Publications

Below you will find a list of publications from work that has been supported by the CCNA. Each title is linked to its PubMed listing and abstract or, if the article is open-access, to the article itself. For those articles that are believed to be of particular interest to the general public, a lay summary is provided.

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FUS Phase Separation Is Modulated by a Molecular Chaperone and Methylation of Arginine Cation-π Interactions

Journal: Cell

LAY SUMMARY

A protein called FUS is involved in several important biochemical reactions inside human cells, including in the synthesis of new proteins from genetic material. FUS can be found in several different physical states: fully dissolved state, phase separated liquid protein droplets like oil and vinegar or phase separated hydrogel states like bits of jelly floating in a liquid. These states play a significant role in the cellular processes in which FUS is involved. Importantly, when these processes go awry, they can trigger diseases such as frontotemporal lobar degeneration (FTLD). Therefore, understanding the molecular and cellular factors that control the transition of the FUS protein from one physical state to another, called phase separation, would be invaluable and could yield avenues for therapeutic interventions in FTLD.

In this study funded in part by CCNA and led by Dr. Peter St George-Hyslop and his team, working in collaboration with several scientists from the UK, Spain and the USA, the researchers uncovered several key elements implicated in the phase separation of the FUS protein. By reconstituting and manipulating key steps of the separation process in the laboratory and using atomic force nano-infrared spectroscopy to visualize the state of the protein, they found that the phase separation of FUS is very tightly regulated by the chemical structure of some specific amino acids forming the protein. They also uncovered the role of another protein, TNPO1, which appears to not function properly in some cases of FTLD.  When these processes are deregulated, the FUS protein condenses into irreversible hydrogels in neurons. This results in the shutdown of the synthesis of new proteins in synapses (junctions between nerve cells).

These results are important because they provide some clues as to why in FTLD, the FUS protein was found to accumulate in some neurons. Importantly several methods developed to conduct this study will be useful tools to further study FUS phase separation and its effects on FTLD, and to search for treatments/preventions of these currently incurable diseases.

Authors: Qamar S., Wang G., Randle S.J., Ruggeri F.S., Varela J.A., Lin J.Q., Phillips E.C., Miyashita A., Williams D., Strohl F., Meadows W., Ferry R., Dardov V.J., Tartaglia G.G., Farrer L.A., Kaminski Schierle G.S., Kaminski C.F., Holt C.E., Fraser P.E., Schmitt-Ulms G., Klenerman D., Knowles T., Vendruscolo M., St George-Hyslop P.

Guidelines for Gait Assessments in the Canadian Consortium on Neurodegeneration in Aging (CCNA)

Journal: Canadian Geriatrics Journal, 2018, In press

LAY SUMMARY

These gait guidelines are the result of a consensus meeting funded by the CCNA, whereby experts from across Canada discussed and ultimately suggested a core set of measures to test mobility and cognition in clinical settings. The experts agreed that gait assessments are an important part of the motor-cognitive evaluation of older adults, and thus the authors of these guidelines describe the assessments that were included in the CCNA COMPASS-ND study. This paper also includes an instructional video for assessors on how to administer these gait assessments, viewable here.

Authors: Cullen S., Montero-Odasso M., Bherer L., Almeida Q., Fraser S., Muir-Hunter S.W., Li K., Liu-Ambrose T., McGibbon C., McIlroy W., Middleton L., Sarquis-Adamson Y., Morais J.A., Beauchet O., McFadyen B.J., Camicioli R. and The Canadian Gait and Cognition Network

Motor and cognitive trajectories before dementia: Results from the “Gait and Brain Study”

Journal: Journal of the American Geriatrics Society, 2018, In press

LAY SUMMARY

This study, by Dr. Montero-Odasso and CCNA colleagues, describes how cognitive and motor trajectories fluctuate in older adults before progressing to dementia. Importantly, this is the first study to provide empirical evidence of the added value of combining objective motor and cognitive declines to detect incident dementia, especially when compared to either motor or cognitive decline alone. Moreover, the results show how a single time-point assessment failed to detect individuals at high risk of dementia, emphasizing the importance of routine assessment of motor performance in older adults with cognitive impairments.

Authors: Montero-Odasso M., Speechley M., Muir-Hunter S.W., Sarquis-Adamson Y., Sposato L., Hachinski V., Borrie M., Wells J., Black A., Sejdić E., Bherer L., Chertkow H., and The Canadian Gait and Cognition Network

Falls in Cognitively Impaired Older Adults: Implications for Risk Assessment and Prevention

Journal: Journal of the American Geriatrics Society

LAY SUMMARY

In this article, Dr. M. Montero-Odasso and Dr. M. Speechley, members of the CCNA’s Team 12 (Memory, Exercise, and Cognition) provide an overview of the role cognition plays in falls, highlight the role of brain motor control deficits in fall risk, and offer pharmaceutical and non-pharmaceutical approaches to fall prevention. The researchers emphasize the importance of fall prevention in older adults who are cognitively impaired, since they experience double the rate of falls of those with normal cognition. This work also sets the stage for the CCNA’s clinical cohort, COMPASS-ND.

