Publications by authors named "Morris Freedman"

86 Publications

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

Authors:
Jerry M Cuttler Eslam Abdellah Yael Goldberg Sarmad Al-Shamaa Sean P Symons Sandra E Black Morris Freedman

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
January 2021

The Impact of Memory Change on Everyday Life Among Older Adults: Association with Cognition and Self-Reported Memory.

Authors:
Komal T Shaikh Erica L Tatham Susan Vandermorris Theone Paterson Kathryn Stokes Morris Freedman Brian Levine Jill B Rich Angela K Troyer

J Int Neuropsychol Soc 2021 Jan 14:1-9. Epub 2021 Jan 14.

Neuropsychology and Cognitive Health Program, Baycrest Health Sciences, Toronto, Canada.

Objectives: Many older adults experience memory changes that can have a meaningful impact on their everyday lives, such as restrictions to lifestyle activities and negative emotions. Older adults also report a variety of positive coping responses that help them manage these changes. The purpose of this study was to determine how objective cognitive performance and self-reported memory are related to the everyday impact of memory change.

Methods: We examined these associations in a sample of 94 older adults (age 60-89, 52% female) along a cognitive ability continuum from normal cognition to mild cognitive impairment.

Results: Correlational analyses revealed that greater restrictions to lifestyle activities (|rs| = .36-.66), more negative emotion associated with memory change (|rs| = .27-.76), and an overall greater burden of memory change on everyday living (|rs| = .28-.61) were associated with poorer objective memory performance and lower self-reported memory ability and satisfaction. Performance on objective measures of executive attention was unrelated to the impact of memory change. Self-reported strategy use was positively related to positive coping with memory change (|r| = .26), but self-reported strategy use was associated with more negative emotions regarding memory change (|r| = .23).

Conclusions: Given the prevalence of memory complaints among older adults, it is important to understand the experience of memory change and its impact on everyday functioning in order to develop services that target the specific needs of this population.
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http://dx.doi.org/10.1017/S1355617720001344DOI Listing
January 2021

Innovation in resident education - Description of the Neurology International Residents Videoconference and Exchange (NIRVE) program.

Authors:
Priti Gros Dalia Rotstein Mark Kinach David K Chan Xavier Montalban Morris Freedman Sanskriti Sasikumar

J Neurol Sci 2021 01 8;420:117222. Epub 2020 Nov 8.

Division of Neurology, University of Toronto, Toronto, Canada; Division of Neurology, St Michael's Hospital, Toronto, Canada.

There is considerable heterogeneity in residency education around the world. The Neurology International Residents Videoconference and Exchange (NIRVE) program aims to deliver neurology educational content to residents across different resource settings and countries through a monthly videoconferencing platform. Its purpose is to fill gaps in didactic teaching, increase exposure to a variety of cases including various practices and delivery of neurology in multiple countries, as well as integrate global health content into neurology education. NIRVE also facilitates resident exchanges among participating sites. In this descriptive article, we report NIRVE's structure and its cumulative productivity. Since its creation, NIRVE has held more than 90 videoconference rounds and has connected 16 sites in North America, South America, Europe, Asia and Africa. We describe challenges encountered since the inception of the program eleven years ago. NIRVE also fosters a culture of long-term international connection and collaboration. During global disease outbreaks, such as the current COVID-19 pandemic, videoconference rounds serve as a sustainable alternative means to deliver education. Future goals include increasing the number of sites involved, including a focus on Africa and Asia, and fostering resident-led advocacy projects.
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http://dx.doi.org/10.1016/j.jns.2020.117222DOI Listing
January 2021

Structural Brain Magnetic Resonance Imaging to Rule Out Comorbid Pathology in the Assessment of Alzheimer's Disease Dementia: Findings from the Ontario Neurodegenerative Disease Research Initiative (ONDRI) Study and Clinical Trials Over the Past 10 Years.

Authors:
Arunima Kapoor Robert Bartha Sandra E Black Michael Borrie Morris Freedman Fuqiang Gao Nathan Herrmann Jennifer Mandzia Miracle Ozzoude Joel Ramirez Christopher J M Scott Sean Symons Corinne E Fischer Andrew Frank Dallas Seitz Michael Uri Wolf Nicolaas Paul L G Verhoeff Gary Naglie William Reichman Mario Masellis Sara B Mitchell David F Tang-Wai Maria Carmela Tartaglia Sanjeev Kumar Bruce G Pollock Tarek K Rajji Elizabeth Finger Stephen H Pasternak Richard H Swartz

J Alzheimers Dis 2020 ;74(3):747-757

Sunnybrook Health Sciences Centre, Toronto, ON, Canada.

Background/objective: Structural brain magnetic resonance imaging (MRI) is not mandatory in Alzheimer's disease (AD) research or clinical guidelines. We aimed to explore the use of structural brain MRI in AD/mild cognitive impairment (MCI) trials over the past 10 years and determine the frequency with which inclusion of standardized structural MRI acquisitions detects comorbid vascular and non-vascular pathologies.

Methods: We systematically searched ClinicalTrials.gov for AD clinical trials to determine their neuroimaging criteria and then used data from an AD/MCI cohort who underwent standardized MRI protocols, to determine type and incidence of clinically relevant comorbid pathologies.

Results: Of 210 AD clinical trials, 105 (50%) included structural brain imaging in their eligibility criteria. Only 58 (27.6%) required MRI. 16,479 of 53,755 (30.7%) AD participants were in trials requiring MRI. In the observational AD/MCI cohort, 141 patients met clinical criteria; 22 (15.6%) had relevant MRI findings, of which 15 (10.6%) were exclusionary for the study.

Discussion: In AD clinical trials over the last 10 years, over two-thirds of participants could have been enrolled without brain MRI and half without even a brain CT. In a study sample, relevant comorbid pathology was found in 15% of participants, despite careful screening. Standardized structural MRI should be incorporated into NIA-AA diagnostic guidelines (when available) and research frameworks routinely to reduce diagnostic heterogeneity.
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http://dx.doi.org/10.3233/JAD-191097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242844PMC
January 2020

Conversion of Mild Cognitive Impairment to Alzheimer Disease in Monolingual and Bilingual Patients.

Authors:
Matthias Berkes Ellen Bialystok Fergus I M Craik Angela Troyer Morris Freedman

Alzheimer Dis Assoc Disord 2020 Jul-Sep;34(3):225-230

Rotman Research Institute at Baycrest.

Purpose: Conversion rates from mild cognitive impairment (MCI) to Alzheimer disease (AD) were examined considering bilingualism as a measure of cognitive reserve.

