The Visual Impairment/Cognitive Impairment Co-morbidity : Examining the Genotype-Structure-Function Relationship

This research was supported by the Canadian National Institute for the Blind Ross C. Purse Doctoral Fellowship (2013), Fonds de Recherche en Sante du Quebec (FRSQ) Doctoral Fellowship, the School of Optometry at the University of Montreal and the Recruitment to Vision Science bursary from the Vision Health Research Network of the FRSQ.Un nombre de recherches rapportent une forte cooccurrence de la dégénérescence maculaire liée à l'âge (DMLA) et la maladie d'Alzheimer (AD), ce qui suggère que les déficiences visuelles et cognitives peuvent être liées. Ceci est davantage soutenu par des similitudes structurelles dans la rétine et le cerveau qui sont des facteurs de risque de maladie partagés et des preuves histopathologiques, y compris le bêta-amyloïde. En raison de cela, l'hypothèse selon laquelle DMLA et AD peuvent également partager des facteurs de risque génétiques. L'objectif de cette recherche était de reproduire des études démontrant une incidence plus élevée d'altération cognitive chez les personnes atteintes de DMLA et d'explorer la relation entre le génotype, la structure, et la fonction dans cette comorbidité. Les résultats ont montré qu'un plus grand nombre de personnes atteintes de DMLA ont obtenu un résultat positif pour déficience cognitive par rapport aux témoins. Le résultat MoCA moyen pour le groupe DMLA était inférieur à celui du groupe témoin, mais ce n'était pas significatif. Ces résultats positifs pour déficience cognitive dans la DMLA et les groupes témoins diffèrent considérablement sur les domaines cognitifs avec lesquels ils avaient des difficultés. Bien que les contrôles aient des difficultés avec la mémoire seulement, ceux avec DMLA ont eu de la difficulté avec la mémoire en plus d'autres domaines cognitifs, ce qui indique un risque plus élevé de progression vers AD. Les résultats génétiques ont montré que les polymorphismes de nucléotide unique (SNP), CFHY402H et ARMS2A69S de DMLA les plus fréquents se produisent dans les fréquences attendues au sein de la population québécoise. FADS1 rs174547, qui a une contribution moins significative à AMD, a été constaté surreprésenter dans la population québécoise, ce qui indique un effet fondateur pour ce SNP. En terme de fonction visuelle, les transporteurs de CFHY402H se sont révélés avoir une mauvaise stabilité de la fixation par rapport aux non-porteurs, tandis que les porteurs d'ARMSA69S avaient une acuité visuelle et une sensibilité au contraste plus médiocres. L'analyse de la structure rétinienne a révélé que CFHY402H était liée à l'augmentation de la zone de Drusen, à la réflexivité moyenne et à l'atrophie géographique, tandis que l'ARMS2A69S avait moins de corrélations avec les caractéristiques du Drusen. Ensemble, ces résultats suggèrent que le SNP de CFH joue un rôle dans la perturbation de l'architecture de la rétine alors que le SNP ARMS2 est impliqué dans le dysfonctionnement des photorécepteurs. Ceci est encore mis en évidence par les résultats des mesures psychophysiques, où les porteurs d'ARMS2A69S avaient une difficulté particulière avec les stimuli de premier ordre qui dépendent fortement de la sensibilité au contraste. Bien qu'aucune différence significative n'a été trouvée dans la performance cognitive basée sur le statut de transporteur CFH ou ARMS2, tous ceux qui ont obtenu une évaluation positive pour une déficience cognitive étaient des porteurs du SNP FADS1 avec des homozygotes ayant les scores cognitifs les plus bas. Ces résultats ont des répercussions sur les domaines de la génétique, de la biologie et de la rééducation à faible vision. En explorant la comorbidité cognitive de DMLA dans l'ensemble du spectre de la fonction génotype-structure, la communication à travers les sciences augmente pour mieux servir la population croissante confrontée à cette comorbidité.Research reports a high co-occurrence of Age-related Macular Degeneration (AMD) and Alzheimer’s Disease (AD), suggesting that visual and cognitive impairments may be related. This is further supported by structural similarities in the retina and brain, shared disease risk factors, and histopathological evidence, including beta-amyloid. Due to this, it is hypothesized that AMD and AD may share genetic risk factors as well. The goal of this research was to replicate studies demonstrating a higher incidence of cognitive impairment among individuals with AMD, and to explore the relationship among genotype, structure, and function in this co-morbidity. The results showed a greater number of individuals with AMD scored positive for mild cognitive impairment (MCI) compared to controls. Mean Montreal Cognitive Assessment score for the AMD group was lower than that of the control group, however this was not significant. Those scoring positive for MCI in the AMD and control groups did differ significantly on the cognitive domains with which they had difficulty. While controls had difficulty with only memory, those with AMD had difficulty with memory in addition to other cognitive domains, indicating a higher risk of progression to AD. The genetic results showed that the most common AMD single nucleotide polymorphisms (SNPs), CFHY402H and ARMS2A69S, occur in the expected frequencies within the Quebec population. FADS1 rs174547, which has a less significant contribution to AMD, was found to be overrepresented in the Quebec population, indicating a possible Founder Effect for this SNP. In terms of visual function, carriers of CFHY402H were found to have greater ecentricity compared to non-carriers while carriers of ARMSA69S had poorer visual acuity and contrast sensitivity. Analysis of retinal structure revealed CFHY402H was related to increased drusen area, mid reflectivity, and geographic atrophy, meanwhile ARMS2A69S had fewer correlations with characteristics of drusen. Taken together, these results suggest that the CFH SNP plays a role in the disruption of retinal architecture while the ARMS2 SNP is involved in photoreceptor dysfunction. This is further evidenced by the results of psychophysical measures, where carriers of ARMS2A69S had particular difficulty with first order stimuli which relies heavily on contrast sensitivity. Although no significant differences were found in cognitive performance based on CFH or ARMS2 carrier status, all those scoring positive for MCI were carriers of the FADS1 SNP with homozygotes having the lowest cognitive scores. These results have implications for the fields of genetics, biology, and low vision rehabilitation. Exploration of the AMD/cognitive impairment co-morbidity across the spectrum of genotype-structure-function increases communication across the sciences to better serve the growing proportion of the population facing this co-morbidity

