Tau Cleavage and Phosphorylation in Tauopathy

K. Ashe, A.B, Ph.D, Chair of Neurology and Neuroscience at Edmund Wallace and Anne Marie Tulloch, Director at N. Bud Grossman Center for Memory Research and Care

It is widely believed that insoluble aggregates of tau underlie its pathogenicity in tauopathies, but recent data implicate a role for soluble tau as well. We identified a candidate soluble tau cleavage product whose formation results in impaired cognition in transgenic mice expressing human tau with the P301L mutation (tauP301L), which causes FTDP-17. This cleavage product, Δtau314, forms when caspase-2 (Casp2) cleaves tauP301L at Asp-314 (D314). Tau is a new, previously unknown substrate of Casp2. Importantly, mutating the site at which Casp2 cleaves tau (D314E) preserves memory function in mice expressing tauP301L, and lowering Casp2 levels in tauP301L-expressing mice restores memory function. When tauP301L is tagged on its N-terminus with GFP and expressed in cultured neurons, a GFP-tagged form of tau mislocalizes to dendritic spines, and this mislocalization depends on both the cleavage and phosphorylation of tau. Tau mislocalization is associated with alterations in synaptic function (diminished amplitudes of mEPSCs) and reduced levels of AMPA receptors (AMPARs) in dendritic spines. Cells lacking Casp2 or expressing Casp2-resistant tauP301L,D314E do not show tau mislocalization or altered dendritic spines. Based on our data, we hypothesize that mutant tauP301L leads to activation of kinases and Casp2, resulting in differential site-specific phosphorylation that is required for Casp2 generation of Δtau314, mislocalization of tau, and reductions in AMPAR number and activity that impair synaptic and cognitive function. 

Vascular health and implications for the brain

J. Barnes, Bruno Balke Biodynamics Laboratory, Department of Kinesiology, University of Wisconsin-Madison, Madison, WI, USA

Aging is associated with impaired vascular health, elevated cardiovascular disease risk, and increased Alzheimer’s disease (AD) pathology. In addition, aging reduces cerebral perfusion and cerebral vascular function, and is associated with brain atrophy. Understanding the effects of physiological aging on cerebral blood flow and brain structure may help to determine effective strategies to mitigate these effects on the population.  Currently, cerebral blood flow regulation during midlife is poorly understood, making it difficult to distinguish age-related physiology from AD-related pathophysiology. Furthermore, age-related changes in the vasculature may accelerate pathophysiological increases in neurodegeneration and AD neuropathology. Understanding how vascular function changes, especially during midlife, is important because this is the critical period where lifestyle and pharmacological intervention can modify the risk of future cognitive impairment.  Exercise may be one strategy to prevent or delay cognitive decline.  Regular exercise has been shown to improve cognition, likely through beneficial adaptations in vascular function in the cerebral vessels.  Additional interventions initiated during midlife that are directed at improving cerebral perfusion and cerebral vascular function are necessary.

Engaging the brain of older adults: The effects of cognitive training on cognition and the brain in healthy aging and mild cognitive impairment

S. Belleville, Psychology Department, University of Montreal, and Director, Research Center, Institut Universitaire de Gériatrie de Montréal

Epidemiological studies have reported that higher education and engagement in cognitively stimulating activities throughout one's life are associated with better cognition in late-life and a lower risk of dementia. This has spurred great interest for cognitive training as a way to improve cognition in older adults and and to prevent decline in persons at risk of dementia. In this talk, I will present results from studies examining the effects of cognitive training on cognition in healthy older adults and in persons with mild cognitive impairment. I will also discuss many important issues regarding this field: whether cognitive training has long-standing effects, whether the effects on cognition transfer to activities of everyday life, and how it impacts the brain. I will also discuss whether different types of training – in particular those involving repeated practice or strategic learning – and whether different dosages have different effects on efficacy and on the brain.