Methods: Older adult bilingual (n=75) and monolingual (n=83) patients attending a memory clinic who were diagnosed with MCI were evaluated for conversion to AD. Age of MCI and AD diagnoses and time to convert were recorded and compared across language groups.

Patients: Patients were consecutive patients diagnosed with MCI at a hospital memory clinic.

Results: Bilingual patients were diagnosed with MCI at a later age than monolingual patients (77.8 and 75.5 y, respectively), a difference that was significant in some analyses. However, bilingual patients converted faster from MCI to AD than monolingual patients (1.8 and 2.8 y, respectively) resulting in no language group difference in age of AD diagnosis. This relationship held after accounting for education, cognitive level, immigration status, and sex.

Discussion: The findings suggest that greater cognitive reserve as measured by language status leads to faster conversion between MCI and AD, all else being equal.
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http://dx.doi.org/10.1097/WAD.0000000000000373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423707PMC
July 2021

Genetic and epigenetic study of an Alzheimer's disease family with monozygotic triplets.

Authors:
Ming Zhang Allison A Dilliott Roaa Khallaf John F Robinson Robert A Hegele Michael Comishen Christine Sato Giuseppe Tosto Christiane Reitz Richard Mayeux Peter St George-Hyslop Morris Freedman Ekaterina Rogaeva

Brain 2019 11;142(11):3375-3381

Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Ave, Toronto, ON, Canada.

Age at onset of Alzheimer's disease is highly variable, and its modifiers (genetic or environmental) could act through epigenetic changes, such as DNA methylation at CpG sites. DNA methylation is also linked to ageing-the strongest Alzheimer's disease risk factor. DNA methylation age can be calculated using age-related CpGs and might reflect biological ageing. We conducted a clinical, genetic and epigenetic investigation of a unique Ashkenazi Jewish family with monozygotic triplets, two of whom developed Alzheimer's disease at ages 73 and 76, while the third at age 85 has no cognitive complaints or deficits in daily activities. One of their offspring developed Alzheimer's disease at age 50. Targeted sequencing of 80 genes associated with neurodegeneration revealed that the triplets and the affected offspring are heterozygous carriers of the risk APOE ε4 allele, as well as rare substitutions in APP (p.S198P), NOTCH3 (p.H1235L) and SORL1 (p.W1563C). In addition, we catalogued 52 possibly damaging rare variants detected by NeuroX array in affected individuals. Analysis of family members on a genome-wide DNA methylation chip revealed that the DNA methylation age of the triplets was 6-10 years younger than chronological age, while it was 9 years older in the offspring with early-onset Alzheimer's disease, suggesting accelerated ageing.
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http://dx.doi.org/10.1093/brain/awz289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821163PMC
November 2019

Genetic Variation in the Ontario Neurodegenerative Disease Research Initiative.

Authors:
Allison A Dilliott Emily C Evans Sali M K Farhan Mahdi Ghani Christine Sato Ming Zhang Adam D McIntyre Henian Cao Lemuel Racacho John F Robinson Michael J Strong Mario Masellis Dennis E Bulman Ekaterina Rogaeva Sandra E Black Elizabeth Finger Andrew Frank Morris Freedman Ayman Hassan Anthony Lang Christen L Shoesmith Richard H Swartz David Tang-Wai Maria Carmela Tartaglia John Turnbull Lorne Zinman Robert A Hegele

Can J Neurol Sci 2019 09 15;46(5):491-498. Epub 2019 Aug 15.

Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.

Background/objective: Apolipoprotein E (APOE) E4 is the main genetic risk factor for Alzheimer's disease (AD). Due to the consistent association, there is interest as to whether E4 influences the risk of other neurodegenerative diseases. Further, there is a constant search for other genetic biomarkers contributing to these phenotypes, such as microtubule-associated protein tau (MAPT) haplotypes. Here, participants from the Ontario Neurodegenerative Disease Research Initiative were genotyped to investigate whether the APOE E4 allele or MAPT H1 haplotype are associated with five neurodegenerative diseases: (1) AD and mild cognitive impairment (MCI), (2) amyotrophic lateral sclerosis, (3) frontotemporal dementia (FTD), (4) Parkinson's disease, and (5) vascular cognitive impairment.

Methods: Genotypes were defined for their respective APOE allele and MAPT haplotype calls for each participant, and logistic regression analyses were performed to identify the associations with the presentations of neurodegenerative diseases.

Results: Our work confirmed the association of the E4 allele with a dose-dependent increased presentation of AD, and an association between the E4 allele alone and MCI; however, the other four diseases were not associated with E4. Further, the APOE E2 allele was associated with decreased presentation of both AD and MCI. No associations were identified between MAPT haplotype and the neurodegenerative disease cohorts; but following subtyping of the FTD cohort, the H1 haplotype was significantly associated with progressive supranuclear palsy.

Conclusion: This is the first study to concurrently analyze the association of APOE isoforms and MAPT haplotypes with five neurodegenerative diseases using consistent enrollment criteria and broad phenotypic analysis.
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http://dx.doi.org/10.1017/cjn.2019.228DOI Listing
September 2019

Cerebral perfusion changes in presymptomatic genetic frontotemporal dementia: a GENFI study.

Authors:
Henri J M M Mutsaerts Saira S Mirza Jan Petr David L Thomas David M Cash Martina Bocchetta Enrico de Vita Arron W S Metcalfe Zahra Shirzadi Andrew D Robertson Maria Carmela Tartaglia Sara B Mitchell Sandra E Black Morris Freedman David Tang-Wai Ron Keren Ekaterina Rogaeva John van Swieten Robert Laforce Fabrizio Tagliavini Barbara Borroni Daniela Galimberti James B Rowe Caroline Graff Giovanni B Frisoni Elizabeth Finger Sandro Sorbi Alexandre de Mendonça Jonathan D Rohrer Bradley J MacIntosh Mario Masellis