Quantitative retinal traits and their association with cardiovascular disease and cardio-metabolic genetic variants in people with type 2 diabetes

Introduction: Type 2 diabetes (T2D) is one of the most prevalent noncommunicable diseases in the world and its cardiovascular complications present a huge socio-economic burden. In 2015, in the UK alone, 3.8 million people have been diagnosed with T2D and cardiovascular disease accounts for almost 1.7 million episodes throughout the country. Early diagnosis of cardiovascular disease in people with T2D thus becomes critical. The retina gives a unique opportunity to study the human microcirculation, which can then offer insights into the pathophysiology of cardiovascular disease. By using semi-automatic software, retinal images can provide quantitative traits derived from the microvasculature. Previous research has found that arteriolar and venular calibres are associated with cardiovascular outcomes such as hypertension and stroke. Moreover, retinal vascular tortuosity, a novel quantitative biomarker which measures the degree to which blood vessels visible in the retina twist and turn, has been associated with traditional cardiovascular risk factors in the general population. However, this area needs to be further explored, especially in the population with T2D and in prospective analyses. Aims: To determine whether quantitative retinal traits such as vessel widths, vessel tortuosity and multifractal dimensions are associated with the subsequent development of major cardiovascular events such as ischaemic heart disease and stroke in people with T2D. Also, to use a genome-wide association approach to investigate if these quantitative retinal traits are associated with cardio-metabolic genetic variants, which could help identify novel biomarkers of cardiovascular disease for future research. Methods: Analyses used the Edinburgh Type 2 Diabetes Study, a prospective cohort of 1066 men and women with T2D aged 60-75 years at baseline with eight years of follow-up for cardiovascular events. A total of 1028 retinal images from baseline were analysed using the semi-automatic retinal software VAMPIRE (Vascular Assessment and Measurement Platform for Images of the Retina). Cross-sectional analyses including ANOVA and Chi-square test were performed along with prospective analysis using Cox regression. Additionally, a genome-wide association study was performed to explore the association of 12 quantitative retinal traits with cardio-metabolic genetic variants. Imputation of variants included in the MetaboChip array was used. Results: In an unadjusted model, there was a significant association between arteriolar tortuosity and incident stroke (Hazard Ratio (HR) 1.26; 95% CI 1.02, 1.57; p=0.03). This association remained significant after full adjustment for age, sex, cardiovascular risk factors (body mass index, HbA1c, total cholesterol, duration of diabetes, renal dysfunction) and previous cardiovascular events (HR 1.26; 95% CI 1.01, 1.58; p=0.04). Multifractal dimensions, a novel retinal biomarker which provides an insight into vascular geometry, was inversely associated with incident stroke (unadjusted HR 0.73; 95% CI 0.57, 0.94; p=0.01). This association also remained significant after adjustment for age, sex, cardiovascular risk factors and previous cardiovascular event (HR 0.73; 95% CI 0.56, 0.94 p=0.02). Associations between other retinal traits and stroke, and between traits and ischaemic heart disease, tended not to be statistically significant, especially after multivariable adjustment. The genome-wide association analysis of arteriovenous ratio (ratio of arteriolar to venular vessel width) revealed a genome wide significant locus, rs73198094 (p = 5.27 x 10-8), an intergenic variant located between ASAH1 and LOC101929066 genes in chromosome 8. The ASAH1 gene has been associated with atrial fibrillation. Although no further single nucleotide polymorphisms reached genome-wide significance, some additional promising findings emerged. Analysis for retinal arteriolar width revealed a genome-wide suggestive intronic locus, rs4944903 (p= 8.5x10-7), of the gene POLD3 in chromosome 11. Identified loci for minimum arteriolar tortuosity, rs7991332 (p=1.54 x 10-6) and rs2172724 (p=2.46 x10-6), are located in the COL4A2 gene in chromosome 13 and another identified variant, rs7319323 (p=3.53 x 10-6), is located in an intron of the neighbouring COL4A1 gene. Previous studies showed the relevance of these genes including an association with stroke and intracerebral haemorrhage. These two genes encode collagen protein chains, which are major components of the vascular basement membrane. Another promising variant identified was the rs34013641 locus, associated with minimum venular tortuosity (p=2.81 x 10- 6), which is located in the MYH11 gene in chromosome 2. This gene encodes smooth muscle myosin heavy chain protein, which is highly expressed in human arteries. Finally, identified loci for the multifractal dimension D0, rs10963694 (p=8.53 x 10-7) and rs4977506 (p=4.95 x 10-6), located on the ADAMTSL-1 gene in chromosome 9, are also strong candidates in the pathophysiology of vascular disorders. Conclusions: In older people with T2D, arteriolar tortuosity and multifractal dimensions were significantly and independently associated with incident stroke. GWAS findings for these and other quantitative retinal traits offer insight into pathophysiological changes of the vasculature, which may result in cardiovascular disease. These findings, in the context of further research, could potentially be used to reveal biological mechanisms related to major cardiovascular complications of T2D and to guide efforts on prevention and early interventions

