Publications by authors named "Sandra E Black"

405 Publications

Brain structure and function in people recovering from COVID-19 after hospital discharge or self-isolation: a longitudinal observational study protocol.

CMAJ Open 2021 Oct-Dec;9(4):E1114-E1119. Epub 2021 Nov 30.

Hurvitz Brain Sciences Program (MacIntosh, Gao, Masellis, Goubran, Lam, Heyn, Black, Graham), Physical Sciences Platform (MacIntosh, Jegatheesan, Goubran, Graham), Evaluative Clinical Sciences, Integrated Community Program (Cheng), Harquail Centre for Neuromodulation (Rabin) and Evaluative Clinical Sciences, Trauma, Emergency & Critical Care Research Program (Fowler), Sunnybrook Research Institute; Department of Medical Biophysics (MacIntosh, Chen, Chad, Jegatheesan, Goubran, Graham), University of Toronto; LC Campbell Cognitive Neurology Research Group (Ji, Gao, Masellis, Lam, Black), Sunnybrook Hospital; Rotman Research Institute (Chen, Gilboa, Roudaia, Sekuler, Chad), Baycrest Health Sciences; Division of Neurology (Masellis, Rabin, Lam, Black), Department of Medicine, University of Toronto; Rehabilitation Sciences Institute (Rabin), Department of Medical Imaging (Heyn) and Department of Psychology (Gilboa, Sekuler), University of Toronto; Department of Medicine (Cheng, Fowler), University of Toronto, Sunnybrook Health Sciences Centre, Toronto, Ont.; Department of Psychology, Neuroscience & Behaviour (Sekuler), McMaster University, Hamilton, Ont.

Background: The detailed extent of neuroinvasion or deleterious brain changes resulting from COVID-19 and their time courses remain to be determined in relation to "long-haul" COVID-19 symptoms. Our objective is to determine whether there are alterations in functional brain imaging measures among people with COVID-19 after hospital discharge or self-isolation.

Methods: This paper describes a protocol for NeuroCOVID-19, a longitudinal observational study of adults aged 20-75 years at Sunnybrook Health Sciences Centre in Toronto, Ontario, that began in April 2020. We aim to recruit 240 adults, 60 per group: people who contracted COVID-19 and were admitted to hospital (group 1), people who contracted COVID-19 and self-isolated (group 2), people who experienced influenza-like symptoms at acute presentation but tested negative for COVID-19 and self-isolated (group 3, control) and healthy people (group 4, control). Participants are excluded based on premorbid neurologic or severe psychiatric illness, unstable cardiovascular disease, and magnetic resonance imaging (MRI) contraindications. Initial and 3-month follow-up assessments include multiparametric brain MRI and electroencephalography. Sensation and cognition are assessed alongside neuropsychiatric assessments and symptom self-reports. We will test the data from the initial and follow-up assessments for group differences based on 3 outcome measures: MRI cerebral blood flow, MRI resting state fractional amplitude of low-frequency fluctuation and electroencephalography spectral power.

Interpretation: If neurophysiologic alterations are detected in the COVID-19 groups in our NeuroCOVID-19 study, this information could inform future research regarding interventions for long-haul COVID-19. The study results will be disseminated to scientists, clinicians and COVID-19 survivors, as well as the public and private sectors to provide context on how brain measures relate to lingering symptoms.
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http://dx.doi.org/10.9778/cmajo.20210023DOI Listing
November 2021

Cognitive and Neuroimaging Profiles of Older Adults With Attention Deficit/Hyperactivity Disorder Presenting to a Memory Clinic.

J Atten Disord 2021 Nov 16:10870547211060546. Epub 2021 Nov 16.

University of Toronto, Toronto, ON, Canada.

Objective: Some features of attention-deficit/hyperactivity disorder (ADHD) may resemble those of mild cognitive impairment (MCI) in older adults, contributing to diagnostic uncertainty in individuals seeking assessment in memory clinics. We systematically compared cognition and brain structure in ADHD and MCI to clarify the extent of overlap and identify potential features unique to each.

Method: Older adults from a Cognitive Neurology clinic (40 ADHD, 29 MCI, 37 controls) underwent neuropsychological assessment. A subsample ( = 80) underwent structural neuroimaging.

Results: Memory was impaired in both patient groups, but reflected a storage deficit in MCI (supported by relatively smaller hippocampi) and an encoding deficit in ADHD (supported by frontal lobe thinning). Both groups displayed normal executive functioning. Semantic retrieval was uniquely impaired in MCI.

Conclusion: Although ADHD has been proposed as a dementia risk factor or prodrome, we propose it is rather a pathophysiologically-unique phenotypic mimic acting via overlap in memory and executive performance.
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http://dx.doi.org/10.1177/10870547211060546DOI Listing
November 2021

The impact of reporting magnetic resonance imaging incidental findings in the Canadian alliance for healthy hearts and minds cohort.

BMC Med Ethics 2021 10 28;22(1):145. Epub 2021 Oct 28.

Department of Medicine and Diagnostic Radiology, McGill University, 1001 Decarie Boulevard, Montreal, QC, H4A 3J1, Canada.

Background: In the Canadian Alliance for Healthy Hearts and Minds (CAHHM) cohort, participants underwent magnetic resonance imaging (MRI) of the brain, heart, and abdomen, that generated incidental findings (IFs). The approach to managing these unexpected results remain a complex issue. Our objectives were to describe the CAHHM policy for the management of IFs, to understand the impact of disclosing IFs to healthy research participants, and to reflect on the ethical obligations of researchers in future MRI studies.

Methods: Between 2013 and 2019, 8252 participants (mean age 58 ± 9 years, 54% women) were recruited with a follow-up questionnaire administered to 909 participants (40% response rate) at 1-year. The CAHHM policy followed a restricted approach, whereby routine feedback on IFs was not provided. Only IFs of severe structural abnormalities were reported.

Results: Severe structural abnormalities occurred in 8.3% (95% confidence interval 7.7-8.9%) of participants, with the highest proportions found in the brain (4.2%) and abdomen (3.1%). The majority of participants (97%) informed of an IF reported no change in quality of life, with 3% of participants reporting that the knowledge of an IF negatively impacted their quality of life. Furthermore, 50% reported increased stress in learning about an IF, and in 95%, the discovery of an IF did not adversely impact his/her life insurance policy. Most participants (90%) would enrol in the study again and perceived the MRI scan to be beneficial, regardless of whether they were informed of IFs. While the implications of a restricted approach to IF management was perceived to be mostly positive, a degree of diagnostic misconception was present amongst participants, indicating the importance of a more thorough consent process to support participant autonomy.

Conclusion: The management of IFs from research MRI scans remain a challenging issue, as participants may experience stress and a reduced quality of life when IFs are disclosed. The restricted approach to IF management in CAHHM demonstrated a fair fulfillment of the overarching ethical principles of respect for autonomy, concern for wellbeing, and justice. The approach outlined in the CAHHM policy may serve as a framework for future research studies. Clinical trial registration https://clinicaltrials.gov/ct2/show/NCT02220582 .
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http://dx.doi.org/10.1186/s12910-021-00706-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551943PMC
October 2021

Feasibility of a continuous, multi-sensor remote health monitoring approach in persons living with neurodegenerative disease.

J Neurol 2021 Oct 27. Epub 2021 Oct 27.