Brain 2019 04;142(4):1108-1120

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

Genetic forms of frontotemporal dementia are most commonly due to mutations in three genes, C9orf72, GRN or MAPT, with presymptomatic carriers from families representing those at risk. While cerebral blood flow shows differences between frontotemporal dementia and other forms of dementia, there is limited evidence of its utility in presymptomatic stages of frontotemporal dementia. This study aimed to delineate the cerebral blood flow signature of presymptomatic, genetic frontotemporal dementia using a voxel-based approach. In the multicentre GENetic Frontotemporal dementia Initiative (GENFI) study, we investigated cross-sectional differences in arterial spin labelling MRI-based cerebral blood flow between presymptomatic C9orf72, GRN or MAPT mutation carriers (n = 107) and non-carriers (n = 113), using general linear mixed-effects models and voxel-based analyses. Cerebral blood flow within regions of interest derived from this model was then explored to identify differences between individual gene carrier groups and to estimate a timeframe for the expression of these differences. The voxel-based analysis revealed a significant inverse association between cerebral blood flow and the expected age of symptom onset in carriers, but not non-carriers. Regions included the bilateral insulae/orbitofrontal cortices, anterior cingulate/paracingulate gyri, and inferior parietal cortices, as well as the left middle temporal gyrus. For all bilateral regions, associations were greater on the right side. After correction for partial volume effects in a region of interest analysis, the results were found to be largely driven by the C9orf72 genetic subgroup. These cerebral blood flow differences first appeared approximately 12.5 years before the expected symptom onset determined on an individual basis. Cerebral blood flow was lower in presymptomatic mutation carriers closer to and beyond their expected age of symptom onset in key frontotemporal dementia signature regions. These results suggest that arterial spin labelling MRI may be a promising non-invasive imaging biomarker for the presymptomatic stages of genetic frontotemporal dementia.
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http://dx.doi.org/10.1093/brain/awz039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439322PMC
April 2019

Correction to: The Toronto cognitive assessment (TorCA): normative data and validation to detect amnestic mild cognitive impairment.

Authors:
Morris Freedman Larry Leach M Carmela Tartaglia Kathryn A Stokes Yael Goldberg Robyn Spring Nima Nourhaghighi Tom Gee Stephen C Strother Mohammad O Alhaj Michael Borrie Sultan Darvesh Alita Fernandez Corinne E Fischer Jennifer Fogarty Barry D Greenberg Michelle Gyenes Nathan Herrmann Ron Keren Josh Kirstein Sanjeev Kumar Benjamin Lam Suvendrini Lena Mary Pat McAndrews Gary Naglie Robert Partridge Tarek K Rajji William Reichmann M Uri Wolf Nicolaas P L G Verhoeff Jordana L Waserman Sandra E Black David F Tang-Wai

Alzheimers Res Ther 2018 12 7;10(1):120. Epub 2018 Dec 7.

Department of Medicine (Neurology), University of Toronto, Toronto, ON, Canada.

Upon publication of this article [1], it was brought to our attention that one of the 303 participants in the normative study should have been deleted from the database.
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http://dx.doi.org/10.1186/s13195-018-0446-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286597PMC
December 2018

The Toronto Cognitive Assessment (TorCA): normative data and validation to detect amnestic mild cognitive impairment.

Authors:
Morris Freedman Larry Leach M Carmela Tartaglia Kathryn A Stokes Yael Goldberg Robyn Spring Nima Nourhaghighi Tom Gee Stephen C Strother Mohammad O Alhaj Michael Borrie Sultan Darvesh Alita Fernandez Corinne E Fischer Jennifer Fogarty Barry D Greenberg Michelle Gyenes Nathan Herrmann Ron Keren Josh Kirstein Sanjeev Kumar Benjamin Lam Suvendrini Lena Mary Pat McAndrews Gary Naglie Robert Partridge Tarek K Rajji William Reichmann M Uri Wolf Nicolaas P L G Verhoeff Jordana L Waserman Sandra E Black David F Tang-Wai

Alzheimers Res Ther 2018 07 18;10(1):65. Epub 2018 Jul 18.

Department of Medicine (Neurology), University of Toronto, Toronto, ON, Canada.

Background: A need exists for easily administered assessment tools to detect mild cognitive changes that are more comprehensive than screening tests but shorter than a neuropsychological battery and that can be administered by physicians, as well as any health care professional or trained assistant in any medical setting. The Toronto Cognitive Assessment (TorCA) was developed to achieve these goals.

Methods: We obtained normative data on the TorCA (n = 303), determined test reliability, developed an iPad version, and validated the TorCA against neuropsychological assessment for detecting amnestic mild cognitive impairment (aMCI) (n = 50/57, aMCI/normal cognition). For the normative study, healthy volunteers were recruited from the Rotman Research Institute registry. For the validation study, the sample was comprised of participants with aMCI or normal cognition based on neuropsychological assessment. Cognitively normal participants were recruited from both healthy volunteers in the normative study sample and the community.

Results: The TorCA provides a stable assessment of multiple cognitive domains. The total score correctly classified 79% of participants (sensitivity 80%; specificity 79%). In an exploratory logistic regression analysis, indices of Immediate Verbal Recall, Delayed Verbal and Visual Recall, Visuospatial Function, and Working Memory/Attention/Executive Control, a subset of the domains assessed by the TorCA, correctly classified 92% of participants (sensitivity 92%; specificity 91%). Paper and iPad version scores were equivalent.

Conclusions: The TorCA can improve resource utilization by identifying patients with aMCI who may not require more resource-intensive neuropsychological assessment. Future studies will focus on cross-validating the TorCA for aMCI, and validation for disorders other than aMCI.
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http://dx.doi.org/10.1186/s13195-018-0382-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6052695PMC
July 2018

Aggression and Agitation in Dementia.

Authors:
M Uri Wolf Yael Goldberg Morris Freedman

Continuum (Minneap Minn) 2018 06;24(3, BEHAVIORAL NEUROLOGY AND PSYCHIATRY):783-803

Purpose Of Review: This article reviews the treatment of aggression and agitation in dementia. Both nonpharmacologic and pharmacologic approaches to responsive behaviors are discussed. Practical treatment strategies are applied to common behavioral symptoms.

Recent Findings: Aggressive and agitated behavior is common in dementia. Behavioral symptoms lead to reduced quality of life and distress for both patients and caregivers. They can also lead to poor outcomes and are associated with significant financial implications for the individual and health care system. A wide range of difficult behaviors exists, with limited evidence for deciding on treatment. Clinicians should integrate the available evidence with practical and commonsense strategies to target these difficult-to-treat behaviors.

Summary: Treating aggression and agitation in dementia is challenging. Viewing behaviors as a response to either internal or external stimuli can help guide treatment. Treatment should emphasize nonpharmacologic approaches as an initial step, using practical and commonsense strategies. Caregivers and family should be actively involved in the planning and implementation of behavioral plans. It is essential to minimize both medical and nonmedical factors that may be contributing to behaviors. When pharmacologic options are required, it is important to choose medications that will target specific behavioral goals, having both practical consideration and the best evidence in mind.
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http://dx.doi.org/10.1212/CON.0000000000000605DOI Listing
June 2018

Clinical Assessment of Prefrontal Lobe Functions.

