Abstract Background & Aims Studies have shown that omega-3 polyunsaturated fatty acids (PUFAs) are associated with brain, cardiovascular and immune function, as well as physical performance and bone ...health in older adults. So far, few studies have highlighted the associations between PUFA status and performance-based tests of physical function. To study the associations between the omega-3 index (red blood cell (RBC) membrane content of omega-3 PUFAs, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) and physical performance measured with the Short Physical Performance Battery (SPPB) in a sample of community-dwelling older adults. Design Cross-sectional study using the baseline data of the Multidomain Alzheimer’s Disease Trial (MAPT), a randomized, placebo-controlled trial. Participants and Measurements 1449 participants with available data on PUFAs were included. Omega-3 index and Short Physical Performance Battery (SPPB) scores were measured at enrollment and the omega-3 index expressed as the percentage of total fatty acid content was calculated. We also dichotomized the omega-3 index as low (lowest quartile) vs. high (three upper quartiles). Results Participants were 75.2 (± 4.4) years old, 64.5% were female. Bivariate analyses found that participants who were in the lowest omega-3 index quartile (Q1) had a SPPB score significantly lower than participants in the three other quartiles (Q2-Q4). However, adjusted (for age, gender, cognitive function, depressive status, Body Mass Index and grip strength) multiple linear regression showed that the omega-3 index-SPPB score association did not reach statistical significance β= - 0.166; (- 0.346; 0.013); p=0.07 in our sample. Conclusion This cross-sectional study found that participants with a low omega-3 index had worse performance-based test results of physical function than people with a high omega-3 index, but this association did not reach statistical significance once confounders were controlled for. Studies looking at the over-time associations between PUFA status and physical performance changes may shed more light on this topic.
We studied variables influencing category and letter fluency in a large population-based sample of elderly participants. Letter and category fluency tasks were administered to 1133 unselected ...non-demented elderly participants in the Paquid cohort on normal and pathological aging. Age, education, principal lifetime occupation and depressive symptomatology independently influenced both category and letter fluency, while gender influenced only category fluency. A conceptualization measure (similarities) was found to influence fluency results mostly through education and prior occupation.
Alzheimer's disease gradually affects several components including the cerebral dimension with brain atrophies, the cognitive dimension with a decline in various functions and the functional ...dimension with impairment in the daily living activities. Understanding how such dimensions interconnect is crucial for AD research. However it requires to simultaneously capture the dynamic and multidimensional aspects, and to explore temporal relationships between dimensions. We propose an original dynamic structural model that accounts for all these features. The model defines dimensions as latent processes and combines a multivariate linear mixed model and a system of difference equations to model trajectories and temporal relationships between latent processes in finely discrete time. Dimensions are simultaneously related to their observed (possibly multivariate) markers through nonlinear equations of observation. Parameters are estimated in the maximum likelihood framework enjoying a closed form for the likelihood. We demonstrate in a simulation study that this dynamic model in discrete time benefits the same causal interpretation of temporal relationships as models defined in continuous time as long as the discretization step remains small. The model is then applied to the data of the Alzheimer's Disease Neuroimaging Initiative. Three longitudinal dimensions (cerebral anatomy, cognitive ability and functional autonomy) measured by 6 markers are analyzed and their temporal structure is contrasted between different clinical stages of Alzheimer's disease. Keywords: causality, difference equations, latent process, longitudinal data, mixed models, multivariate data.
Background
Little is known about the prodromal phase of Dementia with Lewy bodies (DLB). In a large prospective cohort of patients attending memory clinics presenting either subjective cognitive ...impairment (SCI) and mild neurocognitive impairment (MCI) patients, we undertook an ancillary study aiming at detecting early DLB in a longitudinal framework.
Method
We conducted a french nationwide prospective cohort of patients with cognitive complaints and a minimum follow‐up of 4 years. Participants in the Memento cohort study were recruited for either isolated subjective cognitive impairment (SCI) or mild neurocognitive impairment (MCI). Among them, patients from 12 memory resource and research centers, representing eight hundred ninety‐two patients were included in the Lewy sub‐study. Probable Pro‐DLB diagnosis was done using a two‐criteria cut‐off score among the four core clinical features of Dementia with Lewy bodies. This Pro‐DLB group was compared to two other groups: one without any core symptoms (NS group), and the one with one core symptom (1S group). A comprehensive cognitive battery, brain 3D volumetric MRI, CSF, FDG PET and amyloid PET were done.