Department of Kinesiology and Health Sciences, University of Waterloo, Waterloo, ON, Canada.

Background: Remote health monitoring with wearable sensor technology may positively impact patient self-management and clinical care. In individuals with complex health conditions, multi-sensor wear may yield meaningful information about health-related behaviors. Despite available technology, feasibility of device-wearing in daily life has received little attention in persons with physical or cognitive limitations. This mixed methods study assessed the feasibility of continuous, multi-sensor wear in persons with cerebrovascular (CVD) or neurodegenerative disease (NDD).

Methods: Thirty-nine participants with CVD, Alzheimer's disease/amnestic mild cognitive impairment, frontotemporal dementia, Parkinson's disease, or amyotrophic lateral sclerosis (median age 68 (45-83) years, 36% female) wore five devices (bilateral ankles and wrists, chest) continuously for a 7-day period. Adherence to device wearing was quantified by examining volume and pattern of device removal (non-wear). A thematic analysis of semi-structured de-brief interviews with participants and study partners was used to examine user acceptance.

Results: Adherence to multi-sensor wear, defined as a minimum of three devices worn concurrently, was high (median 98.2% of the study period). Non-wear rates were low across all sensor locations (median 17-22 min/day), with significant differences between some locations (p = 0.006). Multi-sensor non-wear was higher for daytime versus nighttime wear (p < 0.001) and there was a small but significant increase in non-wear over the collection period (p = 0.04). Feedback from de-brief interviews suggested that multi-sensor wear was generally well accepted by both participants and study partners.

Conclusion: A continuous, multi-sensor remote health monitoring approach is feasible in a cohort of persons with CVD or NDD.
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http://dx.doi.org/10.1007/s00415-021-10831-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8548705PMC
October 2021

Brain atrophy trajectories predict differential functional performance in Alzheimer's disease: Moderations with apolipoprotein E and sex.

Alzheimers Dement (Amst) 2021 14;13(1):e12244. Epub 2021 Oct 14.

Hurvitz Brain Sciences Research Program Sunnybrook Research Institute Sunnybrook Health Sciences Centre Toronto Ontario Canada.

Introduction: We examine whether distinct brain atrophy patterns (using brain parenchymal fraction [BPF]) differentially predict functional performance and decline in Alzheimer's disease (AD), and are independently moderated by (1) a key AD genetic risk marker (apolipoprotein E []), (2) sex, and (3) high-risk group (women ɛ4 carriers).

Methods: We used a 2-year longitudinal sample of AD patients (baseline = 170; mean age = 71.3 [9.1] years) from the Sunnybrook Dementia Study. We applied latent class analysis, latent growth modeling, and path analysis. We aimed to replicate our findings (= 184) in the Alzheimer's Disease Neuroimaging Initiative.

Results: We observed that high brain atrophy class predicted lower functional performance and steeper decline. This association was moderated by , sex, and high-risk group. Baseline findings as moderated by and high-risk group were replicated.

Discussion: Women ɛ4 carriers may selectively be at a greater risk of functional impairment with higher brain atrophy.
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http://dx.doi.org/10.1002/dad2.12244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8515221PMC
October 2021

Contribution of rare variant associations to neurodegenerative disease presentation.

NPJ Genom Med 2021 Sep 28;6(1):80. Epub 2021 Sep 28.

Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada.

Genetic factors contribute to neurodegenerative diseases, with high heritability estimates across diagnoses; however, a large portion of the genetic influence remains poorly understood. Many previous studies have attempted to fill the gaps by performing linkage analyses and association studies in individual disease cohorts, but have failed to consider the clinical and pathological overlap observed across neurodegenerative diseases and the potential for genetic overlap between the phenotypes. Here, we leveraged rare variant association analyses (RVAAs) to elucidate the genetic overlap among multiple neurodegenerative diagnoses, including Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), mild cognitive impairment, and Parkinson's disease (PD), as well as cerebrovascular disease, using the data generated with a custom-designed neurodegenerative disease gene panel in the Ontario Neurodegenerative Disease Research Initiative (ONDRI). As expected, only ~3% of ONDRI participants harboured a monogenic variant likely driving their disease presentation. Yet, when genes were binned based on previous disease associations, we observed an enrichment of putative loss of function variants in PD genes across all ONDRI cohorts. Further, individual gene-based RVAA identified significant enrichment of rare, nonsynonymous variants in PARK2 in the FTD cohort, and in NOTCH3 in the PD cohort. The results indicate that there may be greater heterogeneity in the genetic factors contributing to neurodegeneration than previously appreciated. Although the mechanisms by which these genes contribute to disease presentation must be further explored, we hypothesize they may be a result of rare variants of moderate phenotypic effect contributing to overlapping pathology and clinical features observed across neurodegenerative diagnoses.
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http://dx.doi.org/10.1038/s41525-021-00243-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478934PMC
September 2021

Effect of Cognitive Reserve on the Association of Vascular Brain Injury With Cognition: Analysis of the PURE and CAHHM Studies.

Neurology 2021 10 9;97(17):e1707-e1716. Epub 2021 Sep 9.

From the Department of Clinical Neurosciences and Hotchkiss Brain Institute (R.D., E.E.S.) and Departments of Radiology and Clinical Neurosciences (C.R.M.), University of Calgary; Department of Medicine and Diagnostic Radiology (M.G.F.), McGill University, Montreal; Population Health Research Institute, Hamilton Health Sciences (K.M.S., K.B., D.D., S.R., K.T., S.Y., S.S.A.), Department of Medicine (K.M.S., K.B., S.R., K.T., S.Y., S.S.A.), Department of Electrical and Computer Engineering, School of Biomedical Engineering (M.D.N.), and Department of Health Evidence and Impact (K.T., S.Y., S.S.A.), McMaster University, Hamilton; Department of Molecular Genetics, Ontario Institute for Cancer Research (P.A.), Department of Medicine (Neurology) (S.B.), Sunnybrook Research Institute (S.B.), and Department of Medical Imaging (A.R.M.), Sunnybrook Health Sciences Centre, University of Toronto; Department of Medical Imaging, St. Michael's Hospital (A.K.), and Department of Medicine, ICES (D.S.L.), University of Toronto; Department of Preventive and Social Medicine, École de Santé Publique (P.B.), and Research Centre, Montreal Heart Institute (D.B., J.-C.T.), Université de Montréal; Research Centre (P.B.), CHU Sainte-Justine, Montreal; School of Population and Public Health (T.D.) and Department of Radiology, St. Paul's Hospital (J.L.), University of British Columbia, Vancouver; Division of Cardiology (A.D.), University of Ottawa Heart Institute, University of Ottawa; Atlantic PATH (J.H.), Dalhousie University, Halifax, Canada; Department of Neurology (T.I.), Government Medical College Thiruvananthapuram, India; Diagnostic Imaging (D.K.), Brampton Civic Hospital, William Osler Health System, Etobicoke; Faculty of Health Sciences (S.A.L.), Simon Fraser University, Burnaby, Canada; National Center for Cardiovascular Diseases (W.L.), Chinese Academy of Medical Sciences, Fu Wai Hospital, Beijing, China; Diagnostic Imaging (M.D.N.), St. Joseph's Health Care, Hamilton; Department of Medical Biophysics and Robarts Research Institute (G.P.), Western University, London; Institut de Cardiologie et de Pneumologie de Quebec (P.P.), Université Laval, Canada; Departments of Psychiatry (D.S.), Angiology (A.S.), Social Medicine (K.Z.), and General and Interventional Radiology and Neuroradiology (A.Z.), Wroclaw Medical University, Poland; and Cancer Research and Analytics (J.E.V.), Cancer Care Control Alberta, Alberta Health Services, Calgary, Canada.