Authors:
Alexandre Henri-Bhargava Donald T Stuss Morris Freedman

Continuum (Minneap Minn) 2018 06;24(3, BEHAVIORAL NEUROLOGY AND PSYCHIATRY):704-726

Purpose Of Review: Whereas it was previously thought that there was a single overarching frontal lobe syndrome, it is now clear that several distinct cognitive and behavioral processes are mediated by the frontal lobes. This article reviews these processes and the underlying neuroanatomy and provides an approach to the assessment of prefrontal lobe functions at the bedside.

Recent Findings: Cognitive and behavioral frontal lobe functions are mediated by the prefrontal regions rather than the frontal lobes as a whole. At least five separate prefrontal functions have been defined: energization, task setting, monitoring, behavioral/emotional regulation, and metacognition. Energization is mediated by the superior medial prefrontal cortices bilaterally, task setting by the left lateral frontal cortex, monitoring by the right lateral prefrontal cortex, behavioral/emotional regulation by the orbitofrontal cortex, and metacognition by the frontal poles. Only task setting and monitoring are considered executive functions.

Summary: Distinct cognitive and behavioral processes are mediated by different parts of the frontal lobe. Lesions in these areas result in characteristic clinical deficits that are discussed in this article. Key messages are that prefrontal regions mediate the higher cortical functions (as opposed to the frontal lobes in general) and that prefrontal functions are not equivalent to executive functions.
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http://dx.doi.org/10.1212/CON.0000000000000609DOI Listing
June 2018

Bedside Approach to the Mental Status Assessment.

Authors:
David F Tang-Wai Morris Freedman

Continuum (Minneap Minn) 2018 06;24(3, BEHAVIORAL NEUROLOGY AND PSYCHIATRY):672-703

Purpose Of Review: This article presents a clinically useful approach to obtaining the history and performing the mental status examination of patients with cognitive, language, or behavioral problems.

Recent Findings: Laboratory and imaging biomarkers are being developed for accurate diagnosis of neurobehavioral disorders, yet few are currently available for clinical use. Moreover, not all centers have access to these potential tools. Practicing clinicians are therefore left primarily with their skills of history taking and examination. Although geared for research, diagnostic criteria have been refined over the past several years and can nevertheless aid the clinician with the diagnosis of disorders such as mild cognitive impairment, Alzheimer disease, frontotemporal dementia, dementia with Lewy bodies, the primary progressive aphasias, corticobasal syndrome, vascular cognitive impairment, and posterior cortical atrophy. Regularly revised criteria reflect ongoing knowledge gained from in-depth studies of these disorders.

Summary: The focused history and mental status examination remain essential tools for the evaluation and diagnosis of neurologic disorders affecting cognition, language, and behavior.
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http://dx.doi.org/10.1212/CON.0000000000000617DOI Listing
June 2018

Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease.

Authors:
Allison A Dilliott Sali M K Farhan Mahdi Ghani Christine Sato Eric Liang Ming Zhang Adam D McIntyre Henian Cao Lemuel Racacho John F Robinson Michael J Strong Mario Masellis Dennis E Bulman Ekaterina Rogaeva Anthony Lang Carmela Tartaglia Elizabeth Finger Lorne Zinman John Turnbull Morris Freedman Rick Swartz Sandra E Black Robert A Hegele

J Vis Exp 2018 04 4(134). Epub 2018 Apr 4.

Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University; Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University;

Next-generation sequencing (NGS) is quickly revolutionizing how research into the genetic determinants of constitutional disease is performed. The technique is highly efficient with millions of sequencing reads being produced in a short time span and at relatively low cost. Specifically, targeted NGS is able to focus investigations to genomic regions of particular interest based on the disease of study. Not only does this further reduce costs and increase the speed of the process, but it lessens the computational burden that often accompanies NGS. Although targeted NGS is restricted to certain regions of the genome, preventing identification of potential novel loci of interest, it can be an excellent technique when faced with a phenotypically and genetically heterogeneous disease, for which there are previously known genetic associations. Because of the complex nature of the sequencing technique, it is important to closely adhere to protocols and methodologies in order to achieve sequencing reads of high coverage and quality. Further, once sequencing reads are obtained, a sophisticated bioinformatics workflow is utilized to accurately map reads to a reference genome, to call variants, and to ensure the variants pass quality metrics. Variants must also be annotated and curated based on their clinical significance, which can be standardized by applying the American College of Medical Genetics and Genomics Pathogenicity Guidelines. The methods presented herein will display the steps involved in generating and analyzing NGS data from a targeted sequencing panel, using the ONDRISeq neurodegenerative disease panel as a model, to identify variants that may be of clinical significance.
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http://dx.doi.org/10.3791/57266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933375PMC
April 2018

Mind-Matter Interactions and the Frontal Lobes of the Brain: A Novel Neurobiological Model of Psi Inhibition.

Authors:
Morris Freedman Malcolm Binns Fuqiang Gao Melissa Holmes Austyn Roseborough Stephen Strother Antonino Vallesi Stanley Jeffers Claude Alain Peter Whitehouse Jennifer D Ryan Robert Chen Michael D Cusimano Sandra E Black

Explore (NY) 2018 Jan - Feb;14(1):76-85. Epub 2017 Oct 23.

Rotman Research Institute, Baycrest Health Sciences, 3560 Bathurst Street, Toronto, Ontario M6A 2E1, Canada; LC Campbell Cognitive Neurology Research Unit and Hurvitz Brain Science Research Program, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada; Department of Medicine (Neurology), University of Toronto, Toronto, Canada; Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.

Context: Despite a large literature on psi, which encompasses a range of experiences including putative telepathy (mind-mind connections), clairvoyance (perceiving distant objects or events), precognition (perceiving future events), and mind-matter interactions, there has been insufficient focus on the brain in relation to this controversial phenomenon. In contrast, our research is based on a novel neurobiological model suggesting that frontal brain systems act as a filter to inhibit psi and that the inhibitory mechanisms may relate to self-awareness.

Objective: To identify frontal brain regions that may inhibit psi.

Design: We used mind-matter interactions to study psi in two participants with frontal lobe damage. The experimental task was to influence numerical output of a Random Event Generator translated into movement of an arrow on a computer screen to the right or left. Brain MRI was analyzed to determine frontal volume loss.

Results: The primary area of lesion overlap between the participants was in the left medial middle frontal region, an area related to self-awareness, and involved Brodmann areas 9, 10, and 32. Both participants showed a significant effect in moving the arrow to the right, i.e., contralateral to the side of primary lesion overlap. Effect sizes were much larger compared to normal participants.

