Summary Background No large trials have been done to investigate the efficacy of an intervention combining a specific compound and several lifestyle interventions compared with placebo for the ...prevention of cognitive decline. We tested the effect of omega 3 polyunsaturated fatty acid supplementation and a multidomain intervention (physical activity, cognitive training, and nutritional advice), alone or in combination, compared with placebo, on cognitive decline. Methods The Multidomain Alzheimer Preventive Trial was a 3-year, multicentre, randomised, placebo-controlled superiority trial with four parallel groups at 13 memory centres in France and Monaco. Participants were non-demented, aged 70 years or older, and community-dwelling, and had either relayed a spontaneous memory complaint to their physician, limitations in one instrumental activity of daily living, or slow gait speed. They were randomly assigned (1:1:1:1) to either the multidomain intervention (43 group sessions integrating cognitive training, physical activity, and nutrition, and three preventive consultations) plus omega 3 polyunsaturated fatty acids (ie, two capsules a day providing a total daily dose of 800 mg docosahexaenoic acid and 225 mg eicosapentaenoic acid), the multidomain intervention plus placebo, omega 3 polyunsaturated fatty acids alone, or placebo alone. A computer-generated randomisation procedure was used to stratify patients by centre. All participants and study staff were blinded to polyunsaturated fatty acid or placebo assignment, but were unblinded to the multidomain intervention component. Assessment of cognitive outcomes was done by independent neuropsychologists blinded to group assignment. The primary outcome was change from baseline to 36 months on a composite Z score combining four cognitive tests (free and total recall of the Free and Cued Selective Reminding test, ten Mini-Mental State Examination orientation items, Digit Symbol Substitution Test, and Category Naming Test) in the modified intention-to-treat population. The trial was registered with ClinicalTrials.gov ( NCT00672685 ). Findings 1680 participants were enrolled and randomly allocated between May 30, 2008, and Feb 24, 2011. In the modified intention-to-treat population (n=1525), there were no significant differences in 3-year cognitive decline between any of the three intervention groups and the placebo group. Between-group differences compared with placebo were 0·093 (95% CI 0·001 to 0·184; adjusted p=0·142) for the combined intervention group, 0·079 (−0·012 to 0·170; 0·179) for the multidomain intervention plus placebo group, and 0·011 (−0·081 to 0·103; 0·812) for the omega 3 polyunsaturated fatty acids group. 146 (36%) participants in the multidomain plus polyunsaturated fatty acids group, 142 (34%) in the multidomain plus placebo group, 134 (33%) in the polyunsaturated fatty acids group, and 133 (32%) in the placebo group had at least one serious emerging adverse event. Four treatment-related deaths were recorded (two in the multidomain plus placebo group and two in the placebo group). The interventions did not raise any safety concerns and there were no differences between groups in serious or other adverse events. Interpretation The multidomain intervention and polyunsaturated fatty acids, either alone or in combination, had no significant effects on cognitive decline over 3 years in elderly people with memory complaints. An effective multidomain intervention strategy to prevent or delay cognitive impairment and the target population remain to be determined, particularly in real-world settings. Funding French Ministry of Health, Pierre Fabre Research Institute, Gerontopole, Exhonit Therapeutics, Avid Radiopharmaceuticals.
The mapping of human brain connections is still an on going task. Unlike deep white matter (DWM), which has been extensively studied and well documented, superficial white matter (SWM) has been often ...left aside. Improving our understanding of the SWM is an important goal for a better understanding of the brain network and its relation to several pathologies. The shape and localization of these short bundles present a high variability across subjects. Furthermore, the small diameter of most superficial bundles and partial volume effects induced by their proximity to the cortex leads to complex tratography issues. Therefore, the mapping of SWM bundles and the use of the resulting atlases for clinical studies requiere dedicated methodologies that are reviewed in this paper.
•Superficial White Matter (SWM) is important to better understand the brain network and its relation to several pathologies.•We describe the main approaches used for the study of SWM based on diffusion MRI and some application examples.•A descriptive comparison between different diffusion models and tractography methods for the study of SWM is also included, as well as an analysis of short association bundle reproducibility, based on the state-of-the-art bundle atlases.