Background And Objectives: To determine whether cognitive reserve attenuates the association of vascular brain injury with cognition.

Methods: Cross-sectional data were analyzed from 2 harmonized studies: the Canadian Alliance for Healthy Hearts and Healthy Minds (CAHHM) and the Prospective Urban and Rural Epidemiology (PURE) study. Markers of cognitive reserve were education, involvement in social activities, marital status, height, and leisure physical activity, which were combined into a composite score. Vascular brain injury was defined as nonlacunar brain infarcts or high white matter hyperintensity (WMH) burden on MRI. Cognition was assessed using the Montreal Cognitive Assessment Tool (MoCA) and the Digit Symbol Substitution Test (DSST).

Results: There were 10,916 participants age 35-81. Mean age was 58.8 years (range 35-81) and 55.8% were female. Education, moderate leisure physical activity, being in a marital partnership, being taller, and participating in social groups were each independently associated with higher cognition, as was the composite cognitive reserve score. Vascular brain injury was associated with lower cognition (β -0.35 [95% confidence interval [CI] -0.53 to -0.17] for MoCA and β -2.19 [95% CI -3.22 to -1.15] for DSST) but the association was not modified by the composite cognitive reserve variable (interaction = 0.59 for MoCA and = 0.72 for DSST).

Conclusions: Both vascular brain injury and markers of cognitive reserve are associated with cognition. However, the effects were independent such that the adverse effects of covert vascular brain injury were not attenuated by higher cognitive reserve. To improve cognitive brain health, interventions to both prevent cerebrovascular disease and promote positive lifestyles are needed.
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http://dx.doi.org/10.1212/WNL.0000000000012765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8605614PMC
October 2021

Leukotriene receptor antagonist use and cognitive decline in normal cognition, mild cognitive impairment, and Alzheimer's dementia.

Alzheimers Res Ther 2021 09 3;13(1):147. Epub 2021 Sep 3.

Dr. Sandra Black Centre for Brain Resilience & Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Canada.

Background: Leukotriene receptor antagonists (LTRAs) alleviate Alzheimer's disease (AD) pathology and improve cognition in animal models; however, clinical evidence is limited. This study aimed to explore the associations between the use of LTRAs (montelukast or zafirlukast) and cognitive performance in people with normal cognition, mild cognitive impairment (MCI), or AD dementia. We hypothesized that LTRA use would be associated with better cognitive performance over time.

Methods: This longitudinal observational study used data from the National Alzheimer's Coordinating Center. Within groups of participants with normal cognition, MCI, or AD dementia, LTRA users were matched 1:3 to non-users using propensity score matching. Cognitive domains including immediate and delayed memory (Wechsler Memory Scale Revised-Logical Memory IA and IIA), psychomotor processing speed (Digit Symbol Substitution Test), and language (animal naming, vegetable naming, and Boston Naming Test) were compared between users and non-users in mixed-effects linear or Poisson regression models.

Results: In AD dementia, LTRA use was associated with a slower decline in psychomotor processing speed, as measured by the Digit Symbol Substitution Test (Β = 1.466 [0.253, 2.678] symbols/year, n = 442), and language, as measured by animal naming (Β = 0.541 [0.215, 0.866] animals/year, n = 566), vegetable naming (B = 0.309 [0.056, 0.561] vegetables/year, n = 565), and the Boston Naming Test (B = 0.529 [0.005, 1.053] items/year, n = 561). Effect sizes were small but persisted after controlling for a 10% false discovery rate. LTRA use was not associated with changes in memory performance in AD, nor was it associated with changes in cognitive performance in people with normal cognition or MCI. In a post hoc analysis, LTRA use was associated with a slower decline in clinical progression in MCI (B = -0.200 [-0.380, -0.019] points/year, n = 800) and AD dementia (B = -0.321 [-0.597, -0.046] points/year, n = 604) as measured by CDR Sum of Boxes.

Conclusions: The use of LTRAs was associated with preserved function in non-amnestic cognitive domains in AD dementia. The role of leukotrienes and their receptors in cognitive decline warrants further investigation and the leukotriene pathway may represent a target for AD treatment.
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http://dx.doi.org/10.1186/s13195-021-00892-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8418104PMC
September 2021

Description of connected speech across different elicitation tasks in the logopenic variant of primary progressive aphasia.

Int J Lang Commun Disord 2021 Aug 12. Epub 2021 Aug 12.

Department of Speech-Language Pathology, University of Toronto, Toronto, ON, Canada.

Background: Despite its importance, in-depth analysis of connected speech is often neglected in the diagnosis of primary progressive aphasia (PPA) - especially for the logopenic variant (lvPPA) for which unreliable differential diagnosis has been documented. Only a few studies have been conducted on this topic in lvPPA.

Aims: The aim of this study was to describe and compare lexico-semantic and morphosyntactic features of connected speech in participants with lvPPA, in comparison with healthy controls, using three different elicitation tasks (i.e., picture description, story narration and semi-structured interviews). In addition to a number of discourse features, we were particularly interested in the presence or absence of syntactic deficits in this PPA variant in line with recent findings.

Methods & Procedures: A prospective group study was conducted to compare lvPPA participants (n = 13) to age- and education-matched healthy controls (n = 13). For each individual, connected speech was obtained using three tasks: (1) The Cookie Theft picture description; (2) Cinderella Story; (3) Topic-directed interview. Production on each task was recorded, transcribed and analysed according to the Quantitative Production Analysis (QPA) protocol, a tool developed by Berndt et al. (2000) for the analysis of sentence production in aphasia. Differences between lvPPA and healthy controls and among elicitation tasks were analysed using repeated measures multilevel mixed-effects regression, separately for each outcome.

Outcomes & Results: Four measures were significantly different between lvPPA participants and healthy controls across all elicitation tasks. Specifically, lvPPA participants produced a reduced proportion of open-class words, a higher proportion of verbs, a higher proportion of pronouns and fewer well-formed sentences. For these measures, the difference between lvPPA and healthy controls was consistent among elicitation tasks, except for the proportion of well-formed sentences, where the difference between the two groups was significantly greater in the story narration task than in the other tasks.

Conclusions & Implications: Across elicitation tasks that used the same analysis protocol (i.e., QPA), a similar pattern of deficits in connected speech emerged in lvPPA patients. Importantly, the findings replicate previous studies, which used different elicitation tasks and analysis protocols. Especially in relation to the documented syntactic deficits, these findings provide implications for differential diagnosis in PPA.

What This Paper Adds: What is already known on the subject Connected speech analysis can provide an important contribution to the language assessment for the logopenic variant of primary progressive aphasia (lvPPA). However, only a few studies have been conducted with this population. What this paper adds to existing knowledge This study highlights differences between patients with lvPPA and healthy controls regarding the proportion of open-class words, nouns, verbs and well-formed sentences. What are the potential or actual clinical implications of this work? Importantly, our results highlight syntactic deficits in the same group of individuals with lvPPA, using the same analysis protocol and across various elicitation tasks, which has implications for differential diagnosis.
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http://dx.doi.org/10.1111/1460-6984.12660DOI Listing
August 2021

The importance of STEM: High school knowledge, skills and occupations in an era of growing inequality.