Conclusions: The medial frontal lobes may act as a biological filter to inhibit psi through mechanisms related to self-awareness. Neurobiological studies with a focus on the brain may open new avenues of research on psi and may significantly advance the state of this poorly understood field.
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http://dx.doi.org/10.1016/j.explore.2017.08.003DOI Listing
September 2018

Motor Phenotype in Neurodegenerative Disorders: Gait and Balance Platform Study Design Protocol for the Ontario Neurodegenerative Research Initiative (ONDRI).

Authors:
Manuel Montero-Odasso Frederico Pieruccini-Faria Robert Bartha Sandra E Black Elizabeth Finger Morris Freedman Barry Greenberg David A Grimes Robert A Hegele Christopher Hudson Peter W Kleinstiver Anthony E Lang Mario Masellis Paula M McLaughlin Douglas P Munoz Stephen Strother Richard H Swartz Sean Symons Maria Carmela Tartaglia Lorne Zinman Michael J Strong William McIlroy

J Alzheimers Dis 2017 ;59(2):707-721

Canadian Partnership for Stroke Recovery Sunnybrook Site, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.

Background: The association of cognitive and motor impairments in Alzheimer's disease and other neurodegenerative diseases is thought to be related to damage in the common brain networks shared by cognitive and cortical motor control processes. These common brain networks play a pivotal role in selecting movements and postural synergies that meet an individual's needs. Pathology in this "highest level" of motor control produces abnormalities of gait and posture referred to as highest-level gait disorders. Impairments in cognition and mobility, including falls, are present in almost all neurodegenerative diseases, suggesting common mechanisms that still need to be unraveled.

Objective: To identify motor-cognitive profiles across neurodegenerative diseases in a large cohort of patients.

Methods: Cohort study that includes up to 500 participants, followed every year for three years, across five neurodegenerative disease groups: Alzheimer's disease/mild cognitive impairment, frontotemporal degeneration, vascular cognitive impairment, amyotrophic lateral sclerosis, and Parkinson's disease. Gait and balance will be assessed using accelerometers and electronic walkways, evaluated at different levels of cognitive and sensory complexity, using the dual-task paradigm.

Results: Comparison of cognitive and motor performances across neurodegenerative groups will allow the identification of motor-cognitive phenotypes through the standardized evaluation of gait and balance characteristics.

Conclusions: As part of the Ontario Neurodegenerative Research Initiative (ONDRI), the gait and balance platform aims to identify motor-cognitive profiles across neurodegenerative diseases. Gait assessment, particularly while dual-tasking, will help dissect the cognitive and motor contribution in mobility and cognitive decline, progression to dementia syndromes, and future adverse outcomes including falls and mortality.
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http://dx.doi.org/10.3233/JAD-170149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5523841PMC
April 2018

White Matter Disruption and Connected Speech in Non-Fluent and Semantic Variants of Primary Progressive Aphasia.

Authors:
Karine Marcotte Naida L Graham Kathleen C Fraser Jed A Meltzer David F Tang-Wai Tiffany W Chow Morris Freedman Carol Leonard Sandra E Black Elizabeth Rochon

Dement Geriatr Cogn Dis Extra 2017 Jan-Apr;7(1):52-73. Epub 2017 Mar 2.

aToronto Rehabilitation Institute - University Health Network, Toronto, Ontario, Canada.

Differential patterns of white matter disruption have recently been reported in the non-fluent (nfvPPA) and semantic (svPPA) variants of primary progressive aphasia (PPA). No single measure is sufficient to distinguish between the PPA variants, but connected speech allows for the quantification of multiple measures. The aim of the present study was to further investigate the white matter correlates associated with connected speech features in PPA. We examined the relationship between white matter metrics and connected speech deficits using an automated analysis of transcriptions of connected speech and diffusion tensor imaging in language-related tracts. Syntactic, lexical, and semantic features were automatically extracted from transcriptions of topic-directed interviews conducted with groups of individuals with nfvPPA or svPPA as well as with a group of healthy controls. A principal component analysis was performed in order to reduce the number of language measures and yielded a five-factor solution. The results indicated that nfvPPA patients differed from healthy controls on a syntactic factor, and svPPA patients differed from controls on two semantic factors. However, the patient groups did not differ on any factor. Moreover, a correlational analysis revealed that the lexical richness factor was significantly correlated with radial diffusivity in the left inferior longitudinal fasciculus, which suggests that semantic deficits in connected speech reflect a disruption of this ventral pathway, and which is largely consistent with the results of previous studies. Using an automated approach for the analysis of connected speech combined with probabilistic tractography, the present findings demonstrate that nfvPPA patients are impaired relative to healthy controls on syntactic measures and have increased radial diffusivity in the left superior longitudinal fasciculus, whereas the svPPA group was impaired on lexico-semantic measures relative to controls and showed increased radial diffusivity in the uncinate and inferior longitudinal fasciculus bilaterally.
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http://dx.doi.org/10.1159/000456710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5465709PMC
March 2017

The Ultimate Outlier: Transitional Care for Persons with Dementia and BPSD.

Authors:
Jiska Cohen-Mansfield Colleen A Ray Tasmia Hai Cristina Marcu Brandy L Callahan Morris Freedman

Curr Alzheimer Res 2017 ;14(9):969-977

Sam and Ida Ross Memory Clinic, Baycrest Health Sciences, Toronto. Canada.

Background: Transitional care units aim to assist caregivers who cannot manage the care for persons with dementia who manifest behavioral and psychological symptoms of dementia (BPSD). However, there is a dearth of research on such care units.

Objective: The current study reviewed one specialized transitional unit to better understand the characteristics of the persons with dementia and behavioral symptoms entering such unit. The study also looked at the change in terms of (a) BPSD, (b) use of psychotropic medications and (c) function of the patients in this unit.

Method: A retrospective chart review of 73 residents of a transitional care unit was conducted. Background and outcome information were collected on electronic data entry sheets.

Results: Patients had an average age of 75.0 years, 74.0% were men. Mean Cognitive Performance Scale score was 4.7. Comparing admission to discharge, there was a significant decrease in BPSD, and a significant increase in number of central nervous system medications. There were no significant changes in cognition or ability to perform activities of daily living.

Conclusion: Patient characteristics differed from those of other long term care settings. This unique population requires further study to optimize the outcomes.
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http://dx.doi.org/10.2174/1567205014666170515141710DOI Listing
May 2018

The Ontario Neurodegenerative Disease Research Initiative (ONDRI).