Population perspectives on the complexity of brain ageing and dementia within changing societies

C. Brayne, Cambridge Institute of Public Health, University of Cambridge

Before the 1980s there were virtually no population based studies of dementia and brain ageing in the world with the exception of Japan and Scandinavia. Since then there have been several waves, each influenced by societies concerns and preoccupations. Research into brain ageing was largely volunteer cohorts and panel surveys, conducted by psychologists earlier than this, some very longstanding and detailed. As this area of interest has grown others have entered the field with engagement of epidemiologists, biostatisticians, broader public health disciplines and many others such as geographers, data scientists. Many of the early studies that were done to address societal need for metrics on numbers of people with dementia (prevalence and incidence) were designed as deep phenotyping platforms for subsequent waves to be able to look in far more detail at risk, protection and natural history. These studies contributed considerably to the understanding that dementia is about more than beta amyloid and that vascular risk plays an important part. As techniques have improved for investigation of genetics, genomics, biomarkers and neuroimaging these have been incorporated into population based cohort studies. These have revealed again how complex brain ageing, the dementia syndrome are in ageing populations and how this research needs to integrate with understanding of frailty. Although researchers often develop their fields separately, such that some definitions of frailty do not include cognition, working with whole ageing populations across geography and time should be at the heart of biomedical research in order to provide the grounding necessary. Such work across time in the UK has revealed dramatic reductions in the prevalence of dementia age for age, and reduced expectation of life with cognitive impairment in more recent older populations but without reduction in overall disability. A key challenge is how to better bring together the direction of the biomedical world with early detection and lifelong treatments for very specific assumed abnormalities with the findings synthesised here.

Healthy Brain Aging: Effects of Exercise

K. Erickson, Department of Psychology, Faculty Member, Center for the Neural Basis of Cognition, Center for Neuroscience at the University of Pittsburgh

A growing body of evidence from neuroscience, epidemiology, and kinesiology suggests that physical activity is effective for preventing, delaying, and potentially treating neurocognitive problems throughout the lifespan. Despite the emerging recognition of physical activity as a powerful method to enhance brain health, there is continued confusion from both the public and scientific communities about what the extant research has discovered about the potential for physical activity to improve neurocognitive health and which questions remain unanswered. From this perspective, I will discuss the current research on exercise, fitness, and brain health and focus on several potential moderators of the effects of exercise on neurocognitive function. I will conclude that physical activity decreases the risk for brain diseases and disorders, ameliorates symptoms, improves function, and increases regional brain volume – especially in the frontal cortex and hippocampus - and that we are beginning to have a better understanding of the factors that moderate and mediate these associations. Overall, physical activity is an important modifiable lifestyle that carries significant consequences for learning, memory, and brain health for people of all ages.

Managing Depression in Dementia

Z. Goodarzi, BHSc (Hon). MD. MSc. FRCPC. Clinical Assistant Professor, Division of Geriatrics, Cumming School of Medicine, University of Calgary

Persons with dementia commonly experience depression. Depression can lead to worsening cognitive and functional impairment, with increased admission to long term care. As such these symptoms cause significant burden on the individual, their caregivers and the health care system. All individuals involved in the care of those with dementia need to be aware depression so we can move towards improving care for these patients. Our goals for this presentation will be to:

  1.  To review the epidemiology depression in those with dementia.
  2. To recognize the impact of depression on those with dementia, their caregivers and health care system.
  3. To cover the case finding tools we can use to detect depressive symptoms in different care settings.
  4. To review the diagnostic challenges for depression in dementia
  5. To understand the evidence for non-pharmacologic and pharmacologic treatment of depression in those with dementia

