The identification of mechanisms associated with Alzheimer's disease (AD) development in mild cognitive impairment (MCI) would be of great usefulness to clarify AD pathogenesis and to develop ...preventive and therapeutic strategies. In this study, blood levels of the candidate microRNAs (small noncoding RNAs that play a pivotal role in gene expression) miR-146a, miR-181a, miR-181b, miR-24-3p, miR-186a, miR-101, miR-339, miR-590, and miR-22 have been investigated for association to AD conversion within 2 years in a group of 45 patients with MCI. Baseline miR-146a (p = 0.036) and miR-181a (p = 0.026) showed a significant upregulation in patients with MCI who later converted to AD. These alterations were related to AD hallmarks: a significant negative correlation was found with amyloid beta cerebrospinal fluid concentration for miR-146a (p = 0.006) and miR-181a (p = 0.001). Moreover, higher levels of miR-146a were associated to apolipoprotein E ε4 allele presence, smaller volume of the hippocampus (p = 0.045) and of the CA1 (p = 0.013) and the subiculum (p = 0.027) subfields. Increased levels of miR-146a (p = 0.031) and miR-181a (p = 0.002) were also linked with diffusivity alterations in the cingulum. These data support a role for miR-146a and miR-181a in the mechanisms of AD progression.
•miR-146a and miR-181a are increased in patients with mild cognitive impairment who converted to Alzheimer's disease.•Alterations in miR-146a and miR-181a are correlated to amyloid beta cerebrospinal fluid concentration.•miR-146a and miR-181a levels are associated to neuroimaging features.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Dopamine agonists used in Parkinson's disease patients are associated with excessive daytime sleepiness and sleep attacks occurring without prior warning.
• ...Parkinson's disease accounts in itself for a variety of sleep disorders. It is therefore important to study the drug‐induced sleepiness in healthy volunteers.
• In healthy subjects, pramipexole has proved to decrease alertness and ropinirole to reduce sleep latency.
WHAT THIS STUDY ADDS
• Results from our study show that pramipexole reduces the mean sleep latency as measured by the Multiple Sleep Latency Test in healthy volunteers, hence providing an objective measure of increased sleepiness.
• Furthermore, the reduction in sleep latency was not associated with a subjective impression of increased sleepiness.
• Such dissociation may underlie the occurrence of sleep attacks without prior warning.
AIMS
To assess the sleepiness induced by pramipexole, a D2/D3‐dopamine receptor agonist commonly used in Parkinson's disease and restless legs syndrome, without the problem of the confounding factors related to the disease.
METHODS
Placebo, bromocriptine (2.5 mg), L‐dopa (100 mg) and pramipexole (0.5 mg) were administered in a single oral dose on four separate days, with at least a 2‐week wash‐out period in a randomized cross‐over design. Induced somnolence was assessed using Multiple Sleep Latency Test (MSLT) and subjective scaling of vigilance. Twelve male subjects (26.3 ± 5.5 years old) without anxiety, mood, sleep or sedation disorders were enrolled.
RESULTS
Pramipexole significantly reduced mean sleep latency compared with placebo 3 h 30 min −6.1 min (−9.8, −2.4), P = 0.002 and 5 h 30 min −5.6 min (−7.7, −3.5), P = 0.003 after administration. In addition, the total duration of sleep during the tests was higher with pramipexole than with placebo +6.0 min (2.3, 9.7), P < 0.001. These differences were not observed with L‐dopa and bromocriptine in comparison with placebo. The induced sleepiness was not associated with an increase in subjective somnolence scaling, indicating that this adverse event may occur without prior warning.
CONCLUSIONS
These results show that a single oral dose of pramipexole induces sleepiness as assessed by MSLT in healthy young subjects, independent of disease‐related sleep dysfunction.