Authors:
Sali M K Farhan Robert Bartha Sandra E Black Dale Corbett Elizabeth Finger Morris Freedman Barry Greenberg David A Grimes Robert A Hegele Chris Hudson Peter W Kleinstiver Anthony E Lang Mario Masellis William E McIlroy Paula M McLaughlin Manuel Montero-Odasso David G Munoz Douglas P Munoz Stephen Strother Richard H Swartz Sean Symons Maria Carmela Tartaglia Lorne Zinman Michael J Strong

Can J Neurol Sci 2017 Mar 22;44(2):196-202. Epub 2016 Dec 22.

2Robarts Research Institute,Western University,London,Canada.

Because individuals develop dementia as a manifestation of neurodegenerative or neurovascular disorder, there is a need to develop reliable approaches to their identification. We are undertaking an observational study (Ontario Neurodegenerative Disease Research Initiative [ONDRI]) that includes genomics, neuroimaging, and assessments of cognition as well as language, speech, gait, retinal imaging, and eye tracking. Disorders studied include Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson's disease, and vascular cognitive impairment. Data from ONDRI will be collected into the Brain-CODE database to facilitate correlative analysis. ONDRI will provide a repertoire of endophenotyped individuals that will be a unique, publicly available resource.
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http://dx.doi.org/10.1017/cjn.2016.415DOI Listing
March 2017

Characterizing familial corticobasal syndrome due to Alzheimer's disease pathology and PSEN1 mutations.

Authors:
Benjamin Lam Aun Khan Julia Keith Ekaterina Rogaeva Juan Bilbao Peter St George-Hyslop Mahdi Ghani Morris Freedman Donald T Stuss Tiffany Chow Sandra E Black Mario Masellis

Alzheimers Dement 2017 May 12;13(5):520-530. Epub 2016 Oct 12.

L.C. Campbell Cognitive Neurology Research Unit, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada; Brain Sciences Research Program, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada; Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Toronto Dementia Research Alliance, Toronto, Ontario, Canada.

Introduction: Corticobasal syndrome (CBS) resulting from genetic Alzheimer's disease (AD) has been described only once. Whether familial CBS-AD is a distinct clinical entity with its own imaging signature remains unknown.

Methods: Four individuals with CBS from two families underwent detailed assessment. For two individuals, regional atrophy and hypoperfusion were compared to autopsy-confirmed typical late-onset AD and corticobasal degeneration, as well as genetically proven PSEN1 cases with an amnestic presentation.

Results: One family harbored a novel mutation in PSEN1:p.Phe283Leu. MRI demonstrated severe parietal, perirolandic, and temporal atrophy, with relative sparing of frontal and ipsilateral hippocampal regions. Autopsy confirmed pure AD pathology. The other family harbored a known PSEN1 mutation:p.Gly378Val.

Discussion: This report confirms familial CBS-AD as a distinct clinical entity, with a parietal-perirolandic-temporal atrophy signature. It illustrates the clinical heterogeneity that can occur despite a shared genetic cause and underscores the need for biomarkers such as amyloid imaging during life.
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http://dx.doi.org/10.1016/j.jalz.2016.08.014DOI Listing
May 2017

Behavioural and neuroimaging changes after naming therapy for semantic variant primary progressive aphasia.

Authors:
Regina Jokel Aneta Kielar Nicole D Anderson Sandra E Black Elizabeth Rochon Simon Graham Morris Freedman David F Tang-Wai

Neuropsychologia 2016 08 11;89:191-216. Epub 2016 Jun 11.

Department of Medicine, (Neurology), University of Toronto, Toronto, Canada; University Health Network, Toronto, Canada.

The objectives of this study were to examine the effects of a successful naming intervention on naming performance and brain activity in individuals with the semantic variant of primary progressive aphasia (svPPA). Four participants with svPPA were scanned while performing phonologically- and semantically-based tasks before and after an intense, 20-h naming therapy that followed the principles of errorless learning whereby errors were eliminated from the learning process. Five healthy control participants were scanned at the outset of the study and did not receive treatment. The results showed that in svPPA participants, successful re-learning of forgotten vocabulary was accompanied by activation of a larger network in bilateral brain regions and that the level of activation in the left anterior lobe may be inversely correlated with severity of semantic impairment. Our findings have implications for treatment in svPPA patients and suggest that semantic cues can improve naming, in spite of significant semantic impairment. The results indicate that intensive language therapy can lead to behavioural gains and neuroplastic changes even in individuals with more advanced anterior temporal lobe atrophy.
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http://dx.doi.org/10.1016/j.neuropsychologia.2016.06.009DOI Listing
August 2016

Interventions Targeting Reversible Dementia in Down Syndrome.

Authors:
Brandy L Callahan Carolyn Wong Peter N Ngang Uri Wolf Morris Freedman

J Am Geriatr Soc 2016 Apr;64(4):917-9

Division of Neurology, Department of Medicine, Baycrest Centre for Geriatric Care, Mt Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1111/jgs.14068DOI Listing
April 2016

Short-Term Effects of Rhythmic Sensory Stimulation in Alzheimer's Disease: An Exploratory Pilot Study.

Authors:
Amy Clements-Cortes Heidi Ahonen Michael Evans Morris Freedman Lee Bartel

J Alzheimers Dis 2016 03;52(2):651-60

Music and Health Research Collaboratory, University of Toronto, Toronto, ON, Canada.

This study assessed the effect of stimulating the somatosensory system of Alzheimer's disease (AD) patients at three stages of their illness with 40 Hz sound. In this AB cross-over study design, 18 participants (6 mild, 6 moderate, 6 severe) each participated in 13 sessions: one intake and 12 treatment. Treatment A consisted of 40 Hz sound stimulation and Treatment B consisted of visual stimulation using DVDs, each provided twice a week over 6 weeks for a total of 6 times per treatment. Outcome measures included: St. Louis University Mental Status Test (SLUMS), Observed Emotion Rating Scale, and behavioral observation by the researcher. Data were submitted to regression analysis for the series of 6 SLUMS scores in treatment A and 6 scores in B with comparison by group. The slopes for the full sample and subgroups in the 40 Hz treatment were all significant beyond alpha = 0.05, while those for the DVD were not. A thematic analysis of qualitative observations supported the statistical findings. 40 Hz treatment appeared to have the strongest impact on persons with mild and moderate AD. Results are promising in terms of a potential new treatment for persons with AD, and further research is needed.
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http://dx.doi.org/10.3233/JAD-160081DOI Listing
March 2016

Amyloid deposition in semantic dementia: a positron emission tomography study.