Res Policy 2021 Sep 2;50(7). Epub 2021 Apr 2.

Departmentof Sociology, University of Minnesota, MN, United States.

Science, Technology, Engineering and Mathematics (STEM) jobs have grown in importance in the labor market in recent decades, and they are widely seen as the jobs of the future. Using data from the U.S. Census and American Community Survey, we first investigate the role of employment in STEM occupations when it comes to recent changes in the occupational employment distribution in the U.S. labor market. Next, with data from the High School and Beyond sophomore cohort (Class of 1982) recent midlife follow-up, we investigate the importance of high school students' mathematics and science coursework, knowledge, and skills for midlife occupations. The Class of 1982 completed high school prior to technological changes altering the demand for labor. We find that individuals who took more advanced levels of high school mathematics coursework enjoyed occupations with a higher percentile rank in the average wage distribution and were more likely to hold STEM-related occupations. Findings suggest that the mathematics coursework enabled workers to adapt and navigate changing labor market demands.
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http://dx.doi.org/10.1016/j.respol.2021.104249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8318355PMC
September 2021

Artificial intelligence for molecular neuroimaging.

Ann Transl Med 2021 May;9(9):822

Departments of Radiology and Medicine, McMaster University, Hamilton, Ontario, Canada.

In recent years, artificial intelligence (AI) or the study of how computers and machines can gain intelligence, has been increasingly applied to problems in medical imaging, and in particular to molecular imaging of the central nervous system. Many AI innovations in medical imaging include improving image quality, segmentation, and automating classification of disease. These advances have led to an increased availability of supportive AI tools to assist physicians in interpreting images and making decisions affecting patient care. This review focuses on the role of AI in molecular neuroimaging, primarily applied to positron emission tomography (PET) and single photon emission computed tomography (SPECT). We emphasize technical innovations such as AI in computed tomography (CT) generation for the purposes of attenuation correction and disease localization, as well as applications in neuro-oncology and neurodegenerative diseases. Limitations and future prospects for AI in molecular brain imaging are also discussed. Just as new equipment such as SPECT and PET revolutionized the field of medical imaging a few decades ago, AI and its related technologies are now poised to bring on further disruptive changes. An understanding of these new technologies and how they work will help physicians adapt their practices and succeed with these new tools.
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http://dx.doi.org/10.21037/atm-20-6220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246223PMC
May 2021

White matter hyperintensities in autopsy-confirmed frontotemporal lobar degeneration and Alzheimer's disease.

Alzheimers Res Ther 2021 07 13;13(1):129. Epub 2021 Jul 13.

Cognitive & Movement Disorders Clinic, Sunnybrook Health Sciences Centre, 2075 Bayview Ave., Room A4 42, Toronto, ON, M4N 3M5, Canada.

Background: We aimed to systematically describe the burden and distribution of white matter hyperintensities (WMH) and investigate correlations with neuropsychiatric symptoms in pathologically proven Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD).

Methods: Autopsy-confirmed cases were identified from the Sunnybrook Dementia Study, including 15 cases of AD and 58 cases of FTLD (22 FTLD-TDP cases; 10 FTLD-Tau [Pick's] cases; 11 FTLD-Tau Corticobasal Degeneration cases; and 15 FTLD-Tau Progressive Supranuclear Palsy cases). Healthy matched controls (n = 35) were included for comparison purposes. Data analyses included ANCOVA to compare the burden of WMH on antemortem brain MRI between groups, adjusted linear regression models to identify associations between WMH burden and neuropsychiatric symptoms, and image-guided pathology review of selected areas of WMH from each pathologic group.

Results: Burden and regional distribution of WMH differed significantly between neuropathological groups (F = 2.67, P' = 0.029), with the FTLD-TDP group having the highest mean volume globally (8032 ± 8889 mm) and in frontal regions (4897 ± 6163 mm). The AD group had the highest mean volume in occipital regions (468 ± 420 mm). Total score on the Neuropsychiatric Inventory correlated with bilateral frontal WMH volume (β = 0.330, P = 0.006), depression correlated with bilateral occipital WMH volume (β = 0.401, P < 0.001), and apathy correlated with bilateral frontal WMH volume (β = 0.311, P = 0.009), all corrected for the false discovery rate. Image-guided neuropathological assessment of selected cases with the highest burden of WMH in each pathologic group revealed presence of severe gliosis, myelin pallor, and axonal loss, but with no distinguishing features indicative of the underlying proteinopathy.

Conclusions: These findings suggest that WMH are associated with neuropsychiatric manifestations in AD and FTLD and that WMH burden and regional distribution in neurodegenerative disorders differ according to the underlying neuropathological processes.
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http://dx.doi.org/10.1186/s13195-021-00869-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278704PMC
July 2021

Reply to: Rethink the classical view of cerebrospinal fluid production.

Nat Rev Neurol 2021 Sep;17(9):590-591

Department of Medicine (Neurology), Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.

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http://dx.doi.org/10.1038/s41582-021-00539-zDOI Listing
September 2021

Diabetes Mellitus Is Associated With Poor In-Hospital and Long-Term Outcomes in Young and Midlife Stroke Survivors.

J Am Heart Assoc 2021 07 3;10(14):e019991. Epub 2021 Jul 3.

Department of Pharmacology & Toxicology University of Toronto Toronto ON Canada.

Background The incidence of ischemic stroke has increased among adults aged 18 to 64 years, yet little is known about relationships between specific risk factors and outcomes. This study investigates in-hospital and long-term outcomes in patients with stroke aged <65 years with preexisting diabetes mellitus. Methods and Results Consecutive patients aged <65 years admitted to comprehensive stroke centers for acute ischemic stroke between 2003 and 2013 were identified from the Ontario Stroke Registry. Multinomial logistic regression was used to estimate adjusted odds ratio (OR [95% CI]) of in-hospital mortality or direct discharge to long-term or continuing care. Cox proportional hazards regression was used to estimate the adjusted hazards ratio (aHR [95% CI]) of long-term mortality, readmission for stroke/transient ischemic attack, admission to long-term care, and incident dementia. Predefined sensitivity analyses examined stroke outcomes among young (aged 18-49 years) and midlife (aged 50-65 years) subgroups. Among 8293 stroke survivors (mean age, 53.6±8.9 years), preexisting diabetes mellitus was associated with a higher likelihood of in-hospital death (adjusted OR, 1.46 [95% CI, 1.14-1.87]) or direct discharge to long-term care (adjusted OR, 1.65 [95% CI, 1.07-2.54]). Among stroke survivors discharged (N=7847) and followed up over a median of 6.3 years, preexisting diabetes mellitus was associated with increased hazards of death (aHR, 1.68 [95% CI, 1.50-1.88]), admission to long-term care (aHR, 1.57 [95% CI, 1.35-1.82]), readmission for stroke/transient ischemic attack (aHR, 1.37 [95% CI, 0.21-1.54]), and incident dementia (aHR, 1.44 [95% CI, 1.17-1.77]). Only incident dementia was not increased for young stroke survivors. Conclusions Focused secondary prevention and risk factor management may be needed to address poor long-term outcomes for patients with stroke aged <65 years with preexisting diabetes mellitus.
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http://dx.doi.org/10.1161/JAHA.120.019991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483482PMC
July 2021

Association of Orthostatic Hypotension With Cerebral Atrophy in Patients With Lewy Body Disorders.