Rural Dementia Action Research (RaDAR) Initiatives in Health Care Delivery

J. Kosteniuk, Canadian Centre for Health and Safety in Agriculture, University of Saskatchewan

The under-resourced nature of health and social services in rural communities is well documented. Limited local health care and social support have been identified as factors related to later diagnosis, avoidable crises, and earlier institutionalization among rural individuals with dementia. To address these challenges, the RaDAR program, led by Debra Morgan at the University of Saskatchewan, uses an interdisciplinary community-based participatory research approach to implement and sustain initiatives in rural dementia care. In collaboration with rural health care providers and other stakeholders, the RaDAR team established the first rural and remote memory clinic in the province of Saskatchewan in 2004. Recommended as a model of dementia care for rural and remote communities in a recent Canadian senate report, the university-based specialist clinic offers assessment of atypical and complex cases by an interdisciplinary team, with in-person and telehealth follow-up. The team also developed a community-based model that consists of elements of high quality dementia care, adapted for rural primary health care settings. The main features of this model include team-based care, decision support tools, and remote specialist-to-provider support. An annual summit provides a venue for regular knowledge exchange between researchers and stakeholders, ensuring that rural perspectives are integrated throughout the research process. Using applied research to address rural-urban disparities in access to quality health and social care for individuals with dementia is one of the main goals of the RaDAR program.

Hunting for clues of tau-spreading in the human brain

G. G. Kovacs, Institute of Neurology, Medical University of Vienna

Introduction: Neurodegenerative diseases are characterized by progressive dysfunction and loss of neurons leading to distinct involvement of functional systems defining clinical presentations. Revolutionary studies demonstrated that proteins with altered physicochemical properties deposit in the human brain and may spread cell-to-cell as a fundamental phenomenon. Tauopathies are major neurodegenerative disorders characterized by the deposition of abnormal tau protein in the brain. Based on the cellular distribution of tau pathology, Pick disease, neurofibrillary tangle-dementia or primary age-related tauopathy (PART), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), argyrophilic grain disease (AGD), and globular glial tauopathies can be distinguished. Further important forms include chronic traumatic encephalopathy (CTE) and ageing-related tau-astrogliopathy (ARTAG). Some of these show subtypes. Neuropathological classification conforms with different bands and isoforms demonstrated in Western blots of insoluble tau. Importantly, in addition to neurons, astroglia and oligodendroglia also accumulate pathological tau and might contribute to its propagation.

Design: To interpret spreading of tau pathology in the brain different aspects need to be considered and anatomical patterns have to be analyzed. For some tauopathies, such as AGD and PART as for tau pathology in Alzheimer disease and CTE, it has been suggested that the pathological alterations follow a stereotypic pattern. Anaqlogously, for PSP progressive involvement of different anatomical areas have been reported. Recently, it has been suggested that in Pick disease and globular glial tauopathy, tau neuropathology might originate in limbic/paralimbic cortices. Detailed evaluation of ARTAG helps to understand the relation of astroglial and neuronal tau pathologies.

Conclusions: The possibility of cell-to-cell propagation is a novel aspect of the pathogenesis of tauopathies, which is partly reflected by the hierarchic involvement of anatomic regions. This concept might have relevance for the development of therapies; however, the exact cytopathological mechanism in the brain awaits further clarifications.

Shared Decision-making with Seniors Living with Dementia and their Caregivers

F. Légaré, B. Sc. Arch, MD, MSc, PhD, CCMF, FCMF, Tier 1 Canada Research Chair in Shared Decision Making and Knowledge Translation, Department of Family Medicine and Emergency Medicine, Faculty of Medicine, Laval University

Shared decision making is a collaborative, interpersonal and relational process whereby health professionals support clients/patients in making decisions that are informed by best evidence and by what matters to them. Shared decision making improves the healthcare experiences of clients and healthcare teams and leads to better healthcare processes, client/patient outcomes and lower health costs. Decision aids help clients/patients to be better informed with more realistic expectations, clarity about their values and activity in decision making, while reducing overuse of ineffective care options and increasing uptake of effective ones. It plays a crucial role in reducing harms and increasing client safety. In a 2018 survey of 1591 Canadians of whom 939 had received health services in the previous year, only 36% of seniors said they were always/often presented with choices, and 35% were always/often asked what mattered to them, with seniors consistently rating lower. This presentation will review barriers to uptake of shared decision making in clinical practices and highlight the most promising strategies that can be used to address them. Lessons learned from recently completed studies with seniors experiencing frailty and their caregivers in the home care context will be shared.