Authors: Montero-Odasso M., Speechley M. 

Integrating sex and gender into neurodegeneration research: A six-component strategy

Journal: Alzheimer's & Dementia: Translational Research & Clinical Interventions

LAY SUMMARY

Despite significant differences between men and women in diseases that affect the brain, there is surprisingly little research undertaken in this area. The Canadian Consortium on Neurodegeneration in Aging (CCNA) – as a network of 350+ leading experts working together on prevention, treatment, and quality of life research projects – provides an ideal setting to study these differences. The Women, Gender, Sex, and Dementia cross-cutting program within the CCNA has developed and implemented a six-component strategy to foster the study of sex differences throughout the network. This strategy included involvement at the executive level, training for researchers and students, research collaboration, review of progress reports, results dissemination, and ongoing manuscript review. Specifically, we reviewed the effects of the strategy over two progress reporting periods in 2016. We found that research productivity in examining sex differences increased substantially for both animal (36% to 45%) and human (56% to 60%) studies. We also examined barriers to greater inclusion, and are working on these to ensure the ongoing study of sex and gender differences. This best practice model could be utilized by a wide variety of large national and international groups to facilitate the study of sex differences.

Authors: Mary C. Tierney, Ashley F. Curtis, Howard Chertkow, R. Jane Rylett

Memory Resilience to Alzheimer’s Genetic Risk: Sex Effects in Predictor Profiles

Journal: The Journals of Gerontology, Series B: Psychological Sciences and Social Sciences

ABSTRACT

OBJECTIVES: Apolipoprotein E (APOE) ɛ4 and Clusterin (CLU) C alleles are risk factors for Alzheimer’s disease (AD) and episodic memory (EM) decline. Memory resilience occurs when genetically at-risk adults perform at high and sustained levels. We investigated whether (a) memory resilience to AD genetic risk is predicted by biological and other risk markers and (b) the prediction profiles vary by sex and AD risk variant.

METHOD: Using a longitudinal sample of nondemented adults (n = 642, aged 53-95) we focused on memory resilience (over 9 years) to 2 AD risk variants (APOE, CLU). Growth mixture models classified resilience. Random forest analysis, stratified by sex, tested the predictive importance of 22 nongenetic risk factors from 5 domains (n = 24-112).

RESULTS: For both sexes, younger age, higher education, stronger grip, and everyday novel cognitive activity predicted memory resilience. For women, 9 factors from functional, health, mobility, and lifestyle domains were also predictive. For men, only fewer depressive symptoms was an additional important predictor. The prediction profiles were similar for APOE and CLU.

DISCUSSION: Although several factors predicted resilience in both sexes, a greater number applied only to women. Sex-specific mechanisms and intervention targets are implied.

Authors: McDermott KL, McFall GP, Andrews SJ, Anstey KJ, Dixon RA

Motor function and incident dementia: A systematic review and meta-analysis

Journal: Age and Ageing

This systematic review and meta-analysis by CCNA Team 12 (Memory, Exercise, and Cognition) members, Dr. M. Montero-Odasso and Dr. M. Speechley is the first to evaluate how performance on motor function tests – including tremors, parkinsonisms, and slowing gait – are associated with the development of dementia syndromes. Their review of the literature supports future research that includes quantitative motor assessment (specifically gait velocity tests) for clinical dementia risk evaluation in the CCNA cohort (COMPASS-ND).

Authors: Kueper J.K., Speechley M., Lingum N.R., Montero-Odasso M.

TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics

Journal: Neuron

SUMMARY

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are age-related neurodegenerative disorders with shared genetic etiologies and overlapping clinical and pathological features. Here we studied a novel ALS/FTD family and identified the P362L mutation in the low-complexity domain (LCD) of T cell-restricted intracellular antigen-1 (TIA1). Subsequent genetic association analyses showed an increased burden of TIA1 LCD mutations in ALS patients compared to controls (p = 8.7 × 10−6). Postmortem neuropathology of five TIA1 mutations carriers showed a consistent pathological signature with numerous round, hyaline, TAR DNA-binding protein 43 (TDP-43)-positive inclusions. TIA1 mutations significantly increased the propensity of TIA1 protein to undergo phase transition. In live cells, TIA1 mutations delayed stress granule (SG) disassembly and promoted the accumulation of non-dynamic SGs that harbored TDP-43. Moreover, TDP-43 in SGs became less mobile and insoluble. The identification of TIA1 mutations in ALS/FTD reinforces the importance of RNA metabolism and SG dynamics in ALS/FTD pathogenesis.