Neurology 2021 08 7;97(8):e814-e824. Epub 2021 Jun 7.

From the Neurology Unit (A. Pilotto, A.S., B.B., A.L., A. Padovani), Department of Clinical and Experimental Sciences, and Neuroradiology Unit (R.G.), Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia; Parkinson's Disease Rehabilitation Centre (A. Pilotto, M.C.R.), FERB ONLUS-S. Isidoro Hospital, Trescore Balneario, Bergamo; Department of Neuroscience "Rita Levi Montalcini" (A.R., E.M., L.L.) and Autonomic Unit (S.M.), Department of Medical Sciences, University of Turin, Italy; Department of Medicine (Neurology) (M.M., C.O.-L., S.E.B.), University of Toronto; Hurvitz Brain Sciences Program (M.M., C.O.-L., S.E.B.), Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Department of Neurology (Y.S., R.T., K.Y., T.H., N.H.), Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Neuroscience Imaging and Clinical Sciences (L.B., S.D.P.), University G. d'Annunzio of Chieti-Pescara, Chieti, Italy; Department of Medicine and Neuroscience and Mental Health Institute (R.C., M.G.), University of Alberta, Edmonton, Canada; Department of Radiology (L.L.W.), and Gardner Family Center for Parkinson's Disease and Movement Disorders (A.J.E.), Department of Neurology, University of Cincinnati, OH; Department of Molecular and Translational Medicine (A.K.D.), Texas Tech University Health Sciences Center, El Paso; Parkinson and Other Movement Disorders Center (K.L., I.L.), Department of Neurosciences, University of California, San Diego, La Jolla; Department of Neurology (F.R.-P.), Medical University of South Carolina, Charleston; Imaging Research Center (M.D), Department of Radiology, Cincinnati Children's Hospital Medical Center; University of Cincinnati College of Medicine (M.D.), OH; Department of Neurology (J.A.V.), Emory University, Atlanta, GA; ASST Spedali Civili Hospital (R.G.), Brescia, Italy; and Department of Neurology (A.M.), The Ohio State University, Columbus .

Objective: To evaluate whether orthostatic hypotension (OH) or supine hypertension (SH) is associated with brain atrophy and white matter hyperintensities (WMH), we analyzed clinical and radiologic data from a large multicenter consortium of patients with Parkinson disease (PD) and dementia with Lewy bodies (DLB).

Methods: Supine and orthostatic blood pressure (BP) and structural MRI data were extracted from patients with PD and DLB evaluated at 8 tertiary-referral centers in the United States, Canada, Italy, and Japan. OH was defined as a systolic/diastolic BP fall ≥20/10 mm Hg within 3 minutes of standing from the supine position (severe ≥30/15 mm Hg) and SH as a BP ≥140/90 mm Hg with normal sitting BP. Diagnosis-, age-, sex-, and disease duration-adjusted differences in global and regional cerebral atrophy and WMH were appraised with validated semiquantitative rating scales.

Results: A total of 384 patients (310 with PD, 74 with DLB) met eligibility criteria, of whom 44.3% (n = 170) had OH, including 24.7% (n = 42) with severe OH and 41.7% (n = 71) with SH. OH was associated with global brain atrophy ( = 0.004) and regional atrophy involving the anterior-temporal ( = 0.001) and mediotemporal ( = 0.001) regions, greater in severe vs nonsevere OH ( = 0.001). The WMH burden was similar in those with and without OH ( = 0.49). SH was not associated with brain atrophy ( = 0.59) or WMH ( = 0.72).

Conclusions: OH, but not SH, was associated with cerebral atrophy in Lewy body disorders, with prominent temporal region involvement. Neither OH nor SH was associated with WMH.
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http://dx.doi.org/10.1212/WNL.0000000000012342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397588PMC
August 2021

Association of apolipoprotein E variation with cognitive impairment across multiple neurodegenerative diagnoses.

Neurobiol Aging 2021 09 24;105:378.e1-378.e9. Epub 2021 Apr 24.

Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.

For many years there has been uncertainty regarding how apolipoprotein E (APOE) E2 and E4 variants may influence overlapping features of neurodegeneration, such as cognitive impairment. We aimed to identify whether the APOE variants are associated with cognitive function across various neurodegenerative and cerebrovascular diagnoses (n = 513). Utilizing a comprehensive neuropsychology battery, multivariate multiple regression was used to assess the influence of APOE carrier status and disease cohort on performance across five cognitive domains. Irrespective of disease cohort, E4 carriers had significantly lower performance in verbal memory and visuospatial domains than those with E3/3, while E2 carriers' cognitive performance was not significantly different. However, E2 carriers with frontotemporal dementia (FTD) performed significantly worse than those with E3/3 in the attention/working memory, executive function, and visuospatial domains. Our results highlight that the influence of APOE variation on cognition is complex, in some cases varying based on diagnosis and possibly underlying disease pathology.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.04.011DOI Listing
September 2021

Resting state fMRI scanner instabilities revealed by longitudinal phantom scans in a multi-center study.

Neuroimage 2021 08 21;237:118197. Epub 2021 May 21.

Rotman Research Institute, University of Toronto, Toronto, ON, Canada; Medical Biophysics, University of Toronto, Toronto, ON, Canada. Electronic address:

Quality assurance (QA) is crucial in longitudinal and/or multi-site studies, which involve the collection of data from a group of subjects over time and/or at different locations. It is important to regularly monitor the performance of the scanners over time and at different locations to detect and control for intrinsic differences (e.g., due to manufacturers) and changes in scanner performance (e.g., due to gradual component aging, software and/or hardware upgrades, etc.). As part of the Ontario Neurodegenerative Disease Research Initiative (ONDRI) and the Canadian Biomarker Integration Network in Depression (CAN-BIND), QA phantom scans were conducted approximately monthly for three to four years at 13 sites across Canada with 3T research MRI scanners. QA parameters were calculated for each scan using the functional Biomarker Imaging Research Network's (fBIRN) QA phantom and pipeline to capture between- and within-scanner variability. We also describe a QA protocol to measure the full-width-at-half-maximum (FWHM) of slice-wise point spread functions (PSF), used in conjunction with the fBIRN QA parameters. Variations in image resolution measured by the FWHM are a primary source of variance over time for many sites, as well as between sites and between manufacturers. We also identify an unexpected range of instabilities affecting individual slices in a number of scanners, which may amount to a substantial contribution of unexplained signal variance to their data. Finally, we identify a preliminary preprocessing approach to reduce this variance and/or alleviate the slice anomalies, and in a small human data set show that this change in preprocessing can have a significant impact on seed-based connectivity measurements for some individual subjects. We expect that other fMRI centres will find this approach to identifying and controlling scanner instabilities useful in similar studies.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118197DOI Listing
August 2021

MRI-visible perivascular space volumes, sleep duration and daytime dysfunction in adults with cerebrovascular disease.

Sleep Med 2021 07 19;83:83-88. Epub 2021 Apr 19.

Hurvitz Brain Sciences Program, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada; Department of Medicine (Neurology), Sunnybrook Health Sciences Centre and University of Toronto, ON, Canada.