Large-scale longitudinal neuroimaging studies with diffusion imaging techniques are necessary to test and validate models of white matter neurophysiological processes that change in time, both in ...healthy and diseased brains. The predictive power of such longitudinal models will always be limited by the reproducibility of repeated measures acquired during different sessions. At present, there is limited quantitative knowledge about the across-session reproducibility of standard diffusion metrics in 3T multi-centric studies on subjects in stable conditions, in particular when using tract based spatial statistics and with elderly people. In this study we implemented a multi-site brain diffusion protocol in 10 clinical 3T MRI sites distributed across 4 countries in Europe (Italy, Germany, France and Greece) using vendor provided sequences from Siemens (Allegra, Trio Tim, Verio, Skyra, Biograph mMR), Philips (Achieva) and GE (HDxt) scanners. We acquired DTI data (2×2×2mm3, b=700s/mm2, 5 b0 and 30 diffusion weighted volumes) of a group of healthy stable elderly subjects (5 subjects per site) in two separate sessions at least a week apart. For each subject and session four scalar diffusion metrics were considered: fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial (AD) diffusivity. The diffusion metrics from multiple subjects and sessions at each site were aligned to their common white matter skeleton using tract-based spatial statistics. The reproducibility at each MRI site was examined by looking at group averages of absolute changes relative to the mean (%) on various parameters: i) reproducibility of the signal-to-noise ratio (SNR) of the b0 images in centrum semiovale, ii) full brain test–retest differences of the diffusion metric maps on the white matter skeleton, iii) reproducibility of the diffusion metrics on atlas-based white matter ROIs on the white matter skeleton. Despite the differences of MRI scanner configurations across sites (vendors, models, RF coils and acquisition sequences) we found good and consistent test–retest reproducibility. White matter b0 SNR reproducibility was on average 7±1% with no significant MRI site effects. Whole brain analysis resulted in no significant test–retest differences at any of the sites with any of the DTI metrics. The atlas-based ROI analysis showed that the mean reproducibility errors largely remained in the 2–4% range for FA and AD and 2–6% for MD and RD, averaged across ROIs. Our results show reproducibility values comparable to those reported in studies using a smaller number of MRI scanners, slightly different DTI protocols and mostly younger populations. We therefore show that the acquisition and analysis protocols used are appropriate for multi-site experimental scenarios.
•We implement a multi-site 3T MRI protocol for brain DTI on 10 EU sites.•We acquire across-session test–retest data on 50 healthy elderly subjects.•We use full brain TBSS and ROI analysis to calculate FA, MD, RD and AD.•Reproducibility errors are in the 2–6% range.•Reproducibility errors tended to be lower in sites with shorter acquisitions.
Introduction
Despite increasing evidence of a role of rare genetic variation in the risk of Alzheimer's disease (AD), limited attention has been paid to its contribution to AD‐related biomarker ...traits indicative of AD‐relevant pathophysiological processes.
Methods
We performed whole‐exome gene‐based rare‐variant association studies (RVASs) of 17 AD‐related traits on whole‐exome sequencing (WES) data generated in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF‐AD MBD) study (n = 450) and whole‐genome sequencing (WGS) data from ADNI (n = 808).
Results
Mutation screening revealed a novel probably pathogenic mutation (PSEN1 p.Leu232Phe). Gene‐based RVAS revealed the exome‐wide significant contribution of rare coding variation in RBKS and OR7A10 to cognitive performance and protection against left hippocampal atrophy, respectively.
Discussion
The identification of these novel gene–trait associations offers new perspectives into the role of rare coding variation in the distinct pathophysiological processes culminating in AD, which may lead to identification of novel therapeutic and diagnostic targets.
To date, limited data are available regarding the inter-site consistency of test-retest reproducibility of functional connectivity measurements, in particular with regard to integrity of the Default ...Mode Network (DMN) in elderly participants. We implemented a harmonized resting-state fMRI protocol on 13 clinical scanners at 3.0T using vendor-provided sequences. Each site scanned a group of 5 healthy elderly participants twice, at least a week apart. We evaluated inter-site differences and test-retest reproducibility of both temporal signal-to-noise ratio (tSNR) and functional connectivity measurements derived from: i) seed-based analysis (SBA) with seed in the posterior cingulate cortex (PCC), ii) group independent component analysis (ICA) separately for each site (site ICA), and iii) consortium ICA, with group ICA across the whole consortium. Despite protocol harmonization, significant and quantitatively important inter-site differences remained in the tSNR of resting-state fMRI data; these were plausibly driven by hardware and pulse sequence differences across scanners which could not be harmonized. Nevertheless, the tSNR test-retest reproducibility in the consortium was high (ICC=0.81). The DMN was consistently extracted across all sites and analysis methods. While significant inter-site differences in connectivity scores were found, there were no differences in the associated test-retest error. Overall, ICA measurements were more reliable than PCC-SBA, with site ICA showing higher reproducibility than consortium ICA. Across the DMN nodes, the PCC yielded the most reliable measurements (≈4% test-retest error, ICC=0.85), the medial frontal cortex the least reliable (≈12%, ICC=0.82) and the lateral parietal cortices were in between (site ICA). Altogether these findings support usage of harmonized multisite studies of resting-state functional connectivity to characterize longitudinal effects in studies that assess disease progression and treatment response.
PDF