Neuroimaging-genetics cohorts gather two types of data: brain imaging and genetic data. They allow the discovery of associations between genetic variants and brain imaging features. They are ...invaluable resources to study the influence of genetics and environment in the brain features variance observed in normal and pathological populations. This study presents a genome-wide haplotype analysis for 123 brain sulcus opening value (a measure of sulcal width) across the whole brain that include 16,304 subjects from UK Biobank. Using genetic maps, we defined 119,548 blocks of low recombination rate distributed along the 22 autosomal chromosomes and analyzed 1,051,316 haplotypes. To test associations between haplotypes and complex traits, we designed three statistical approaches. Two of them use a model that includes all the haplotypes for a single block, while the last approach considers each haplotype independently. All the statistics produced were assessed as rigorously as possible. Thanks to the rich imaging dataset at hand, we used resampling techniques to assess False Positive Rate for each statistical approach in a genome-wide and brain-wide context. The results on real data show that genome-wide haplotype analyses are more sensitive than single-SNP approach and account for local complex Linkage Disequilibrium (LD) structure, which makes genome-wide haplotype analysis an interesting and statistically sound alternative to the single-SNP counterpart.
BACKGROUND/OBJECTIVES
Cognitive decline associated with impaired kidney function might involve neurodegeneration. Our objectives were to evaluate the longitudinal association between kidney function ...and cognitive decline in older adults and to assess the involvement of cortical beta‐amyloid and hippocampal atrophy (features of Alzheimer's disease (AD)) in this association.
DESIGN
Secondary analysis of the randomized controlled Multidomain Alzheimer Preventive Trial (MAPT).
SETTINGS
Thirteen memory centers (France and Monaco, 2008–2016).
PARTICIPANTS
A total of 1,334 community‐dwellers >70 years old without dementia at baseline.
MEASUREMENTS
We estimated glomerular filtration rate (eGFR) from serum creatinine using CKD‐Epi equation. Cognition was assessed at baseline, 6, 12, 24, 36, 48, and 60 months using a composite Z‐score designed for MAPT. The Clinical Dementia Rating (CDR) score was used to assess cognition and functional independence. We examined the association between eGFR and (1) evolution of the composite cognitive Z‐score using mixed‐effect models and (2) progression on CDR using Cox models and mixed‐effect models. Adjustments were made for age, sex, education, ApoE genotype, cardiovascular risk factors and disease, hippocampal volume (measured with magnetic resonance), and cortical beta‐amyloid (measured with positron emission tomography).
RESULTS
Median (IQR) eGFR was 73(60–84) mL/min/1.73 m2. Two hundred sixty‐nine participants experienced progression on CDR score during follow‐up. eGFR<60 was significantly associated with progression on CDR score (adjusted hazard ratio (aHR) = 1.35, 95% CI 1.01–1.80) and with both the cognitive and functional independence components of CDR, but not with the evolution of the composite cognitive Z‐score (adjusted β‐coefficient −0.004, 95% CI −0.014; 0.006). Associations were not modified after further adjustment for beta‐amyloid (subsample: n = 252) and hippocampal volume (subsample: n = 270).
CONCLUSIONS
We did not find a mild to moderate renal insufficiency to be associated with brain imaging features of AD, and our results do not support the involvement of AD mechanisms in the incidence of cognitive impairment and functional decline associated with chronic kidney disease.
•We present a new superficial white matter (SWM) atlas of short association bundles created by an unsupervised method based on different levels of fiber clustering, over probabilistic tractography ...data.•The resulting atlas is composed of 525 bundles of short association fibers along the whole brain, with 384 bundles connecting pairs of different ROIs (cortical circumvolutions) and 141 bundles connecting portions of the same ROI.•The reproducibility of the atlas bundles was verified using an automatic segmentation applied to new subjects from three different tractogram databases, with a high reproducibility found for HCP probabilistic tractography.•Compared to previous whole-brain SWM atlases, our atlas features better cortical surface coverage and a larger number of bundles, with 97 bundles not described in previous atlases (58 in the left hemisphere and 39 in the right hemisphere).