Objectives: Recent studies suggest that interindividual genetic differences in glial-dependent CSF flow through the brain parenchyma, known as glymphatic flow, may trigger compensatory changes in human sleep physiology. In animal models, brain perivascular spaces are a critical conduit for glymphatic flow. We tested the hypothesis that MRI-visible PVS volumes, a putative marker of perivascular dysfunction, are associated with compensatory differences in real-world human sleep behavior.

Methods: We analyzed data from 152 cerebrovascular disease patients from the Ontario Neurodegenerative Disease Research Initiative (ONDRI). PVS volumes were measured using 3T-MRI. Self-reported total sleep time, time in bed, and daytime dysfunction were extracted from the Pittsburgh Sleep Quality Index.

Results: Individuals with greater PVS volumes reported longer time in bed (+0.85 h per log10 proportion of intracranial volume (ICV) occupied by PVS, SE = 0.30, p = 0.006) and longer total sleep times (+0.70 h per log10 proportion of ICV occupied by PVS volume, SE = 0.33, p = 0.04), independent of vascular risk factors, sleep apnea, nocturnal sleep disturbance, depression, and global cognitive status. Further analyses suggested that the positive association between PVS volumes and total sleep time was mediated by greater time in bed. Moreover, despite having on average greater total sleep times, individuals with greater basal ganglia PVS volumes were more likely to report daytime dysfunction (OR 5.63 per log10 proportion of ICV occupied by PVS, 95% CI: 1.38-22.26, p = 0.018).

Conclusions: Individuals with greater PVS volumes spend more time in bed, resulting in greater total sleep time, which may represent a behavioral compensatory response to perivascular space dysfunction.
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http://dx.doi.org/10.1016/j.sleep.2021.03.043DOI Listing
July 2021

Combined Atlas and Convolutional Neural Network-Based Segmentation of the Hippocampus from MRI According to the ADNI Harmonized Protocol.

Sensors (Basel) 2021 Apr 1;21(7). Epub 2021 Apr 1.

Department of Clinical Neurosciences, University of Calgary, Calgary, AB T2N 1N4, Canada.

Hippocampus atrophy is an early structural feature that can be measured from magnetic resonance imaging (MRI) to improve the diagnosis of neurological diseases. An accurate and robust standardized hippocampus segmentation method is required for reliable atrophy assessment. The aim of this work was to develop and evaluate an automatic segmentation tool (DeepHarp) for hippocampus delineation according to the ADNI harmonized hippocampal protocol (HarP). DeepHarp utilizes a two-step process. First, the approximate location of the hippocampus is identified in T1-weighted MRI datasets using an atlas-based approach, which is used to crop the images to a region-of-interest (ROI) containing the hippocampus. In the second step, a convolutional neural network trained using datasets with corresponding manual hippocampus annotations is used to segment the hippocampus from the cropped ROI. The proposed method was developed and validated using 107 datasets with manually segmented hippocampi according to the ADNI-HarP standard as well as 114 multi-center datasets of patients with Alzheimer's disease, mild cognitive impairment, cerebrovascular disease, and healthy controls. Twenty-three independent datasets manually segmented according to the ADNI-HarP protocol were used for testing to assess the accuracy, while an independent test-retest dataset was used to assess precision. The proposed DeepHarp method achieved a mean Dice similarity score of 0.88, which was significantly better than four other established hippocampus segmentation methods used for comparison. At the same time, the proposed method also achieved a high test-retest precision (mean Dice score: 0.95). In conclusion, DeepHarp can automatically segment the hippocampus from T1-weighted MRI datasets according to the ADNI-HarP protocol with high accuracy and robustness, which can aid atrophy measurements in a variety of pathologies.
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http://dx.doi.org/10.3390/s21072427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036492PMC
April 2021

Exploratory Assessment of K-means Clustering to Classify 18F-Flutemetamol Brain PET as Positive or Negative.

Clin Nucl Med 2021 Aug;46(8):616-620

Department of Electrical and Computer Engineering, University of Waterloo, Waterloo, Ontario, Canada.

Rationale: We evaluated K-means clustering to classify amyloid brain PETs as positive or negative.

Patients And Methods: Sixty-six participants (31 men, 35 women; age range, 52-81 years) were recruited through a multicenter observational study: 19 cognitively normal, 25 mild cognitive impairment, and 22 dementia (11 Alzheimer disease, 3 subcortical vascular cognitive impairment, and 8 Parkinson-Lewy Body spectrum disorder). As part of the neurocognitive and imaging evaluation, each participant had an 18F-flutemetamol (Vizamyl, GE Healthcare) brain PET. All studies were processed using Cortex ID software (General Electric Company, Boston, MA) to calculate SUV ratios in 19 regions of interest and clinically interpreted by 2 dual-certified radiologists/nuclear medicine physicians, using MIM software (MIM Software Inc, Cleveland, OH), blinded to the quantitative analysis, with final interpretation based on consensus. K-means clustering was retrospectively used to classify the studies from the quantitative data.

Results: Based on clinical interpretation, 46 brain PETs were negative and 20 were positive for amyloid deposition. Of 19 cognitively normal participants, 1 (5%) had a positive 18F-flutemetamol brain PET. Of 25 participants with mild cognitive impairment, 9 (36%) had a positive 18F-flutemetamol brain PET. Of 22 participants with dementia, 10 (45%) had a positive 18F-flutemetamol brain PET; 7 of 11 participants with Alzheimer disease (64%), 1 of 3 participants with vascular cognitive impairment (33%), and 2 of 8 participants with Parkinson-Lewy Body spectrum disorder (25%) had a positive 18F-flutemetamol brain PET. Using clinical interpretation as the criterion standard, K-means clustering (K = 2) gave sensitivity of 95%, specificity of 98%, and accuracy of 97%.

Conclusions: K-means clustering may be a powerful algorithm for classifying amyloid brain PET.
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http://dx.doi.org/10.1097/RLU.0000000000003668DOI Listing
August 2021

Low Doses of Ionizing Radiation as a Treatment for Alzheimer's Disease: A Pilot Study.

J Alzheimers Dis 2021 ;80(3):1119-1128

Baycrest Health Sciences, Toronto, ON, Canada.

Background: In 2015, a patient in hospice with Alzheimer's disease (AD) was treated with ionizing radiation to her brain using repeated CT scans. Improvement in cognition, speech, movement, and appetite was observed. These improvements were so momentous that she was discharged from the hospice to a long-term care home. Based on this case, we conducted a pilot clinical trial to examine the effect of low-dose ionizing radiation (LDIR) in severe AD.

Objective: To determine whether the previously reported benefits of LDIR in a single case with AD could be observed again in other cases with AD when the same treatments are given.

Methods: In this single-arm study, four patients were treated with three consecutive treatments of LDIR, each spaced two weeks apart. Qualitative changes in communication and behavior with close relatives were observed and recorded. Quantitative measures of cognition and behavior were administered pre and post LDIR treatments.

Results: Minor improvements on quantitative measures were noted in three of the four patients following treatment. However, the qualitative observations of cognition and behavior suggested remarkable improvements within days post-treatment, including greater overall alertness. One patient showed no change.

