parkinsonism, and four had atypical parkinsonism associated with motor neuron disease, 44 of the patients with PSP or atypical parkinsonism were male. The patients with atypical parkinsonism had symmetrical rigidity and bradykinesia, and no levodopa peak-dose dyskinesias. Patients with PSP differed from those with atypical parkinsonism because they had supranuclear vertical down-gaze palsy, severe gait and balance problems, and frontal-lobe syndrome. 29 patients with PSP reported regular consumption of pawpaw fruit, and 26 drank herbal tea. 30 patients with atypical parkinsonism reported regular consumption of pawpaw fruit, and 24 drank herbal tea. Both of these groups consumed significantly more fruit and herbal tea than patients with Parkinsons disease (fruit: odds ratio 23.6; herbal tea: 28.2); and controls (fruit: 20.7; herbal tea: 6.48). INTERPRETATION Our study confirms the over-representation of atypical parkinsonism and PSP in patients with parkinsonism in the French West Indies. Chronic exposure to neurotoxic alkaloids could be an important aetiological factor because these compounds induce parkinsonism in animals. A larger epidemiological study, to clarify the link between these fruits with atypical parkinsonism and PSP, is proposed.

Professional exposure to pesticides and Parkinson disease.

We studied the relation between Parkinson disease (PD) and professional exposure to pesticides in a community‐based case‐control study conducted in a population characterized by a high prevalence of exposure. Our objective was to investigate the role of specific pesticide families and to perform dose‐effect analyses.

Common variants at 12q14 and 12q24 are associated with hippocampal volume

Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimers disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of <4.0 × 10−7. In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 × 10−11) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 × 10−11). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 × 10−7) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 × 10−7); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794). The SNP in ASTN2 also showed suggestive association with decline in cognition in a largely independent sample (n = 1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8) and neuronal migration (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4), indicating new genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia.

Familial aggregation of Parkinson's disease : A population-based case-control study in Europe

Objective: To investigate the familial aggregation of PD in a large collaborative population-based case-control study. Background: Most previous case-control studies of the familial aggregation of PD have been hospital- or clinic-based. Methods: We included 219 prevalent cases ascertained in three European populations (centers), using a two-phase design consisting of screening and examination by a neurologist. Each case was matched by age, sex, and center to three controls drawn from the same populations (n = 657). Presence of PD among first-degree relatives (parents and siblings) was determined using the family history approach for 175 cases and 481 controls. Results: Overall, a positive family history (at least one parent or sibling affected by PD) was reported in 10.3% of patients and 3.5% of controls (odds ratio [OR] = 3.2; 95% confidence interval [CI] = 1.6 to 6.6). A similar association was observed when analyses were restricted to nondemented patients and controls (OR = 3.9; 95% CI = 1.7 to 8.7) or to newly diagnosed patients (OR = 3.3; 95% CI = 0.9 to 11.9). We found a significant trend of increasing risk with increasing number of affected relatives (p = 0.003). Analyses stratified by age showed a stronger association for younger PD patients (OR = 7.6; 95% CI = 1.5 to 38.9) than for older patients (OR = 2.5; 95% CI = 1.1 to 5.7). Conclusions: In this large sample of prevalent PD patients and population-matched controls, PD significantly aggregates in families, with the strength of the association being age-dependent. Therefore, familial factors, which can be genetic, environmental, or both, play a role in PD.