Result
The pro‐DLB group comprised 148 patients (16.6%). Compared to the other two groups, the neuropsychological profile of the pro‐DLB group showed, regarding cognition, more multidomain (59.8%) MCI with slower processing speed, semantic and neurovisual impairment, and regarding behavior, a higher proportion of patients with depression, anxiety, and apathy. Pro‐DLB patients also presented more autonomic symptoms, including lower libido, constipation, rhinorrhea, sicca syndrome, and photophobia. The Pro‐DLB group had isolated lower P‐Tau and no difference in terms of amyloid PET and FDG PET. Brain MRI analysis showed widening of sulci including fronto‐insular, occipital and olfactory sulci (FDR corrected). Evolution to dementia was not different between the three groups after 4 years of follow‐up.
Conclusion
Patients with pro‐DLB represented 16.6% of SCI and MCI patients, a finding consistent with the proportion observed at the stage of dementia. In addition to the core symptoms, pro‐DLB patients presented cognitive, behavioral and autonomic symptoms. Biomarkers confirmed the non‐Alzheimer profile. The occipital, fronto‐insular, and olfactory bulb involvement on brain MRI was consistent with the symptoms and known neuropathology.
Abstract
Background
Little is known about the prodromal phase of Dementia with Lewy bodies (DLB). In a large prospective cohort of patients attending memory clinics presenting either subjective ...cognitive impairment (SCI) and mild neurocognitive impairment (MCI) patients, we undertook an ancillary study aiming at detecting early DLB in a longitudinal framework.
Method
We conducted a french nationwide prospective cohort of patients with cognitive complaints and a minimum follow‐up of 4 years. Participants in the Memento cohort study were recruited for either isolated subjective cognitive impairment (SCI) or mild neurocognitive impairment (MCI). Among them, patients from 12 memory resource and research centers, representing eight hundred ninety‐two patients were included in the Lewy sub‐study. Probable Pro‐DLB diagnosis was done using a two‐criteria cut‐off score among the four core clinical features of Dementia with Lewy bodies. This Pro‐DLB group was compared to two other groups: one without any core symptoms (NS group), and the one with one core symptom (1S group). A comprehensive cognitive battery, brain 3D volumetric MRI, CSF, FDG PET and amyloid PET were done.
Result
The pro‐DLB group comprised 148 patients (16.6%). Compared to the other two groups, the neuropsychological profile of the pro‐DLB group showed, regarding cognition, more multidomain (59.8%) MCI with slower processing speed, semantic and neurovisual impairment, and regarding behavior, a higher proportion of patients with depression, anxiety, and apathy. Pro‐DLB patients also presented more autonomic symptoms, including lower libido, constipation, rhinorrhea, sicca syndrome, and photophobia. The Pro‐DLB group had isolated lower P‐Tau and no difference in terms of amyloid PET and FDG PET. Brain MRI analysis showed widening of sulci including fronto‐insular, occipital and olfactory sulci (FDR corrected). Evolution to dementia was not different between the three groups after 4 years of follow‐up.
Conclusion
Patients with pro‐DLB represented 16.6% of SCI and MCI patients, a finding consistent with the proportion observed at the stage of dementia. In addition to the core symptoms, pro‐DLB patients presented cognitive, behavioral and autonomic symptoms. Biomarkers confirmed the non‐Alzheimer profile. The occipital, fronto‐insular, and olfactory bulb involvement on brain MRI was consistent with the symptoms and known neuropathology.
Background
Late‐life aging is often associated with appetite reduction and weight loss. Physical activity (PA) may prevent these processes, but the molecular mechanisms involved remain elusive. The ...present study investigated the putative mediating aspect of growth differentiation factor 15 (GDF‐15), a stress signalling protein involved in aging, exercise and appetite control, on the association between PA and late‐life‐associated weight loss.