Learning objectives:
At the end of the session, the participant will be able to:

  1. Define shared decision making
  2. Identify the most promising strategies for implementing shared decision making in clinical settings
  3. Discuss the relevance of shared decision making for seniors living with dementia and their caregivers

Reshaping the Path of Mild Cognitive Impairment with Exercise

T. Lui-Ambrose, PhD, PT, Professor, physical therapist and Canada Research Chair, University of British Columbia, Department of Physical Therapy

Cerebrovascular disease is the second most common cause of dementia in older adults, behind Alzheimer’s. Research suggests that reducing heart health risk factors, such as high blood pressure and high cholesterol, may reduce dementia risk, and possibly even slow down the progression of cognitive decline due to small vessel disease. Worldwide, sub-cortical ischemic vascular ischaemia (SIVCI) is the second most common etiology contributing to cognitive impairment among older adults. Yet, SIVCI may the most treatable form of cognitive impairment as many of its risk factors can be reduced with exercise, particularly aerobic exercise. Nevertheless, few randomized controlled trials to date have specifically assessed the efficacy of exercise training on cognitive and neural outcomes in this high-risk group. Thus, we conducted a 6-month proof-of-concept randomized controlled trial of thrice-weekly aerobic exercise training (AE) among 71 adults with mild SIVCI. In the presentation, we will discuss the results of our randomized controlled trial. Overall, the results that suggest AE promotes cognitive and neural outcomes in older adults with mild SIVIC. In addition, the efficacy of AE may be different between females and males with SIVCI.

Addressing heterogeneity in neurodegenerative diseases: Application of biomarkers and precision medicine to overcome the challenges

M. Masellis, MSc, MD, PhD, FRCPC, Clinician Scientist & Assistant Professor, Sunnybrook Health Sciences Centre, University of Toronto

Due to the aging of the baby boomer population, neurodegenerative diseases will become an epidemic in the next several years. Disease-modifying agents and other interventions are urgently needed to prevent or delay dementia, and to slow progression once it is symptomatic, not only for Alzheimer’s disease (AD), but also other common, often co-morbid conditions, including Parkinson’s-Lewy Body Disease (PD-LBD), Vascular Cognitive Impairment (VCI), and Frontotemporal Dementia (FTD). However, the development of such therapeutic agents will be significantly challenged by the substantial clinical and pathological heterogeneity observed, especially in the late onset, sporadic forms of these disorders. Indeed, this is one of several potential reasons for the recent failure of drug trials targeting neurodegenerative diseases. In this lecture, a review of next generation strategies to addressing the complex nature of these disorders that dissect out this heterogeneity will be provided. This will be followed by a discussion of the state of the art in clinical trial design as it relates to neurodegenerative diseases. Finally, insights from Canada focusing on international collaborative synergies will be highlighted.

Learning objectives:

At the end of this lecture, attendees will be able to:

1)      Understand clinical and pathological heterogeneity in neurodegenerative diseases and how this has hampered the development of disease-modifying agents
2)      Understand how precision medicine strategies can be applied to overcome these challenges

Alzheimer’s Biomarkers Discriminate Non-demented Cognitive Aging Trajectories and Phenotypes

G.P. McFall, Post-Doctoral Research Associate at University of Alberta, Assistant Director of the NIH-funded Victoria Longitudinal Study

Developing biomarkers and quantitative technologies for early detection of Alzheimer’s disease (AD) risk has become an important focus of current research on promoting healthy brain aging and preventing (or delaying) dementia. However, longitudinal studies have revealed a significant challenge: Actual individualized trajectories of non-demented cognitive change are highly variable (within person) and broadly differential (across persons). Specifically, these dynamic trajectories vary in three important components: performance (e.g., level), trajectories (e.g., slope), and clinical outcomes (e.g., dementia). In this talk, I discuss how both modifiable and non-modifiable AD-risk biomarkers can be deployed in various combinations to (a) objectively classify dynamic phenotypes of cognitive change and (b) discriminate predictors of these phenotypes. I discuss how two quantitative technologies (dynamic trajectory analyses and machine learning prediction analyses) can be used in combination to identify and compare important biomarkers of early risk (and possible protection). I report that AD-related biomarkers from multiple domains vary in their prediction status across cognitive trajectory subgroups and between males and females. A conclusion is that mechanisms of preclinical aging may vary systematically and that precision and multi-model interventions may usefully target empirically delineated subgroups.