Conclusion: LDIR may be a promising, albeit controversial therapy for AD. Trials of patients with less severe AD, double-blind and placebo-controlled, should be carried out to determine the benefits of LDIR. Quantitative measures are needed that are sensitive to the remarkable changes induced by LDIR, such as biological markers of oxidative stress that are associated with AD.
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http://dx.doi.org/10.3233/JAD-200620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150498PMC
September 2021

Non-invasive brain stimulation as add-on therapy for subacute post-stroke aphasia: a randomized trial (NORTHSTAR).

Eur Stroke J 2020 Dec 30;5(4):402-413. Epub 2020 Jun 30.

Jewish General Hospital, Lady Davis Institute for Medical Research, Department of Neurology & Neurosurgery, McGill University, Montreal, Quebec.

Introduction: Non-invasive brain stimulation (NIBS) with speech therapy might improve recovery from post-stroke aphasia. This three-armed sham-controlled blinded prospective proof-of-concept study tested 1 Hz subthreshold repetitive transcranial magnetic stimulation (rTMS) and 2-mA cathodal transcranial direct current stimulation (ctDCS) on the right pars triangularis in subacute post-stroke aphasia.

Patients And Methods: Sixty-three patients with left middle cerebral artery infarcts were recruited in five hospitals (Canada/United States/Germany, 01-2014/03-2018) and randomized to receive rTMS ( = 20), ctDCS ( = 24) or sham stimulation ( = 19) with ST for 10 days. Primary outcome variables were -score changes in naming, semantic fluency and comprehension tests and adverse event frequency. Secondary outcome variable was the percent change in the Unified Aphasia Score. Intention-to-treat analyses tested between-group effects at days 1 and 30 post-treatment with a pre-planned subgroup analysis for lesion location (affecting Broca's area or not).

Results: Naming was significantly improved by rTMS (median = 1.91/interquartile range = 0.77/=.01) at 30 days versus ctDCS (median = 1.11/interquartile range = 1.51) and sham stimulation (median = 1.02/interquartile range = 1.71). All other primary results were non-significant. The rTMS effect was driven by the patient subgroup with intact Broca's area where NIBS tended to improve UnAS (median = 33.2%/interquartile range = 46.7%/=.062) versus sham stimulation (median = 12.5%/interquartile range = 7.9%) at day 30. Conversely, in patients with infarcted Broca's area, UnAS tended to improve more with sham stimulation (median = 75.0%/interquartile range = 86.9%/=.053) versus NIBS (median = 12.7%/interquartile range = 31.7). We found a delayed positive effect of low-frequency rTMS targeting the right pars triangularis on the recovery of naming performance in subacute post-stroke aphasia. This intervention may be beneficial only in patients with morphologically intact Broca's area.
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http://dx.doi.org/10.1177/2396987320934935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856587PMC
December 2020

Gait variability across neurodegenerative and cognitive disorders: Results from the Canadian Consortium of Neurodegeneration in Aging (CCNA) and the Gait and Brain Study.

Alzheimers Dement 2021 08 16;17(8):1317-1328. Epub 2021 Feb 16.

Gait and Brain Lab, Parkwood Institute, Lawson Health Research Institute, London, Ontario, Canada.

Introduction: Gait impairment is common in neurodegenerative disorders. Specifically, gait variability-the stride-to-stride fluctuations in distance and time-has been associated with neurodegeneration and cognitive impairment. However, quantitative comparisons of gait impairments across the cognitive spectrum of dementias have not been systematically investigated.

Methods: Older adults (N = 500) with subjective cognitive impairment, Parkinson disease (PD), mild cognitive impairment (MCI), PD-MCI, Alzheimer's disease (AD), PD-dementia, Lewy body dementia, and frontotemporal dementia, as well cognitive normal controls, who were assessed for their gait and cognitive performance.

Results: Factor analyses grouped 11 quantitative gait parameters and identified four independent gait domains: rhythm, pace, variability, and postural control, for group comparisons and classification analysis. Among these domains, only high gait variability was associated with lower cognitive performance and accurately discriminated AD from other neurodegenerative and cognitive conditions.

Discussion: Our findings indicate that high gait variability is a marker of cognitive-cortical dysfunction, which can help to identify Alzheimer's disease dementia.
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http://dx.doi.org/10.1002/alz.12298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8451764PMC
August 2021

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture.

Nat Genet 2021 03 15;53(3):294-303. Epub 2021 Feb 15.

Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London, UK.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.
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http://dx.doi.org/10.1038/s41588-021-00785-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946812PMC
March 2021

The use of angiotensin-converting enzyme inhibitors vs. angiotensin receptor blockers and cognitive decline in Alzheimer's disease: the importance of blood-brain barrier penetration and APOE ε4 carrier status.

Alzheimers Res Ther 2021 02 11;13(1):43. Epub 2021 Feb 11.

Department of Pharmacology & Toxicology Room 4207, University of Toronto, Medical Sciences Building 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.

Background: The antihypertensive angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACE-Is) have similar indications and mechanisms of action, but prior work suggests divergence in their effects on cognition.

Methods: Participants in the National Alzheimer's Coordinating Center database with a clinical diagnosis of dementia due to Alzheimer's disease (AD) using an ACE-I or an ARB at any visit were selected. The primary outcome was delayed recall memory on the Wechsler Memory Scale Revised - Logical Memory IIA. Other cognitive domains were explored, including attention and psychomotor processing speed (Trail Making Test [TMT]-A and Digit Symbol Substitution Test [DSST]), executive function (TMT-B), and language and semantic verbal fluency (Animal Naming, Vegetable Naming, and Boston Naming Tests). Random slopes mixed-effects models with inverse probability of treatment weighting were used, yielding rate ratios (RR) or regression coefficients (B), as appropriate to the distribution of the data. Apolipoprotein (APOE) ε4 status and blood-brain barrier (BBB) penetrance were investigated as effect modifiers.

Results: Among 1689 participants with AD, ARB use (n = 578) was associated with 9.4% slower decline in delayed recall performance over a mean follow-up of 2.28 years compared with ACE-I use (n = 1111) [RR = 1.094, p = 0.0327]; specifically, users of BBB-crossing ARBs (RR = 1.25, p = 0.002), BBB-crossing ACE-Is (RR = 1.16, p = 0.010), and non-BBB-crossing ARBs (RR = 1.20, p = 0.005) had better delayed recall performance over time compared with non-BBB-crossing ACE-I users. An interaction with APOE ε4 status (drug × APOE × time RR = 1.196, p = 0.033) emerged; ARBs were associated with better delayed recall scores over time than ACE-Is in non-carriers (RR = 1.200, p = 0.003), but not in carriers (RR = 1.003, p = 0.957). ARB use was also associated with better performance over time on the TMT-A (B = 2.023 s, p = 0.0004) and the DSST (B = 0.573 symbols, p = 0.0485), and these differences were significant among APOE ε4 non-carriers (B = 4.066 s, p = 0.0004; and B = 0.982 symbols, p = 0.0230; respectively). Some differences were seen also in language and verbal fluency among APOE ε4 non-carriers.

Conclusions: Among APOE ε4 non-carriers with AD, ARB use was associated with greater preservation of memory and attention/psychomotor processing speed, particularly compared to ACE-Is that do not cross the blood-brain-barrier.
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http://dx.doi.org/10.1186/s13195-021-00778-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876820PMC
February 2021

Improved Segmentation of the Intracranial and Ventricular Volumes in Populations with Cerebrovascular Lesions and Atrophy Using 3D CNNs.