Methods
One thousand eighty‐three healthy adults (63.8% women) aged 70 years and over who participated in the Multidomain Alzheimer Preventive Trial were included. Bodyweight (kg) and PA levels (square root of metabolic equivalent of task‐min/week) were assessed repeatedly from baseline to the 3‐year visit, whereas plasma GDF‐15 (pg/mL) was measured at the 1‐year visit. Multiple linear regressions were performed to test the association between first‐year mean PA level, 1‐year visit GDF‐15 concentration and subsequent bodyweight changes. Mediation analyses were used to investigate whether GDF‐15 mediated the association between first‐year mean PA levels and consecutive bodyweight changes.
Results
Multiple regression analyses demonstrated that higher first‐year mean PA levels significantly predicted lower GDF‐15 and bodyweight at 1 year (B = −2.22; SE = 0.79; P = 0.005). In addition, higher 1‐year visit GDF‐15 levels were associated with faster subsequent bodyweight loss (Time × GDF‐15 interaction B = −0.0004; SE = 0.0001; P = 0.003). Mediation analyses confirmed that GDF‐15 mediated the association between first‐year mean PA levels and subsequent bodyweight changes (mediated effect ab = 0.0018; bootstrap SE = 0.001; P < 0.05) and revealed that mean PA had no direct effect on subsequent bodyweight changes (c′ = 0.006; SE = 0.008; P > 0.05).
Conclusions
This study suggests that GDF‐15 may be one of the molecules mediating the link between PA and late‐life weight loss, but mechanistic studies are necessary to further support the present findings.
The rate of cognitive decline in Alzheimer’s disease (AD) varies considerably between individuals, with some subjects showing substantial deterioration and others showing little or no change over the ...course of the disease. These wide variations support the relatively new concept of Rapid Cognitive Decline (RCD). Patients with an accelerated rate of cognitive decline have showed to present a worse evolution in terms of mortality, loss of autonomy and institutionalisation. The conclusions from RCD studies conducted in the past years remain very heterogeneous and sometimes contradictory. This is possibly due to methodological differences, mainly the different “a priori” definitions of RCD used to identify rapid decliners. Consequently of this, there is considerable variation in reported frequency of patients with RCD which may vary from 9.5% to 54%. The lack of both consensus definition and consensual clinical assessment tools is one of the major barriers for establishing an appropriated management of rapid decliners in clinical practice. Presently, management of rapid decliners in AD remains to be a challenge waiting to better know predictive factors of a RCD. To date no specific guidelines exist to follow-up or to treat patients with this condition. This consensus paper proposes the loss of 3 points or greater in Mini-Mental State Examination (MMSE) during six months as an empirical definition of rapid cognitive decline to be used in routine medical practice and to be relevant for clinical-decision making in patients with mild to moderately-severe AD.
Next-generation sequencing technologies made it possible to assay the effect of rare variants on complex diseases. As an extension of the "common disease-common variant" paradigm, rare variant ...studies are necessary to get a more complete insight into the genetic architecture of human traits. Association studies of these rare variations show new challenges in terms of statistical analysis. Due to their low frequency, rare variants must be tested by groups. This approach is then hindered by the fact that an unknown proportion of the variants could be neutral. The risk level of a rare variation may be determined by its impact but also by its position in the protein sequence. More generally, the molecular mechanisms underlying the disease architecture may involve specific protein domains or inter-genic regulatory regions. While a large variety of methods are optimizing functionality weights for each single marker, few evaluate variant position differences between cases and controls. Here, we propose a test called DoEstRare, which aims to simultaneously detect clusters of disease risk variants and global allele frequency differences in genomic regions. This test estimates, for cases and controls, variant position densities in the genetic region by a kernel method, weighted by a function of allele frequencies. We compared DoEstRare with previously published strategies through simulation studies as well as re-analysis of real datasets. Based on simulation under various scenarios, DoEstRare was the sole to consistently show highest performance, in terms of type I error and power both when variants were clustered or not. DoEstRare was also applied to Brugada syndrome and early-onset Alzheimer's disease data and provided complementary results to other existing tests. DoEstRare, by integrating variant position information, gives new opportunities to explain disease susceptibility. DoEstRare is implemented in a user-friendly R package.
PDF