Disrupted functional and anatomical connectivity and other markers of cognitive decline in PD

O. Monchi, Professor and Tourmaline Chair in Parkinson’s Disease, Canada Research Chair in Non-Motor Symptoms of Parkinson’s disease, Departments of Clinical Neurosciences and Radiology, Hotchkiss Brain Institute, University of Calgary

Cognitive impairment is highly prevalent and has a severe negative effect on health related and perceived quality of life in Parkinson’s disease (PD). It is now established that 25 to 40% of persons with PD will develop cognitive deficits early in the disease. Moreover, the risk of developing dementia is six times higher in PD patients than in age-matched controls and it is estimated that 80% of patients will develop dementia after 20 years of the disease. In order to address these symptoms properly it is crucial to identify very early in the disease the patients who are most likely to develop dementia rapidly. Persons who meet criteria for mild cognitive impairment (MCI) exhibit measurable cognitive deficits but those deficits are not severe enough to interfere significantly with daily life. While the presence of MCI in PD increases the chance of developing dementia, various studies suggest that PD-MCI might consist of distinct subtypes with different pathophysiologies and prognoses.

In this talk we will review different clinical characteristics linked to neuropsychological and neuropsychiatric function as well as sleep that can affect cognition in PD. We will also discuss genetic, and other blood biomarkers as well as neuropathological ones that are associated with cognitive decline and dementia in PD. We will focus on different neuroimaging methods that attempt to characterize better the various cognitive profiles and patterns of evolution observed with PD. In particular we will discuss disrupted functional connectivity and MRI based diffusion weighted. tractography in PD-MCI.

We will argue that the data coming from most of these methodologies indicate multiple pathological processes at the origins of cognitive decline in PD, resulting in great disparity of clinical cognitive manifestations and evolution amongst patients.

Structural brain network disturbances and cognition in patients with cerebral amyloid angiopathy

Y.D. Reijmer, Brain Center Rudolf Magnus, University Medical Center Utrecht, the Netherlands

Cerebral amyloid angiopathy (CAA) is a common form of small-vessel disease and an important risk factor for cognitive impairment. I will present data suggesting that CAA partly affects cognition through disruption of structural brain connectivity. First I will show that white matter connectivity is disrupted in patients with CAA compared to controls and related to worse cognitive functioning. Graph theory is used to quantify the effect of the white matter disturbances on the efficiency of the brain network. Secondly, I will present few longitudinal data suggesting that the disruptions in white matter connectivity in CAA worsen over time and are related to cognitive decline. Possible mechanisms for the observed brain network disturbances are discussed, including the severity of small vessel disease on MRI and the severity of cortical amyloid on PET. Finally I will present some preliminary ex vivo data on histopathological correlates of brain network disturbances in CAA that supports the in vivo imaging results. Altogether, the findings suggest that disrupted brain connectivity mediates the relationship between advanced CAA and cognitive dysfunction. Large-scale structural brain network measures may represent a useful outcome marker for tracking disease progression in clinical trials.

Predictive analysis of an AD-disease cascade based on VBM- or Cortical-thickness-based networks

S. Stother, Rotman Research, Baycrest, Toronto and ADMdx, Inc, Chicago, Padeep Raamana, Rotman Research, Baycrest and University of Toronto, Ana Lukic, ADMdx, Inc, Chicago, Randolph Andrews, ADMdx, Inc, Chicago, Miles Wernick, Illinois Institute of Technology and ADMdx, Inc, Chicago, Dawn Matthews, ADMdx, Inc, Chicago