Neuroinformatics 2021 10 1;19(4):597-618. Epub 2021 Feb 1.

Hurvitz Brain Sciences Program, Sunnybrook Research Institute, University of Toronto, Toronto, Canada.

Successful segmentation of the total intracranial vault (ICV) and ventricles is of critical importance when studying neurodegeneration through neuroimaging. We present iCVMapper and VentMapper, robust algorithms that use a convolutional neural network (CNN) to segment the ICV and ventricles from both single and multi-contrast MRI data. Our models were trained on a large dataset from two multi-site studies (N = 528 subjects for ICV, N = 501 for ventricular segmentation) consisting of older adults with varying degrees of cerebrovascular lesions and atrophy, which pose significant challenges for most segmentation approaches. The models were tested on 238 participants, including subjects with vascular cognitive impairment and high white matter hyperintensity burden. Two of the three test sets came from studies not used in the training dataset. We assessed our algorithms relative to four state-of-the-art ICV extraction methods (MONSTR, BET, Deep Extraction, FreeSurfer, DeepMedic), as well as two ventricular segmentation tools (FreeSurfer, DeepMedic). Our multi-contrast models outperformed other methods across many of the evaluation metrics, with average Dice coefficients of 0.98 and 0.96 for ICV and ventricular segmentation respectively. Both models were also the most time efficient, segmenting the structures in orders of magnitude faster than some of the other available methods. Our networks showed an increased accuracy with the use of a conditional random field (CRF) as a post-processing step. We further validated both segmentation models, highlighting their robustness to images with lower resolution and signal-to-noise ratio, compared to tested techniques. The pipeline and models are available at: https://icvmapp3r.readthedocs.io and https://ventmapp3r.readthedocs.io to enable further investigation of the roles of ICV and ventricles in relation to normal aging and neurodegeneration in large multi-site studies.
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http://dx.doi.org/10.1007/s12021-021-09510-1DOI Listing
October 2021

Vascular Contributions to Neurodegeneration: Protocol of the COMPASS-ND Study.

Can J Neurol Sci 2021 Jan 28:1-8. Epub 2021 Jan 28.

Department of Medicine (Neurology), Hurvitz Brain Sciences Research Program, LC Campbell Cognitive Neurology Unit, Canadian Partnership for Stroke Recovery, University of Toronto, London, Ontario, Canada.

Objective: To describe the neuroimaging and other methods for assessing vascular contributions to neurodegeneration in the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) study, a Canadian multi-center, prospective longitudinal cohort study, including reliability and feasibility in the first 200 participants.

Methods: COMPASS-ND includes persons with Alzheimer's disease (AD; n = 150), Parkinson's disease (PD) and Lewy body dementias (LBDs) (200), mixed dementia (200), mild cognitive impairment (MCI; 400), subcortical ischemic vascular MCI (V-MCI; 200), subjective cognitive impairment (SCI; 300), and cognitively intact elderly controls (660). Magnetic resonance imaging (MRI) was acquired according to the validated Canadian Dementia Imaging Protocol and visually reviewed by either of two experienced readers blinded to clinical characteristics. Other relevant assessments include history of vascular disease and risk factors, blood pressure, height and weight, cholesterol, glucose, and hemoglobin A1c.

Results: Analyzable data were obtained in 197/200 of whom 18 of whom were clinically diagnosed with V-MCI or mixed dementia. The overall prevalence of infarcts was 24.9%, microbleeds was 24.6%, and high white matter hyperintensity (WMH) was 31.0%. MRI evidence of a potential vascular contribution to neurodegeneration was seen in 12.9%-40.0% of participants clinically diagnosed with another condition such as AD. Inter-rater reliability was good to excellent.

Conclusion: COMPASS-ND will be a useful platform to study vascular brain injury and its association with risk factors, biomarkers, and cognitive and functional decline across multiple age-related neurodegenerative diseases. Initial findings show that MRI-defined vascular brain injury is common in all cognitive syndromes and is under-recognized clinically.
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http://dx.doi.org/10.1017/cjn.2021.19DOI Listing
January 2021

Associations between brain amyloid accumulation and the use of angiotensin-converting enzyme inhibitors versus angiotensin receptor blockers.

Neurobiol Aging 2021 04 16;100:22-31. Epub 2020 Dec 16.

Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada; Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada; Canadian Partnership for Stroke Recovery, Toronto, Ontario, Canada; KITE - Toronto Rehabilitation Institute, University Health Network, Toronto, Ontario, Canada. Electronic address:

Some studies suggest that angiotensin II type 1 receptor blockers (ARBs) may protect against memory decline more than angiotensin-converting enzyme inhibitors (ACE-Is), but few have examined possible mechanisms. We assessed longitudinal differences between ARB versus ACE-I users in global and sub-regional amyloid-β accumulation by F-florbetapir. In cognitively normal older adults (n= 142), propensity-weighted linear mixed-effects models showed that ARB versus ACE-I use was associated with slower amyloid-β accumulation in the cortex, and specifically in the caudal anterior cingulate and precuneus, and in the precentral and postcentral gyri. In amyloid-positive participants with Alzheimer's disease dementia or mild cognitive impairment (n = 169), ARB versus ACE-I use was not associated with different rates of amyloid-β accumulation. Apolipoprotein E ε4 carrier status explained some heterogeneity in the different rates of amyloid-β accumulation between users of ARBs versus ACE-Is in the study. Replicative studies and clinical trials are warranted to confirm potential benefits of ARBs on rates of amyloid-β accumulation in the contexts of Alzheimer's disease prevention and treatment.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.12.011DOI Listing
April 2021

Canadian Platform for Trials in Noninvasive Brain Stimulation (CanStim) Consensus Recommendations for Repetitive Transcranial Magnetic Stimulation in Upper Extremity Motor Stroke Rehabilitation Trials.

Neurorehabil Neural Repair 2021 02;35(2):103-116

McGill University, Montreal, Quebec, Canada.

. To develop consensus recommendations for the use of repetitive transcranial magnetic stimulation (rTMS) as an adjunct intervention for upper extremity motor recovery in stroke rehabilitation clinical trials. . The Canadian Platform for Trials in Non-Invasive Brain Stimulation (CanStim) convened a multidisciplinary team of clinicians and researchers from institutions across Canada to form the CanStim Consensus Expert Working Group. . Four consensus themes were identified: (1) patient population, (2) rehabilitation interventions, (3) outcome measures, and (4) stimulation parameters. Theme leaders conducted comprehensive evidence reviews for each theme, and during a 2-day Consensus Meeting, the Expert Working Group used a weighted dot-voting consensus procedure to achieve consensus on recommendations for the use of rTMS as an adjunct intervention in motor stroke recovery rehabilitation clinical trials. . Based on best available evidence, consensus was achieved for recommendations identifying the target poststroke population, rehabilitation intervention, objective and subjective outcomes, and specific rTMS parameters for rehabilitation trials evaluating the efficacy of rTMS as an adjunct therapy for upper extremity motor stroke recovery. . The establishment of the CanStim platform and development of these consensus recommendations is a first step toward the translation of noninvasive brain stimulation technologies from the laboratory to clinic to enhance stroke recovery.
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http://dx.doi.org/10.1177/1545968320981960DOI Listing
February 2021
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