The study of short association fibers is still an incomplete task due to their higher inter-subject variability and the smaller size of this kind of fibers in comparison to known long association bundles. However, their description is essential to understand human brain dysfunction and better characterize the human brain connectome. In this work, we present a multi-subject atlas of short association fibers, which was computed using a superficial white matter bundle identification method based on fiber clustering. To create the atlas, we used probabilistic tractography from one hundred subjects from the HCP database, aligned with non-linear registration. The method starts with an intra-subject clustering of short fibers (30-85 mm). Based on a cortical atlas, the intra-subject cluster centroids from all subjects are segmented to identify the centroids connecting each region of interest (ROI) of the atlas. To reduce computational load, the centroids from each ROI group are randomly separated into ten subgroups. Then, an inter-subject hierarchical clustering is applied to each centroid subgroup, followed by a second level of clustering to select the most-reproducible clusters across subjects for each ROI group. Finally, the clusters are labeled according to the regions that they connect, and clustered to create the final bundle atlas.
The resulting atlas is composed of 525 bundles of superficial short association fibers along the whole brain, with 384 bundles connecting pairs of different ROIs and 141 bundles connecting portions of the same ROI. The reproducibility of the bundles was verified using automatic segmentation on three different tractogram databases. Results for deterministic and probabilistic tractography data show high reproducibility, especially for probabilistic tractography in HCP data. In comparison to previous work, our atlas features a higher number of bundles and greater cortical surface coverage.
As it provides the only method for mapping white matter fibers
in vivo, diffusion MRI tractography is gaining importance in clinical and neuroscience research. However, despite the increasing ...availability of different diffusion models and tractography algorithms, it remains unclear how to select the optimal fiber reconstruction method, given certain imaging parameters. Consequently, it is of utmost importance to have a quantitative comparison of these models and algorithms and a deeper understanding of the corresponding strengths and weaknesses. In this work, we use a common dataset with known ground truth and a reproducible methodology to quantitatively evaluate the performance of various diffusion models and tractography algorithms. To examine a wide range of methods, the dataset, but not the ground truth, was released to the public for evaluation in a contest, the “Fiber Cup”. 10 fiber reconstruction methods were evaluated. The results provide evidence that: 1. For high SNR datasets, diffusion models such as (fiber) orientation distribution functions correctly model the underlying fiber distribution and can be used in conjunction with streamline tractography, and 2. For medium or low SNR datasets, a prior on the spatial smoothness of either the diffusion model or the fibers is recommended for correct modelling of the fiber distribution and proper tractography results. The phantom dataset, the ground truth fibers, the evaluation methodology and the results obtained so far will remain publicly available on:
http://www.lnao.fr/spip.php?rubrique79 to serve as a comparison basis for existing or new tractography methods. New results can be submitted to
fibercup09@gmail.com and updates will be published on the webpage.
► Provide the first realistic diffusion MR phantom with known ground truth. ► Define an interpretable methodology to compare tractographs to the ground truth. ► Compare qualitatively and quantitatively 10 tractography methods with ranking. ► Give practical recommendations on tractography methods that should be used or avoided.
Objective
To explore associations between changes of lower extremity function (LEF) parameters over a 5‐year period and diffusion tensor imaging (DTI) parameters of white matter tracts among ...community‐dwelling older adults.
Design
A secondary analysis on image and physical function data collected from the Multidomain Alzheimer's Preventive Trial (MAPT).
Participants
208 older adults (aged 75 ± 4 years, with spontaneous memory complaint or limited instrumental daily living activity or slow gait speed, 60% female) of the MAPT‐magnetic resonance imaging (MRI) ancillary study. The time interval between a participant's enrolment and MRI scan was on average 110 ± 97 days.
Measurements
Forty‐eight white matter tracts (WMTs) were measured. LEF parameters (measured after the MRI scan) were assessed as the short physical performance battery (SPPB) score, gait speed, and chair stands time over a 5‐year period. Mixed‐effects models were performed to explore the associations between baseline DTI values and the progression of LEF parameters. Bonferroni correction was applied for multiple comparison correction.
Results
The progression of LEF was associated with 35 baseline DTI parameters from 24 WMTs. Higher baseline DTI parameter values were related to more decreases in SPPB score and gait speed, and greater increases in chair stands time. Bilateral uncinate fasciculus was associated with all LEF parameters. Other WMTs in cingulum, cerebral and cerebellar peduncle, internal capsule, and corpus callosum also showed close connections with LEF changes.
Conclusions
Our findings show that DTI parameters of some WMTs are associated with the 5‐year decline in LEF, suggesting that alterations in WMT integrity (evaluated by DTI parameters) might be used to explore potential causes of impaired mobility in older adults when no clear explanations can be found.
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