Our goal in this presentation is to illustrate the utility and relative importance of different approaches to defining structural MRI brain networks. We will present results for machine learning analyses based on two distinct approaches to measuring pairwise regional similarity metrics as network measures. The first uses the pairwise similarities defined by voxel-voxel covariances of the MRI volumetric inputs to a standard VBM analysis. The second uses multiple metrics defined between the cortical thickness distributions of surface patches output by Freesurfer. These network-definition approaches are applied to a multi-class classification problem defined by an AD-disease cascade containing progressive disease groups each drawn from the ADNI cohort, e.g., Amyloid negative normal controls, and Amyloid positive groups such as normal controls, early MCI, late MCI, MCI to AD converters, AD. In all examples we will use crossvalidation based on nested training-test-validation samples to assess the generalizability of classifier performance. We will show that both structural-network approaches produce viable predictive models of AD progression, and highlight their strengths and weaknesses.

Making Advance Care Planning Easier

R. Sudore, MD, director of Innovation Center for Action-oriented Research (I-CARE) in Aging & Palliative Care, Vulnerable Populations for Aging Research Core of the NIA-funded Pepper Center

Millions of older adults and their caregivers, especially those with cognitive impairment, will face complex medical decisions over the course of advanced illness, yet most are unprepared. Lack of preparation can lead to uninformed choices, receipt of care inconsistent with personal goals, and lack of patient empowerment during clinical encounters, especially for individuals with limited health literacy. Conventional preparation, called advance care planning (ACP), has typically focused on having patients pre-specify preferences for life prolonging procedures, such as mechanical ventilation and to document these choices in an advance directive or similar legal form or code status. Yet, these legal forms and ACP information can be hard to understand and are often not completed, especially by culturally diverse populations.

Over the past decade the ACP field has evolved and broadened its focus to include preparation of patients and surrogates to participate with clinicians in making informed medical decisions that are aligned with patients’ current values and wishes.  The field has also evolved to consider ACP as a process that involves a series of discussions over time in addition to a single advance directive or a one-time code status order. However, barriers to ACP include a lack of training and system resources. This session will provide an overview of: (a) the evolving ACP field; (b) practical advice for clear communication principles concerning ACP; and (c) the creation of ACP tools for culturally diverse older adults with limited health literacy and cognitive impairment. This session will also discuss the evidence-based PREPARE For Your Care ACP program ( and tools that can be used in the clinical and community environment to promote ACP engagement

Strains of Protein Aggregates in Neurodegenerative Diseases

J. Watts, PHD, Laboratory Medicine and Pathobiology,  University of Toronto, Principal Investigator for Neurodegenerative Diseases, Tanz Centre

An emerging theory is that the progressive nature of Alzheimer’s disease (AD) and Parkinson’s disease (PD) stems from the formation and spread of prion-like, self-propagating protein aggregates throughout the brain. Additionally, evidence is accumulating that several neurodegenerative disease-associated proteins, such as Aβ in AD and α-synuclein (α-syn) in PD, can exist as distinct aggregate “strains”. Prion strains, which are encoded by different conformations of protein aggregates, underlie the clinical and pathological heterogeneity observed amongst prion disease subtypes. We have hypothesized that distinct strains of Aβ and α-syn may be responsible for enciphering disease variability in AD, PD, and related neurological disorders. Using transgenic mouse models of AD and PD, we have shown that distinct clinical and pathological disease phenotypes can be induced by injection with unique aggregate strains. In particular, injection of transgenic mice with different strains of α-syn aggregates causes distinct signs of neurological illness, unique morphologies of cerebral α-syn deposits, and the production of distinct conformational states of α-syn aggregates within the brain. These differences are maintained following multiple passages in transgenic mice, suggesting that α-syn strains “breed true” upon transmission. Our results reveal that α-syn strains exhibit all the biochemical and pathological hallmarks of prion strains. This suggests that prion-like templating, as opposed to selective neuronal vulnerability, is the dominant mechanism driving the observed spread of α-syn aggregates in PD and related illnesses.

 Learning Objectives

After this educational session, participants will be able to:

  • Identify the pathological and biochemical hallmarks of neurodegenerative diseases
  • Differentiate between prion diseases and prion-like disorders
  • Outline the potential role of protein aggregate strains in neurodegenerative diseases

Check back soon: more abstracts will be added in the coming days.