Authors:
Eric E Brown Ariel Graff-Guerrero Sylvain Houle Romina Mizrahi Alan A Wilson Bruce G Pollock Benoit H Mulsant Daniel Felsky Aristotle N Voineskos David F Tang-Wai Nicolaas P L G Verhoeff Morris Freedman Zahinoor Ismail Tiffany W Chow

Int J Geriatr Psychiatry 2016 09 25;31(9):1064-74. Epub 2016 Jan 25.

Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.

Background: Pittsburgh compound B ([11C]-PIB) identifies amyloid-β (Aβ) deposition in vivo. Asymptomatic Aβ deposition has been reported consistently in some healthy older subjects. Of patients with frontotemporal dementia, those who have later onset have a higher potential for Aβ deposition.

Objective: Comparison of Aβ deposition in Alzheimer's disease (AD), healthy older controls, and patients with early- and late-onset semantic dementia (SD), a subtype of frontotemporal dementia.

Methods: Subjects were recruited from tertiary academic care centers specializing in assessment and management of patients with neurodegenerative disease. We used the radiotracer [11C]-PIB in a high-resolution positron emission tomography scanner to evaluate 11 participants with SD (six with onset before age 65 and five with later onset), 9 with probable AD, and 10 controls over age 60. The main outcome measures were frontal, temporal, parietal, and total [11C]-PIB standardized uptake value ratios to establish PIB-positive (PIB+) cutoff.

Results: The five patients with late-onset SD were PIB-negative. Two of six with early-onset SD, seven of nine with AD, and 1 of 10 controls were PIB+. The SD participants who were PIB+ did not have memory or visuospatial deficits that are typical in AD.

Conclusions: Aβ deposition does not seem to be associated with late-onset SD. Future larger studies might confirm whether a significant minority of early-onset SD patients exhibit Aβ deposition. Copyright © 2016 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/gps.4423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6139433PMC
September 2016

Reversible long-standing severe disability in idiopathic normal pressure hydrocephalus.

Authors:
Ayman M Selim Colleen Ray Michael D Cusimano Eloise Karp Morris Freedman

Neurol Clin Pract 2015 Dec;5(6):505-508

Division of Neurology (AMS, MF), Department of Medicine; Centre for Memory and Neurotherapeutics (CR), Department of Neuropsychology and Cognitive Health; Department of Physiotherapy (EK); and Rotman Research Institute (MF), Baycrest, Toronto, Ontario, Canada; Division of Neurology (AMS, MF), Department of Medicine; Division of Neurosurgery (MDC) Department of Surgery, University of Toronto, Ontario, Canada; Department of Neurology (AMS), Zagazig University, Zagazig, Egypt; Division of Neurosurgery (MDC), Department of Surgery, St. Michael's Hospital, Toronto, Ontario, Canada; and Division of Neurology (MF), Department of Medicine, Mt. Sinai Hospital, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1212/CPJ.0000000000000149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684672PMC
December 2015

Trajectories of Behavioural Disturbances Across Dementia Types.

Authors:
Alexandra B Linds Alana B Kirstein Morris Freedman Nicolaas P L G Verhoeff Uri Wolf Tiffany W Chow

Can J Neurol Sci 2015 Nov 2;42(6):389-94. Epub 2015 Sep 2.

2Rotman Research Institute of Baycrest,Mt. Sinai,Toronto,Ontario,Canada.

Objective: To replicate a previous finding that the trajectory of the Neuropsychiatric Inventory (NPI) shifts in the sixth year of behavioural variant frontotemporal dementia (bvFTD). We evaluated longitudinal tracking with both the Frontal Behavioural Inventory (FBI) and NPI, comparing bvFTD against other dementias.

Methods: Chart reviews over two to five years for patients with bvFTD (n=30), primary progressive aphasia (PPA, n=13) and Alzheimer's disease (AD, n=118) at an urban Canadian tertiary clinic specializing in dementia. Linear regressions of the longitudinal data tested predictors of annualized rates of change (ROC) in NPI and FBI total and subscales for apathy and disinhibition among dementia groups.

Results: The mode of the overall sample for the most advanced duration of illness observed was 5 years, with the median at 7 years. We did not find a crescendo-decrescendo pattern in scores although, for bvFTD and AD, high initial scores correlated with ensuing downward ROCs on the NPI and FBI. Educational level showed an influence on disinhibition ROCs. The FBI was no more revealing than the NPI for apathy and disinhibition scores in these dementias.

Conclusions: A cognitive reserve effect on behavioural disturbance was supported but it may take longer than our 4 years of observing the clinical sample to record inflection points in the behavioural and psychiatric symptoms seen in bvFTD. The current data only imply that both apathy and disinhibition will diminish over the course of dementia.
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http://dx.doi.org/10.1017/cjn.2015.266DOI Listing
November 2015

Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis.

Authors:
Jonathan D Rohrer Jennifer M Nicholas David M Cash John van Swieten Elise Dopper Lize Jiskoot Rick van Minkelen Serge A Rombouts M Jorge Cardoso Shona Clegg Miklos Espak Simon Mead David L Thomas Enrico De Vita Mario Masellis Sandra E Black Morris Freedman Ron Keren Bradley J MacIntosh Ekaterina Rogaeva David Tang-Wai Maria Carmela Tartaglia Robert Laforce Fabrizio Tagliavini Pietro Tiraboschi Veronica Redaelli Sara Prioni Marina Grisoli Barbara Borroni Alessandro Padovani Daniela Galimberti Elio Scarpini Andrea Arighi Giorgio Fumagalli James B Rowe Ian Coyle-Gilchrist Caroline Graff Marie Fallström Vesna Jelic Anne Kinhult Ståhlbom Christin Andersson Håkan Thonberg Lena Lilius Giovanni B Frisoni Michela Pievani Martina Bocchetta Luisa Benussi Roberta Ghidoni Elizabeth Finger Sandro Sorbi Benedetta Nacmias Gemma Lombardi Cristina Polito Jason D Warren Sebastien Ourselin Nick C Fox Martin N Rossor Giuliano Binetti

Lancet Neurol 2015 Mar 4;14(3):253-62. Epub 2015 Feb 4.

Dementia Research Centre, University College London, London, UK. Electronic address:

Background: Frontotemporal dementia is a highly heritable neurodegenerative disorder. In about a third of patients, the disease is caused by autosomal dominant genetic mutations usually in one of three genes: progranulin (GRN), microtubule-associated protein tau (MAPT), or chromosome 9 open reading frame 72 (C9orf72). Findings from studies of other genetic dementias have shown neuroimaging and cognitive changes before symptoms onset, and we aimed to identify whether such changes could be shown in frontotemporal dementia.