Authors: Mackenzie IR, Nicholson AM, Sarkar M, Messing J, Purice MD, Pottier C, Annu K, Baker M, Perkerson RB, Kurti A, Matchett BJ, Mittag T, Temirov J, Hsiung GYR, Krieger C, Murray ME, Kato M, Fryer JD, Petrucelli L, Zinman L, Weintraub S, Mesulam M, Keith J, Zivkovic SA, Hirsch-Reinshagen V, Roos RP, Zuchner S, Graff-Radford N, Petersen RC, Caselli RJ, Wszolek ZK, Finger E, Lippa C, Lacomis D, Stewart H, Dickson DW, Kim HJ, Rogaeva E, Bigio E, Boylan KB, Taylor JP.

DNA methylation age-acceleration is associated with disease duration and age at onset in C9orf72 patients

Journal: Acta Neuropathologica

ABSTRACT

The repeat expansion in C9orf72 is the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia. C9orf72 patients present with a wide range in disease duration and age of onset. The strongest risk factor for both syndromes is aging, which was linked to DNA methylation (DNAm) age based on the cumulative assessment of the methylation levels of 353 CpGs included on the genome-wide 450k BeadChip. DNAm age may reflect biological age better than chronological age. We conducted a genome-wide blood DNA methylation study of 46 unrelated C9orf72 patients. After correction for multiple testing, none of the CpGs demonstrated association between its methylation level and disease duration or age of onset. However, we detected a significant reverse correlation of DNAm age-acceleration with disease duration and age of onset, suggesting that for every 5-year increase in DNAm age-acceleration there is a 3.2-year earlier age of onset and 1.5-year shorter disease duration. The significant correlations remain after adjusting for gender, TMEM106B genotypes, disease phenotype and C9orf72 5’CpG island methylation status. A similar trend was observed for the blood DNA of affected members of an extended C9orf72 family; and tissues from the central nervous system of C9orf72 autopsy cases. For instance, regression analysis suggested that a 5-year increase in DNAm age-acceleration is linked to an earlier age of onset by 4.7 or 5.5 years for frontal cortex or spinal cord, respectively. Blood DNAm age may be a useful biomarker for biological age, because blood DNAm age-acceleration was similar to all investigated brain tissues, except for cerebellum that ages more slowly. In conclusion, DNA methylation analysis of C9orf72 patients revealed that increased DNAm age-acceleration is associated with a more severe disease phenotype with a shorter disease duration and earlier age of onset.

Authors: Zhang M, Tartaglia MC, Moreno D, Sato C, McKeever P, Weichert A, Keith J, Robertson J, Zinman L, Rogaeva E

Association of Dual-Task Gait With Incident Dementia in Mild Cognitive Impairment

Journal: JAMA Neurology

This research from Montero-Odasso and colleagues investigated how speed of walking while performing a demanding cognitive task can predict whether a patient with Mild Cognitive Impairment (MCI) might later develop dementia. MCI, a condition where individuals present with small changes in their memory and mental functions, is often a precursor to dementia, though not everyone who has MCI goes onto develop dementia. Montero-Odasso and colleagues followed 112 older adults over six years who presented with MCI. Every two years, the participants were asked to first walk normally for six meters without doing a simultaneous task (single-task), and then to walk while simultaneously doing a secondary task that requires thinking and attention, such as counting backwards by one, by seven, or while naming animals (dual-task). In all tasks, the participants’ walking speed was measured. Over six years, 24% of the initial sample of older adults with MCI (27/112) developed dementia. The researchers found that the mean normal (single-task) walking speed of these 27 older adults was equivalent to the normal walking speed of the 85 older adults who did not develop dementia. In contrast, the older adults who eventually developed dementia were slower than those that did not develop dementia when they were walking while simultaneously doing a secondary task (e.g. counting backwards, or naming animals). In fact, the risk of progressing to dementia was two to three times greater in older adults with MCI whose walking speed diminished by at least 20 percent (e.g. slowing from one meter per second to 0.8 meters per second) in the dual-task walking condition relative to the single-task walking condition. The results of this study suggest that a significant slowing down in walking speed while doing a cognitively demanding task relative to normal walking speed (without doing a cognitively demanding task) can be used by clinicians to detect older adults with MCI who are at risk of developing dementia.

Authors: Manuel M. Montero-Odasso, Yanina Sarquis-Adamson, Mark Speechley, Michael J. Borrie, Vladimir C. Hachinski, Jennie Wells, Patricia M. Riccio, Marcelo Schapira, Ervin Sejdic, Richard M. Camicioli, Robert Bartha, William E. McIlroy, Susan Muir-Hunter