Earth-vertical motion perception assessment using an elevator: a feasibility study

A feasible, inexpensive, rapid, and easy-to-use method to measure vestibular vertical movement perception is needed to assess the sacculus-mediated low-frequency otolith function of dizzy patients. To evaluate the feasibility of reaction time assessment in response to vertical motion induced by an elevator in healthy young individuals. We recorded linear acceleration/deceleration reaction times (LA-RT/LD-RT) of 20 healthy (13 female) subjects (mean age: 22 years ± 1 SD) as a measure of vertical vestibular motion perception. LA-RT/LD-RT were defined as the time elapsed from the start of elevator acceleration or deceleration to the time at which subjects in a sitting position indicated perceiving a change in velocity by pushing a button with their thumb. The light reaction time was measured as a reference. All 20 subjects tolerated the assessment with repeated elevator rides and reported no adverse events. Over all experiments, one upward and four downward rides had to be excluded for technical reasons (2.5%). The fraction of premature button presses varied among the four conditions, possibly related to elevator vibration (upward rides: LA-RT-up 66%, LD-RT-up 0%; downward rides: LA-RT-down 12%, LD-RT-down 4%). Thus LD-RT-up yielded the most robust results. The reaction time to earth-vertical deceleration elicited by an elevator provides a consistent indicator of linear vestibular motion perception in healthy humans. The testing procedure is inexpensive and easy to use. Deceleration on upward rides yielded the most robust measurements

A National Spinal Muscular Atrophy Registry for Real-World Evidence.

BACKGROUND: Spinal muscular atrophy (SMA) is a devastating rare disease that affects individuals regardless of ethnicity, gender, and age. The first-approved disease-modifying therapy for SMA, nusinursen, was approved by Health Canada, as well as by American and European regulatory agencies following positive clinical trial outcomes. The trials were conducted in a narrow pediatric population defined by age, severity, and genotype. Broad approval of therapy necessitates close follow-up of potential rare adverse events and effectiveness in the larger real-world population. METHODS: The Canadian Neuromuscular Disease Registry (CNDR) undertook an iterative multi-stakeholder process to expand the existing SMA dataset to capture items relevant to patient outcomes in a post-marketing environment. The CNDR SMA expanded registry is a longitudinal, prospective, observational study of patients with SMA in Canada designed to evaluate the safety and effectiveness of novel therapies and provide practical information unattainable in trials. RESULTS: The consensus expanded dataset includes items that address therapy effectiveness and safety and is collected in a multicenter, prospective, observational study, including SMA patients regardless of therapeutic status. The expanded dataset is aligned with global datasets to facilitate collaboration. Additionally, consensus dataset development aimed to standardize appropriate outcome measures across the network and broader Canadian community. Prospective outcome studies, data use, and analyses are independent of the funding partner. CONCLUSION: Prospective outcome data collected will provide results on safety and effectiveness in a post-therapy approval era. These data are essential to inform improvements in care and access to therapy for all SMA patients

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

Earth-vertical motion perception assessment using an elevator: a feasibility study

Abstract A feasible, inexpensive, rapid, and easy-to-use method to measure vestibular vertical movement perception is needed to assess the sacculus-mediated low-frequency otolith function of dizzy patients. To evaluate the feasibility of reaction time assessment in response to vertical motion induced by an elevator in healthy young individuals. We recorded linear acceleration/deceleration reaction times (LA-RT/LD-RT) of 20 healthy (13 female) subjects (mean age: 22 years ± 1 SD) as a measure of vertical vestibular motion perception. LA-RT/LD-RT were defined as the time elapsed from the start of elevator acceleration or deceleration to the time at which subjects in a sitting position indicated perceiving a change in velocity by pushing a button with their thumb. The light reaction time was measured as a reference. All 20 subjects tolerated the assessment with repeated elevator rides and reported no adverse events. Over all experiments, one upward and four downward rides had to be excluded for technical reasons (2.5%). The fraction of premature button presses varied among the four conditions, possibly related to elevator vibration (upward rides: LA-RT-up 66%, LD-RT-up 0%; downward rides: LA-RT-down 12%, LD-RT-down 4%). Thus LD-RT-up yielded the most robust results. The reaction time to earth-vertical deceleration elicited by an elevator provides a consistent indicator of linear vestibular motion perception in healthy humans. The testing procedure is inexpensive and easy to use. Deceleration on upward rides yielded the most robust measurements

Mapping autism risk loci using genetic linkage and chromosomal rearrangements.

Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs

Mapping autism risk loci using genetic linkage and chromosomal rearrangements.

Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs

Nat Commun

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease