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

Neuropsychiatric symptoms predict hypometabolism in preclinical Alzheimer disease

Journal: Neurology

ABSTRACT

OBJECTIVE: To identify regional brain metabolic dysfunctions associated with neuropsychiatric symptoms (NPS) in preclinical Alzheimer disease (AD).

METHODS: We stratified 115 cognitively normal individuals into preclinical AD (both amyloid and tau pathologies present), asymptomatic at risk for AD (either amyloid or tau pathology present), or healthy controls (no amyloid or tau pathology present) using [18F]florbetapir PET and CSF phosphorylated tau biomarkers. Regression and voxel-based regression models evaluated the relationships between baseline NPS measured by the Neuropsychiatric Inventory (NPI) and baseline and 2-year change in metabolism measured by [18F]fluorodeoxyglucose (FDG) PET.

RESULTS: Individuals with preclinical AD with higher NPI scores had higher [18F]FDG uptake in the posterior cingulate cortex (PCC), ventromedial prefrontal cortex, and right anterior insula at baseline. High NPI scores predicted subsequent hypometabolism in the PCC over 2 years only in individuals with preclinical AD. Sleep/nighttime behavior disorders and irritability and lability were the components of the NPI that drove this metabolic dysfunction.

CONCLUSIONS: The magnitude of NPS in preclinical cases, driven by sleep behavior and irritability domains, is linked to transitory metabolic dysfunctions within limbic networks vulnerable to the AD process and predicts subsequent PCC hypometabolism. These findings support an emerging conceptual framework in which NPS constitute an early clinical manifestation of AD pathophysiology.

Authors: Ng KP, Pascoal TA, Mathotaarachchi S, Chung CO, Benedet AL, Shin M, Kang MS, Li X, Ba M, Kandiah N, Rosa-Neto P, Gauthier S

A systematic review of intervention approaches for driving cessation in older adults

Journal: The American Journal of Geriatric Psychiatry

ABSTRACT

OBJECTIVE: The aim of this project was to review the literature on interventions aimed at facilitating driving cessation in older adults, with and without dementia.

METHODS: A literature search was performed using the databases MEDLINE, CINAHL, Cochrane Central, Embase, and PsycINFO, from 1994 to September 2014. Two independent raters screened articles for inclusion and extracted study data. We only included articles if they directly addressed the topic of intervention approaches to facilitate the process of driving cessation in older adults or to support the adaptation of older adults who have had to stop driving and included a control group.

RESULTS: Of an initial 477 unique records identified, 111 pertained to driving cessation in older adults, and only three articles were controlled trials of intervention approaches related to driving cessation. One article described an intervention for retired drivers with dementia, while another was aimed at caregivers of drivers with dementia, and the third included retired and retiring drivers without dementia. Outcomes such as reduced depressive symptoms, increased trips out of home, and efficacy in dealing with the driving cessation process were positive, but the specific outcome measures and magnitude of effects varied across studies.

CONCLUSIONS: Although the results summarized in this review point toward potentially promising effects of interventions for facilitating driving cessation in older adults, these findings must be interpreted with caution given the significant methodological limitations of the studies, including small samples, participant attrition, lack of blinding, and non-validated outcome measures. Copyright © 2017 John Wiley & Sons, Ltd.

Authors: Rapoport MJ, Cameron DH, Sanford S, Naglie G, on behalf of the Canadian Consortium on Neurodegeneration in Aging Driving and Dementia Team

Statistical power and prediction accuracy in multisite resting-state fMRI connectivity

Journal: Neuroimage

ABSTRACT

Connectivity studies using resting-state functional magnetic resonance imaging are increasingly pooling data acquired at multiple sites. While this may allow investigators to speed up recruitment or increase sample size, multisite studies also potentially introduce systematic biases in connectivity measures across sites. In this work, we measure the inter-site effect in connectivity and its impact on our ability to detect individual and group differences. Our study was based on real, as opposed to simulated, multisite fMRI datasets collected in N=345 young, healthy subjects across 8 scanning sites with 3T scanners and heterogeneous scanning protocols, drawn from the 1000 functional connectome project. We first empirically show that typical functional networks were reliably found at the group level in all sites, and that the amplitude of the inter-site effects was small to moderate, with a Cohen’s effect size below 0.5 on average across brain connections. We then implemented a series of Monte-Carlo simulations, based on real data, to evaluate the impact of the multisite effects on detection power in statistical tests comparing two groups (with and without the effect) using a general linear model, as well as on the prediction of group labels with a support-vector machine. As a reference, we also implemented the same simulations with fMRI data collected at a single site using an identical sample size. Simulations revealed that using data from heterogeneous sites only slightly decreased our ability to detect changes compared to a monosite study with the GLM, and had a greater impact on prediction accuracy. However, the deleterious effect of multisite data pooling tended to decrease as the total sample size increased, to a point where differences between monosite and multisite simulations were small with N=120 subjects. Taken together, our results support the feasibility of multisite studies in rs-fMRI provided the sample size is large enough.

Authors: Dansereau C, Benhajali Y, Risterucci C, Pich EM, Orban P, Arnold D, Bellec P

Executive function performance and change in aging is predicted by apolipoprotein E, intensified by catechol-O-methyltransferase and brain-derived neurotrophic factor, and moderated by age and lifestyle

Journal: Neurobiology of Aging

ABSTRACT

Recent studies have reported several genetic, health, and aging interaction effects in predicting cognitive performance and change. We used an accelerated longitudinal design to examine interactions among genetic, lifestyle, and aging for executive function (EF) in non-demented older adults (n = 634; age range = 53-95 years). The polymorphisms were apolipoprotein E (APOE), catechol-O-methyltransferase (COMT), and brain-derived neurotrophic factor (BDNF). We tested (1) independent and additive effects of APOE, COMT, and BDNF and (2) APOE effect modification for COMT + BDNF, on EF performance and 9-year change as separated by age and lifestyle activities. First, APOE ε4+ carriers had poorer EF performance and steeper 9-year decline. Second, APOE ε4+ carriers with (1) BDNF Met/Met genotype and (2) increasing allelic risk in the COMT + BDNF risk panel had poorer EF performance; these effects were moderated by lifestyle activities (composite of everyday social, physical, and cognitive activities). Examining APOE effect modification for COMT + BDNF risk panel effects with other moderating factors may help identify complex neurobiological and genetic underpinnings of polygenic phenotypes such as EF in aging.

Authors: Sapkota S, Backman L, Dixon RA

Antipsychotic Use in Dementia: Is There a Problem and Are There Solutions?

Journal: Canadian Journal of Psychiatry

ABSTRACT

Antipsychotics are necessary for many older adults to treat major mental illnesses or reduce distressing psychiatric symptoms. Current controversy exists over the role of antipsychotics in the management of neuropsychiatric symptoms (NPS) in persons with dementia. Although some NPS may be appropriately and safely treated with antipsychotics, a fine balance must be achieved between the benefits of these medications, which are often modest, and adverse events, which may have significant consequences. Approximately one-third of all persons with dementia are currently prescribed antipsychotic medications, and there is significant variation in the use of antipsychotics across care settings and providers. Reducing the inappropriate or unnecessary use of antipsychotics among persons with dementia has been the focus of increasing attention owing to better awareness of the potential problems associated with these medications. Several approaches can be used to curb the use of antipsychotics among persons with dementia, including policy or regulatory changes, public reporting, and educational outreach. Recently, there has been encouraging evidence of a downward trend in the use of antipsychotics in many long-term care settings, although prescribing rates are still higher than what is likely optimal. Although reducing the inappropriate use of antipsychotics is a complex task, psychiatrists can play an important role via the provision of clinical care and research evidence, contributing to improved care of persons with dementia in Canada and elsewhere.

Authors: Kirkham J, Sherman C, Velkers C, Maxwell C, Gill S, Rochon P, Seitz D

Analysis of C9orf72 repeat expansions in a large international cohort of dementia with Lewy bodies

Journal: Neurobiology of Aging

ABSTRACT

C9orf72 repeat expansions are a common cause of amyotrophic lateral sclerosis and frontotemporal dementia. To date, no large-scale study of dementia with Lewy bodies (DLB) has been undertaken to assess the role of C9orf72 repeat expansions in the disease. Here, we investigated the prevalence of C9orf72 repeat expansions in a large cohort of DLB cases and identified no pathogenic repeat expansions in neuropathologically or clinically defined cases, showing that C9orf72 repeat expansions are not causally associated with DLB.

Authors: Kun-Rodrigues C, Ross OA, Orme T, Shepherd C, Parkkinen L, Darwent L, Hernandez D, Ansorge O, Clark LN, Honig LS, Marder K, Lemstra A, Scheltens P, van der Flier W, Louwersheimer E, Holstege H, Rogaeva E, St George-Hyslop P, Londos E, Zetterberg H, Barber I, Braae A, Brown K, Morgan K, Maetzler W, Berg D, Troakes C, Al-Sarraj S, Lashley T, Holton J, Compta Y, Van Deerlin V, Trojanowski JQ, Serrano GE, Beach TG, Clarimon J, Lleo A, Morenas-Rodriguez E, Lesage S, Galasko D, Masliah E, Santana I, Diez M, Pastor P, Tienari PJ, Myllykangas L, Oinas M, Revesz T, Lees A, Boeve BF, Petersen RC, Ferman TJ, Escott-Price V, Graff-Radford N, Cairns NJ, Morris JC, Stone DJ, Pickering-Brown S, Mann D, Dickson DW, Halliday GM, Singleton A, Guerreiro R, Bras J

The prevalence and biomarkers’ characteristic of rapidly progressive Alzheimer’s disease from the Alzheimer’s Disease Neuroimaging Initiative database

Journal: Alzheimer's & Dementia

ABSTRACT

INTRODUCTION: The prevalence and detailed biomarkers’ characteristic of rapidly progressive Alzheimer’s disease (rpAD) remain incompletely understood.

METHODS: A total of 312 mild AD patients from the Alzheimer’s Disease Neuroimaging Initiative database were chosen and dichotomized into rpAD and non-rpAD groups. We performed the prevalence and comprehensive biomarker evaluation.

RESULTS: The prevalence of rpAD was 17.6% in mild AD. Compared with non-rpAD, there were no differences in APOEε4/ε4, APOE ε3/ε4, and APOE ε2/ε4 genotype distribution, cerebrospinal fluid tau, phosphorylated tau (p-tau), amyloid-β, hippocampus volume, and amyloid deposition in rpAD. Yet, a lower p-tau/tau ratio was observed in rpAD (P = .04). rpAD showed region-specific hypometabolism ([18F]fluorodeoxyglucose-positron emission tomography [FDG-PET]) (P = .001). Receiver-operating characteristic analysis of FDG-PET demonstrated that left angular and left temporal cortices were the regions with higher area under the curve and predictive value for identifying clinical at-risk rpAD.

DISCUSSION: We identified that rpAD commonly existed in mild AD. Cerebral hypometabolism could provide potential clinical differential value for rpAD in the short-term follow-up period.

Authors: Ba M, Li X, Ng KP, Pascoal TA, Mathotaarachchi S, Rosa-Neto P, Gauthier S, Alzheimer Disease Neuroimaging I

Resting-state network dysfunction in Alzheimer’s disease: A systematic review and meta-analysis

Journal: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring

ABSTRACT

INTRODUCTION: We performed a systematic review and meta-analysis of the Alzheimer’s disease (AD) literature to examine consistency of functional connectivity alterations in AD dementia and mild cognitive impairment, using resting-state functional magnetic resonance imaging.

METHODS: Studies were screened using a standardized procedure. Multiresolution statistics were performed to assess the spatial consistency of findings across studies.

RESULTS: Thirty-four studies were included (1363 participants, average 40 per study). Consistent alterations in connectivity were found in the default mode, salience, and limbic networks in patients with AD dementia, mild cognitive impairment, or in both groups. We also identified a strong tendency in the literature toward specific examination of the default mode network.

DISCUSSION: Convergent evidence across the literature supports the use of resting-state connectivity as a biomarker of AD. The locations of consistent alterations suggest that highly connected hub regions in the brain might be an early target of AD.

Authors: Badhwar, A., Tam, A., Dansereau, C., Orban, P., Hoffstaedter, F., & Bellec, P.

C9orf72 and ATXN2 repeat expansions coexist in a family with ataxia, dementia, and parkinsonism.

Journal: Movement Disorders

ABSTRACT

BACKGROUND: Intermediate interrupted ataxin 2 (ATXN2) alleles (27-33 CAG-repeats) increase the risk for amyotrophic lateral sclerosis and are reported as modifiers in chromosome 9 open reading frame 72 (C9orf72) carriers, rendering susceptibility to amyotrophic lateral sclerosis rather than frontotemporal lobar degeneration. The clinical presentation of C9orf72 patients with pathogenic ATXN2 alleles (≥35 CAG-repeats) is unknown.

METHODS: Blood samples were collected from a family affected by ataxia, dementia, and parkinsonism, but not amyotrophic lateral sclerosis. Mutation analyses of the proband included C9orf72 and 14 ataxia genes, followed by segregation analyses in family members.

RESULTS: Both affected siblings carry an uninterrupted 37-repeat expansion in ATXN2 and a methylated G4 C2 -repeat allele in C9orf72 that is typical of large pathogenic expansions.

CONCLUSIONS: The CAG-expansion in ATXN2 likely caused the ataxia, whereas the dementia may be linked to both C9orf72 and ATXN2 repeat expansions. The pathological uninterrupted ATXN2 repeat may not have the same modifying effect as intermediate interrupted alleles. © 2016 International Parkinson and Movement Disorder Society.

Authors: Zhang M, Xi Z, Misquitta K, Sato C, Moreno D, Liang Y, Slow E, Rogaeva E, Tartaglia MC

Meta-analysis of Driving Cessation and Dementia: Does Sex Matter?

Journal: The Journals of Gerontology, Series B: Psychological Sciences and Social Sciences, 2016, online

This meta-analysis is the first of its kind to study sex differences in driving cessation among individuals with and without dementia. Drs. Mary Tierney, Mark Rapoport, Gary Naglie, and Ms. Nicolette Baines found that driving cessation is significantly more prevalent in women with dementia than men. What’s more, the same pattern was found in men and women without dementia. Their review highlights the need for more research on the reasons for the observed sex differences, which may be due to biological sex differences as well as gender differences in roles and relationships between men and women. Longitudinal studies are also needed in order to estimate the incidence of sex differences in driving cessation in participants who have undergone diagnostic assessments to both include and exclude dementia. These longitudinal studies should also compare driving cessation in regions with different population densities and transportation options, the researchers explain. Above all, their findings show that sex and gender differences may have important implications for supportive responses offered to drivers with dementia both prior to and following driving cessation.

Authors: Baines N, Au B, Rapoport MJ, Naglie G, Tierney MC

Disentangling Cognitive-Frailty: Results From the Gait and Brain Study

Journal: The Journal of Gerontology, Series A: Biological Sciences and Medical Sciences, 2016, 71(11): 1476-1482

A relatively new concept, “Cognitive-Frailty” describes the overlapping presence of two syndromes that can occur with aging: cognitive impairment and physical frailty, which is characterized by weakness, decreased energy, and reduced activity. It has been suggested that having cognitive-frailty makes one more likely to develop dementia than frailty alone. Dr. Montero-Odasso and colleagues tested this hypothesis, and also examined whether a combination of cognitive impairment (defined as a total score below 26/30 on the Montreal Cognitive Assessment (MoCA)) and a slow walking speed (defined as walking slower than 1 meter per second) was a predictor of developing dementia. What they found was that people with frailty were more likely to have cognitive impairment than people without frailty, but cognitive-frailty did not lead to dementia more often than frailty alone. Those with cognitive impairment and slow walking speed, however, were the most likely to develop dementia. This suggests that a simple motor test, such as one’s walking speed, and a reliable cognitive test, such as the MoCA, are superior to the cognitive-frailty construct for detecting individuals at risk for dementia.

Authors: Montero-Odasso MM, Barnes B, Speechley M, Muir Hunter SW, Doherty TJ, Duque G, Gopaul K, Sposato LA, Casas-Herrero A, Borrie MJ, Camicioli R, Wells JL

Canadian Consensus Guidelines on Use of Amyloid Imaging in Canada: Update and Future Directions from the Specialized Task Force on Amyloid imaging in Canada

Journal: Canadian Journal of Neurological Sciences

ABSTRACT

Positron emission tomography (PET) imaging of brain amyloid beta is now clinically available in several countries including the United States and the United Kingdom, but not Canada. It has become an established technique in the field of neuroimaging of aging and dementia, with data incorporated in the new consensus guidelines for the diagnosis of Alzheimer disease and predementia Alzheimer’s disease-related conditions. At this point, there are three US Food and Drug Administration- and European Union-approved tracers. Guided by appropriate use criteria developed in 2013 by the Alzheimer’s Association and the Society of Nuclear Medicine and Molecular Imaging, the utility of amyloid imaging in medical practice is now supported by a growing body of research. In this paper, we aimed to provide an update on the 2012 Canadian consensus guidelines to dementia care practitioners on proper use of amyloid imaging. We also wished to generate momentum for the industry to submit a new drug proposal to Health Canada. A group of local, national, and international dementia experts and imaging specialists met to discuss scenarios in which amyloid PET could be used appropriately. Peer-reviewed and published literature between January 2004 and May 2015 was searched. Technical and regulatory considerations pertaining to Canada were considered. The results of a survey of current practices in Canadian dementia centers were considered. A set of specific clinical and research guidelines was agreed on that defines the types of patients and clinical circumstances in which amyloid PET could be used in Canada. Future research directions were also outlined, notably the importance of studies that would assess the pharmaco-economics of amyloid imaging.

Authors: Authors: Laforce R, Rosa-Neto P, Soucy JP, Rabinovici GD, Dubois B, Gauthier S

VoxelStats: A MATLAB Package for Multi-Modal Voxel-Wise Brain Image Analysis

Journal: Frontiers in Neuroinformatics, 2016, online

ABSTRACT

In healthy individuals, behavioral outcomes are highly associated with the variability on brain regional structure or neurochemical phenotypes. Similarly, in the context of neurodegenerative conditions, neuroimaging reveals that cognitive decline is linked to the magnitude of atrophy, neurochemical declines, or concentrations of abnormal protein aggregates across brain regions. However, modeling the effects of multiple regional abnormalities as determinants of cognitive decline at the voxel level remains largely unexplored by multimodal imaging research, given the high computational cost of estimating regression models for every single voxel from various imaging modalities. VoxelStats is a voxel-wise computational framework to overcome these computational limitations and to perform statistical operations on multiple scalar variables and imaging modalities at the voxel level. VoxelStats package has been developed in Matlab(®) and supports imaging formats such as Nifti-1, ANALYZE, and MINC v2. Prebuilt functions in VoxelStats enable the user to perform voxel-wise general and generalized linear models and mixed effect models with multiple volumetric covariates. Importantly, VoxelStats can recognize scalar values or image volumes as response variables and can accommodate volumetric statistical covariates as well as their interaction effects with other variables. Furthermore, this package includes built-in functionality to perform voxel-wise receiver operating characteristic analysis and paired and unpaired group contrast analysis. Validation of VoxelStats was conducted by comparing the linear regression functionality with existing toolboxes such as glim_image and RMINC. The validation results were identical to existing methods and the additional functionality was demonstrated by generating feature case assessments (t-statistics, odds ratio, and true positive rate maps). In summary, VoxelStats expands the current methods for multimodal imaging analysis by allowing the estimation of advanced regional association metrics at the voxel level.

Authors: Authors: Mathotaarachchi S, Wang S, Shin M, Pascoal TA, Benedet AL, Kang MS, Beaudry T, Fonov VS, Gauthier S, Labbe A, Rosa-Neto P

Changes in Frailty Predict Changes in Cognition in Older Men: The Honolulu-Asia Aging Study

Journal: Journal of Alzheimer's Disease

ABSTRACT

BACKGROUND: As cognitive decline mostly occurs in late life, where typically it co-exists with many other ailments, it is important to consider frailty in understanding cognitive change.

OBJECTIVE: Here, we examined the association of change in frailty status with cognitive trajectories in a well-studied cohort of older Japanese-American men.

METHODS: Using the prospective Honolulu-Asia Aging Study (HAAS), 2,817 men of Japanese descent were followed (aged 71-93 at baseline). Starting in 1991 with follow-up health assessments every two to three years, cognition was measured using the Cognitive Abilities Screening Instrument (CASI). For this study, health data was used to construct an accumulation of deficits frailty index (FI). Using six waves of data, multilevel growth curve analyses were constructed to examine simultaneous changes in cognition in relation to changes in FI, controlling for baseline frailty, age, education, and APOE-ɛ4 status.

RESULTS: On average, CASI scores declined by 2.0 points per year (95% confidence interval 1.9-2.1). Across six waves, each 10% within-person increase in frailty from baseline was associated with a 5.0 point reduction in CASI scores (95% confidence interval 4.7-5.2). Baseline frailty and age were associated both with lower initial CASI scores and with greater decline across the five follow-up assessments (p < 0.01).

DISCUSSION: Cognition is adversely affected by impaired health status in old age. Using a multidimensional measure of frailty, both baseline status and within-person changes in frailty were predictive of cognitive trajectories.

Authors: Authors: Armstrong JJ, Godin J, Launer LJ, White LR, Mitnitski A, Rockwood K, Andrew MK

Analysis of C9orf72 in patients with frontotemporal dementia and amyotrophic lateral sclerosis from Argentina

Journal: Neurobiology of Aging

Abstract

Pathologic expansion of the G4C2 repeat in C9orf72 is the main genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). To evaluate the frequency of the G4C2 expansion in a Latin American cohort of FTD and ALS patients, we used a 2-step genotyping strategy. For FTD, we observed an overall expansion frequency of 18.2% (6 of 33 unrelated cases). Moreover, the C9orf72 expansion accounted for 37.5% of all familial FTD cases (6 of 16 families). The expansion frequency in sporadic ALS cases was 2% (1 of 47 unrelated patients), whereas we observed the expansion in 1 of 3 families with a positive history for ALS. Overall, the expansion frequency in our FTD group was similar to that reported for patients in Europe and North America, whereas the frequency in our sporadic ALS group was significantly lower. To our knowledge, this is the first report on the frequency of the C9orf72 expansion in a Latin American population.

Authors: Authors: Itzcovich T, Xi Z, Martinetto H, Chrem-Mendez P, Russo MJ, de Ambrosi B, Uchitel OD, Nogues M, Silva E, Rojas G, Bagnatti P, Amengual A, Campos J, Rogaeva E, St George-Hyslop P, Allegri R, Sevlever G, Surace EI

Ethical Considerations for the Use of Next-Generation Alzheimer Drugs in Symptomatic and At-Risk Patients

Journal: Continuum

ABSTRACT

This article presents a case in which a patient with mild Alzheimer disease requests a prescription for a newly developed Alzheimer disease drug, after which the patient’s daughter inquires about its potential usefulness as a prevention strategy for herself. The article discusses the physician’s responsibility to balance the ethical principles of beneficence, nonmaleficence, and respect for patient autonomy when evaluating requests for medications from patients with neurocognitive disease as well as from asymptomatic but at-risk patients.

Authors: Authors: Gauthier S, Rosa-Neto P, Kass JS

Aerobic Glycolysis in the Frontal Cortex Correlates with Memory Performance in Wild-Type Mice But Not the APP/PS1 Mouse Model of Cerebral Amyloidosis

Journal: Journal of Neuroscience

This CCNA-funded study suggests that, while lactic acid production is beneficial for memory in the healthy aging brain, it might be detrimental in Alzheimer’s disease (AD). These findings will help guide the development of drugs to alter lactic acid metabolism for the treatment of AD. Specifically, this article demonstrates that lactic acid (a metabolite), and the enzymes that generate it, decrease with age in the brains of normal mice. Although an increase of lactic acid-producing enzymes is correlated with improved memory in older mice, when it comes to an Alzheimer’s disease mouse model, elevated levels are – surprisingly – associated with poorer memory.

Authors: Authors: Harris RA, Tindale L, Lone A, Singh O, Macauley SL, Stanley M, Holtzman DM, Bartha R, Cumming R

Combination Therapy of Anti-Tau and Anti-Amyloid Drugs for Disease Modification in Early-Stage Alzheimer’s Disease: Socio-Economic Considerations Modeled on Treatments for Tuberculosis, HIV/AIDS and Breast Cancer

Journal: The Journal of Prevention of Alzheimer's Disease

This article describes a study design that aims to prove that the combination of two drugs – acting on the two major pathophysiological mechanisms of Alzheimer’s disease (i.e. amyloid deposition and tau hyperphosphorylation) – can modify the disease’s progression. We suggest that these drugs would work best in delaying progression to dementia in persons with mild cognitive impairment that is due to Alzheimer’s disease. Furthermore we propose that if such a drug combination is effective, it could be affordable using the models of drug combinations against tuberculosis, AIDS/HIV and breast cancer. This article, written by a first year medical student at McGill University, is an example of the importance of exposing physicians in training to the social impact of clinical research. This is the first publication of the Ethical, Legal, Social Impact (ELSI) committee of the Canadian Consortium on Neurodegeneration in Aging (CCNA).

Authors: Authors: Tomaszewski S, Gauthier S, Wimo A, Rosa-Neto P.

Determining composition of micron-scale protein deposits in neurodegenerative disease by spatially targeted optical microproteomics

Journal: eLife

In many neurodegenerative diseases – including Alzheimer’s disease – deposits of misfolded proteins form in the brain. While visible through a microscope, these deposits are too small to be isolated and extracted. In this article, researchers show how their new technique – spatially targeted microproteomics (STOMP) – makes use of tightly-focused laser light to attach chemical handles to these protein deposits, so that they can be recovered for identification and analysis. Through using STOMP, researchers have identified a number of proteins not previously associated with pathology in Alzheimer’s disease (including some proteins involved in signalling across synapses between neurons), and hope to see STOMP used to explore the underlying biology of other neurodegenerative diseases.

Authors: Authors: Hadley KC, Rakhit R, Guo H, Sun Y, Jonkman JE, McLaurin J, Hazrati LN, Emili A, Chakrabartty A