Methods: We recruited participants to this multicentre study who either were known carriers of a pathogenic mutation in GRN, MAPT, or C9orf72, or were at risk of carrying a mutation because a first-degree relative was a known symptomatic carrier. We calculated time to expected onset as the difference between age at assessment and mean age at onset within the family. Participants underwent a standardised clinical assessment and neuropsychological battery. We did MRI and generated cortical and subcortical volumes using a parcellation of the volumetric T1-weighted scan. We used linear mixed-effects models to examine whether the association of neuropsychology and imaging measures with time to expected onset of symptoms differed between mutation carriers and non-carriers.

Findings: Between Jan 30, 2012, and Sept 15, 2013, we recruited participants from 11 research sites in the UK, Italy, the Netherlands, Sweden, and Canada. We analysed data from 220 participants: 118 mutation carriers (40 symptomatic and 78 asymptomatic) and 102 non-carriers. For neuropsychology measures, we noted the earliest significant differences between mutation carriers and non-carriers 5 years before expected onset, when differences were significant for all measures except for tests of immediate recall and verbal fluency. We noted the largest Z score differences between carriers and non-carriers 5 years before expected onset in tests of naming (Boston Naming Test -0·7; SE 0·3) and executive function (Trail Making Test Part B, Digit Span backwards, and Digit Symbol Task, all -0·5, SE 0·2). For imaging measures, we noted differences earliest for the insula (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume was 0·80% in mutation carriers and 0·84% in non-carriers; difference -0·04, SE 0·02) followed by the temporal lobe (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume 8·1% in mutation carriers and 8·3% in non-carriers; difference -0·2, SE 0·1).

Interpretation: Structural imaging and cognitive changes can be identified 5-10 years before expected onset of symptoms in asymptomatic adults at risk of genetic frontotemporal dementia. These findings could help to define biomarkers that can stage presymptomatic disease and track disease progression, which will be important for future therapeutic trials.

Funding: Centres of Excellence in Neurodegeneration.
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http://dx.doi.org/10.1016/S1474-4422(14)70324-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742501PMC
March 2015

Verb production in the nonfluent and semantic variants of primary progressive aphasia: the influence of lexical and semantic factors.

Authors:
Karine Marcotte Naida L Graham Sandra E Black David Tang-Wai Tiffany W Chow Morris Freedman Elizabeth Rochon Carol Leonard

Cogn Neuropsychol 2014 ;31(7-8):565-83

a Toronto Rehabilitation Institute , Toronto , Canada.

Differential patterns of impairment with respect to noun and verb production have been observed in the nonfluent and semantic variants of primary progressive aphasia. However, the factors influencing this discrepancy remain unclear. The present study evaluates verb retrieval in primary progressive aphasia using a naming task and a story completion task. Findings indicate that patients with the semantic variant are influenced by familiarity, frequency, and age of acquisition in both object and action naming, whereas patients with the nonfluent variant are not. Surprisingly, there were no differences in either group between object and action naming, presumably because the lists were well matched on pertinent variables. In the story completion task, greater impairment in semantically heavier than in semantically lighter verbs was observed for the semantic variant, and grammaticality and verb tense agreement was significantly lower in the nonfluent variant. The present findings suggest that lexicosemantic attributes affect verb production in the semantic variant, whereas both lexicosemantic and syntactic attributes affect verb production in the nonfluent variant.
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http://dx.doi.org/10.1080/02643294.2014.970154DOI Listing
March 2015

Delaying onset of dementia: are two languages enough?

Authors:
Morris Freedman Suvarna Alladi Howard Chertkow Ellen Bialystok Fergus I M Craik Natalie A Phillips Vasanta Duggirala Surampudi Bapi Raju Thomas H Bak

Behav Neurol 2014 18;2014:808137. Epub 2014 May 18.

Human Cognitive Neuroscience and Centre for Cognitive Aging and Cognitive Epidemiology School of Philosophy, Psychology and Language Sciences, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK ; Centere for Clinical Brain Sciences, University of Edinburgh, 49 Little France Crescent, Edinburgh EH16 4SB, UK.

There is an emerging literature suggesting that speaking two or more languages may significantly delay the onset of dementia. Although the mechanisms are unknown, it has been suggested that these may involve cognitive reserve, a concept that has been associated with factors such as higher levels of education, occupational status, social networks, and physical exercise. In the case of bilingualism, cognitive reserve may involve reorganization and strengthening of neural networks that enhance executive control. We review evidence for protective effects of bilingualism from a multicultural perspective involving studies in Toronto and Montreal, Canada, and Hyderabad, India. Reports from Toronto and Hyderabad showed a significant effect of speaking two or more languages in delaying onset of Alzheimer's disease by up to 5 years, whereas the Montreal study showed a significant protective effect of speaking at least four languages and a protective effect of speaking at least two languages in immigrants. Although there were differences in results across studies, a common theme was the significant effect of language use history as one of the factors in determining the onset of Alzheimer's disease. Moreover, the Hyderabad study extended the findings to frontotemporal dementia and vascular dementia.
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http://dx.doi.org/10.1155/2014/808137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4052164PMC
December 2014

Effects of bilingualism on the age of onset and progression of MCI and AD: evidence from executive function tests.

Authors:
Ellen Bialystok Fergus I M Craik Malcolm A Binns Lynn Ossher Morris Freedman

Neuropsychology 2014 Mar 18;28(2):290-304. Epub 2013 Nov 18.

Rotman Research Institute at Baycrest.

Previous articles have reported that bilingualism is associated with a substantial delay in the onset of both Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI). The present study reports results from 74 MCI patients and 75 AD patients; approximately half of the patients in each group were bilingual. All patients were interviewed to obtain details of their language use, onset of their condition, and lifestyle habits. Patients performed three executive function (EF) tests from the D-KEFS battery (Trails, Color-Word Interference, Verbal Fluency) on 3 occasions over a period of approximately 1 year. Results replicated the finding that bilingual patients are several years older than comparable monolinguals at both age of symptom onset and date of first clinic visit. This result could not be attributed to language group differences in such lifestyle variables as diet, smoking, alcohol consumption, physical activity, or social activity. On the first testing occasion, performance on the EF tasks was generally comparable between the language groups, contesting arguments that bilinguals wait longer before attending the clinic. Finally, EF performance tended to decline over the 3 sessions, but no differences were found between monolinguals and bilinguals in the rate of decline.
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http://dx.doi.org/10.1037/neu0000023DOI Listing
March 2014