Aerospace Medicine and Biology: A continuing bibliography with indexes (supplement 272)

This bibliography lists 360 reports, articles, and other documents introduced into the NASA scientific and technical information system in May 1985

Aerospace Medicine and Biology: A continuing bibliography with indexes (supplement 258)

This bibliography lists 308 reports, articles and other documents introduced into the NASA scientific and technical information system in April 1984

Aerospace Medicine and Biology: A continuing bibliography with indexes

This bibliography lists 356 reports, articles and other documents introduced into the NASA scientific and technical information system in June 1982

Decisional tools for cost-effective bioprocess design for cell therapies and patient-specific drug discovery tools

A specific challenge to the translation of cell therapies and stem-cell derived products is the ability to develop and manufacture such products in a cost-effective, scalable and robust manner. To this end, this thesis investigates the creation and application of a set of computational tools designed to aid bioprocess design decisions for cell therapy and stem-cell derived research products. The decision-support tools comprise advanced bioprocess economics models with databases tailored to cellular products. These are linked to Monte Carlo simulation for uncertainty analysis and techniques to identify optimal bioprocess designs that include brute-force search algorithms, an evolutionary algorithm, and multi-attribute decision making analysis. A trio of industrially-relevant case studies is presented within this thesis, along with an additional study included in the appendices of this work, in order to demonstrate the applicability of the decisional tools to bioprocess design for different cell therapies (allogeneic, human embryonic stem cell-derived retinal pigment epithelial (RPE) cells for macular degeneration, allogeneic CAR-T cells for oncology) and induced pluripotent stem cells (iPSCs) for drug discovery applications. Questions tackled included manual versus automated production, costeffective inflection points of planar vs microcarrier-based bioprocess strategies, and the identification optimal process technologies for an allogeneic CAR-T cell therapy based on both qualitative and quantitative attributes. The analyses highlighted key bioprocess economic drivers and process bottlenecks. Furthermore, the Monte Carlo simulation technique was used in order to capture the effects of the inherent uncertainty associated with cell therapy bioprocessing on manufacturing costs and process throughputs. Future process improvements required to create financially feasible bioprocesses were also identified. This thesis presents the application of a series of decisional tools to bioprocess design problems and demonstrates how they can facilitate informed decisions regarding cost-effective process design in the cell therapy sector

Aerospace Medicine and Biology: A cumulative index to the 1982 issues

This publication is a cumulative index to the abstracts contained in the Supplements 229 through 240 of Aerospace Medicine and Biology: A continuing Bibliography. It includes three indexes: subject, personal author, and corporate source

Aerospace Medicine and Biology: A continuing bibliography with indexes, supplement 267, January 1985

This publication is a cumulative index to the abstracts contained in the Supplements 255 through 266 of Aerospace Medicine and Biology: A Continuing Bibliography. It includes seven indexes--subject, personal author, corporate source, foreign technology, contract number, report number, and accession number