ContextThe human tau gene, which promotes assembly of neuronal microtubules, has been associated with several rare neurologic diseases that clinically include parkinsonian features. We recently observed linkage in idiopathic Parkinson disease (PD) to a region on chromosome 17q21 that contains the tau gene. These factors make tau a good candidate for investigation as a susceptibility gene for idiopathic PD, the most common form of the disease.ObjectiveTo investigate whether the tau gene is involved in idiopathic PD.Design, Setting, and ParticipantsAmong a sample of 1056 individuals from 235 families selected from 13 clinical centers in the United States and Australia and from a family ascertainment core center, we tested 5 single-nucleotide polymorphisms (SNPs) within the tau gene for association with PD, using family-based tests of association. Both affected (n = 426) and unaffected (n = 579) family members were included; 51 individuals had unclear PD status. Analyses were conducted to test individual SNPs and SNP haplotypes within the tau gene.Main Outcome MeasureFamily-based tests of association, calculated using asymptotic distributions.ResultsAnalysis of association between the SNPs and PD yielded significant evidence of association for 3 of the 5 SNPs tested: SNP 3, P = .03; SNP 9i, P = .04; and SNP 11, P = .04. The 2 other SNPs did not show evidence of significant association (SNP 9ii, P = .11, and SNP 9iii, P = .87). Strong evidence of association was found with haplotype analysis, with a positive association with one haplotype (P = .009) and a negative association with another haplotype (P = .007). Substantial linkage disequilibrium (P<.001) was detected between 4 of the 5 SNPs (SNPs 3, 9i, 9ii, and 11).ConclusionsThis integrated approach of genetic linkage and positional association analyses implicates tau as a susceptibility gene for idiopathic PD.
The "European Prospective Investigation into Cancer and Nutrition" cohort (EPIC-Europe) is a prospective study including ~520,000 participants recruited across Europe (1991-2000) with in-depth baseline data on nutritional, lifestyle, medical, and anthropometric variables, and baseline blood samples. Here we introduce EPIC4ND, a case-cohort study within EPIC designed to identify biomarkers predicting a future onset of dementia, Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS). EPIC4ND comprises 6,346 initially non-diseased participants (aged 35-80 years, mean age at baseline: 54 +/- 9, 65% women) with up to 30 years of follow-up and data on at least one omics domain available from pre-disease blood samples. EPIC4ND includes 4,604 subcohort members (4,447 non-cases and 157 incident cases) and 1,742 additional incident cases ascertained from the broader EPIC cohort. Among the incident cases, there are 1,190 dementia cases (818 AD), 534 PD cases, and 199 ALS cases. Additionally, 72 prevalent PD cases and 118 incident Parkinsonism cases are available for comparison. Molecular data generated encompass proteomics, genome-wide DNA methylation, and SNP genotyping with 4,065 EPIC4ND participants (2,497 non-cases, 1,568 incident cases) having data on all three domains. Smaller studies include data on metals, metabolites, and environmental chemicals, while ongoing efforts focus on ultrasensitive targeted biomarker measurements and small RNA sequencing. Genome-wide association studies and analyses of epidemiological risk factors validate the dataset by confirming many known risk factors. Leveraging these extensive pre-disease multi-layered omics data offers a unique opportunity to identify biomarker signatures predicting neurodegenerative diseases and to explore their interplay with epidemiological risk factors.
<a><b>Objective:</b></a> Type 2 diabetes is an established risk factor for dementia. However, the roles of glycaemic control and diabetic complications in the development of dementia have been less well substantiated. This large-scale cohort study aims to examine associations of longitudinal HbA1c levels and diabetic complications with the risk of dementia incidence among patients with type 2 diabetes. <p><b>Research Design and Methods: </b>Data of eligible diabetes patients, aged over 50 years in the UK Clinical Practice Research Datalink from 1987 to 2018, were analysed. Time-varying Cox regressions were used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for dementia risk.<b></b></p> <p><b>Results: </b>Among 457,902 diabetes patients, 28,627 (6.3%) incident dementia cases were observed during a median of six years follow-up. Patients with recorded hypoglycaemic events or microvascular complications were at higher risk of dementia incidence compared to those without such complications (HR [95% CI]=1.30 [1.22-1.39] and 1.10 [1.06-1.14], respectively). The HbA1c level, modelled as a time-varying exposure, was associated with increased dementia risk (HR=1.08, 95% CI: 1.07-1.09 per 1% HbA1c increment) among 372,287 diabetes patients with post-diagnosis HbA1c records. Similarly, higher coefficient of variation of HbA1c during the initial three years of follow-up was associated with higher subsequent dementia risk (HR=1.03, 95% CI: 1.01-1.04 per 1 SD increment).</p> <p><b>Conclusions: </b>Higher or unstable HbA1c levels and the presence of diabetic complications in patients with type 2 diabetes are associated with increased dementia risk. Effective management of glycaemia might have significant role in maintaining cognitive health among older adults with diabetes.</p>
Type 2 diabetes (T2D) and dementia are both costly and rapidly growing global health crises, and major contributors to comorbidities and mortality. Recent improvements in treatments for T2D have improved survival, but people with T2D are subjected to a two-fold increase in risk of dementia. Associations of cardio-metabolic factors with dementia among patients with type 2 diabetes (T2D) are uncertain, and possibly driven by reverse causation, as dementia develops progressively long before diagnosis. Thus, assessing longitudinal trajectories over longer-follow up may help elucidate this relationship.
Methods
We identified 227,580 patients with T2D aged >42 years between 1st January 1999 and 31st December 2018. Annual mean levels of eight routinely measured cardiometabolic factors were extracted from the Clinical Practice Research Datalink (England). Multivariable-adjusted multilevel piecewise and non-piecewise growth curve models assessed retrospective trajectories of cardio-metabolic factors among patients with T2D by dementia status from up to 19 years before dementia diagnosis (dementia) or last contact with healthcare (no dementia) at baseline.
Results
23,319 patients developed dementia; mean (SD) follow-up was 10.0 (5.8) years. Patients with dementia at baseline had a lower systolic blood pressure (SBP), body mass index (BMI), but higher fasting plasma glucose (FPG), HbA1c, and cholesterol compared to patients without dementia. In the dementia group, mean SBP increased 16–19 years before dementia diagnosis compared with patients without dementia, but declined more steeply from 16 years before diagnosis (-0.16 (95% CI -0.18, -0.14) mmHg per year). Diastolic blood pressure generally declined at similar rates, but levels at baseline by dementia status was not significantly different (0.11 mmHg, p=0.063). Mean FPG and HbA1c were generally higher among patients with dementia throughout follow-up, ranging between 0.09 to 0.21 mmol/L (p<0.03) and 0.66 to 5.07 mmol/mol (p<0.005) respectively. Mean BMI followed a steeper non-linear decline from 11 years before diagnosis in the dementia group, where group differences ranged between -0.22 to -1.26 kg/m2 (p<0.001). Mean blood lipid levels (total cholesterol, low-density lipoprotein, high-density lipoprotein) were generally higher in the dementia group compared with those without dementia and followed similar patterns of change.
Conclusion
Marked changes in levels of cardiometabolic factors are apparent up to two decades prior to diagnosis of dementia, and could be potential targets for early intervention to prevent and delay the onset of dementia among older adults.
A random sample of 5% of NSW general practitioners was surveyed in December 1986 regarding their attitudes to health promotion in clinical practice. The results were compared with those of simultaneous surveys of trainee general practitioners and fourth-year medical students. Smoking, alcohol and weight reduction were the health behaviours that were considered by general practitioners to be the most difficult to change. More general practitioners than did students or general-practitioner trainees reported finding less difficulty in changing health behaviours. More than three-quarters of the general practitioners were in favour of promoting health in their practices. A commonly reported barrier was the current Medicare financing arrangements for preventive practice. Other barriers included a lack of time for preventive practice. The complaint of a lack of training was expressed commonly; half the sample was willing to participate in advanced training in health promotion that would be organized by The Royal Australian College of General Practitioners.
Background/Aims: Large epidemiological prospective studies represent an important opportunity for investigating risk factors for rare diseases such as Parkinson's disease (PD). Here we describe the procedures we used for ascertaining PD cases in the EPIC (European Prospective Investigation into Cancer and Nutrition) study. Methods: The following three-phase procedure was used: (1) elaboration of a NeuroEPIC4PD template for clinical data collection, (2) identification of all potential PD cases via record linkage and (3) validation of the diagnosis through clinical record revision, in a population of 220,494 subjects recruited in 7 European countries. All cases were labelled with the NeuroEPIC4PD diagnoses of ‘definite', ‘very likely', ‘probable', or ‘possible' PD. Results: A total of 881 PD cases were identified, with over 2,741,780 person-years of follow-up (199 definite, 275 very likely, 146 probable, and 261 possible). Of these, 734 were incident cases. The mean age at diagnosis was 67.9 years (SD 9.2) and 458 patients (52.0%) were men. Bradykinesia was the most frequent presenting motor sign (76.5%). Tremor-dominant and akinetic rigid forms of PD were the most common types of PD. A total of 289 patients (32.8%) were dead at the time of the last follow-up. Conclusions: This exercise proved that it is feasible to ascertain PD in large population-based cohort studies and offers a potential framework to be replicated in similar studies.
There is limited information on people with minimal cognitive changes who are likely to progress to both the earliest stage of cognitive impairment due to Alzheimer's disease (AD) and then clinically evident dementia of the Alzheimer's type. Characterizing change in cognition is essential to identify opportunity for intervention at the earliest stage of disease. This project utilizes an ongoing project, CHARIOT (Cognitive Health in Ageing Register: Investigational, Observational and Trial studies in dementia research), at the Imperial College London. CHARIOT is a community-based register of individuals, over age 60 and without dementia, recruited from surgeries of General Practitioners in the London area. Participants undergo a series of neuropsychological evaluations to characterize the patterns of cognitive change and their inter-relationship in the earliest stages of cognitive impairment. In addition, how changes relate to the clinical presentation of cognitive impairment of the Alzheimer's type may be evaluated over time. An opportunity is possible to identify and characterize individuals with different likelihoods of progressing along different clinical paths, which may form a framework for evaluation of interventions. The study is a prospective single center cohort study of approximately 700 participants self-referred or recruited from the CHARIOT register who will be followed for up to 4 years. The goals of the investigation are to better understand the natural history of cognitive and functional changes in participants at risk for MCI-AD, as well as develop a well-characterized, longitudinally followed prospective readiness cohort for future early AD clinical trials. To-date approximately 500 participants have been enrolled in CHARIOT-PRO. The average age is approximately 70-years-old, >50% have a college education or higher, women are more likely to enroll than men and most are Caucasian (>95%). Approximately 75% are retired, with almost equal split on marital status. Approximately two-thirds are APOE-. Overall, this study is designed as the largest head-to-head study of clinical outcome assessments collecting real world information regarding prognostic factors, disease course, functional decline and disease burden on participants in the earliest stage of disease, that also is developing a well-characterized, longitudinally followed prospective readiness cohort for future early AD clinical trials.
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