Background

Dementia affects over half a million Canadians, with Alzheimer’s disease (AD) accounting for 60-80 percent of the cases (1,2). The disease mainly affects cognitive functioning and is often progressive (meaning it worsens over time), which leaves the affected individuals highly debilitated. Currently, in most progressive dementias, including AD, there is no cure or treatment to slow or stop the progression (2). As the aging population grows, dementia poses a rising challenge in our healthcare system. It is projected that the healthcare cost associated with dementia will increase to $16.6 billion by 2031 (3). This crisis calls for a need to expand on research for novel approaches to diagnose and treat dementia.

The Translational Biomarkers in Aging and Dementia (TRIAD) cohort was established in 2017 to conduct leading studies on AD and other types of dementias. The cohort is composed of patients from the MCSA and the general public. Currently, over 1000 people are enrolled in the TRIAD cohort and around 500 of them are participating in a study. The specific study measurements for subjects depend on the project, but the subjects generally undergo baseline and yearly follow-up appointments that include the following

  • Clinical assessments.
  • Biosample collection: Blood, urine and saliva.
  • Cerebrospical fluid (CSF) collection through lumbar puncture (optional).
  • MRI
  • PET scan: amyloid and tau scans + scans specific for the different studies
  • Coginitive and neuropsychological assessments.

Aims

  • To develop novel approaches for accurate and early diagnosis of Alzheimer’s Disease (AD). The neuropathological changes in AD start to accumulate 10-15 years before the onset of the frist clinical symptoms. The ability to diagnose AD during the pre-clinical phase would allow the development of potential drug interventions that may modify the disease progression. Some promising methods of diagnosis that are being investigated in our Centre include PET scans to detect amyloid and tau protein levels and biofluid-based biomarkers of AD.

  • To explore the epigenetic mechanisms underlying AD. Epigenetic dysregulation is increasingly recognized in the pathophysiology of AD. Our Centre studies a family of enzymes that controls gene transcription called histone deacetylases (HDACs) and their relation to amyloid and tau protein levels. Recently, they were shown to play an important role in regulating neuroplasticity and cognitive function. Defining the epigenetic processes associated with AD could lead to developments of new therapies that target the epigenetic molecules in the brain.

  • To track the progression of neuroinflammation and tau aggregates in preclinical AD. As a response to amyloid protein accumulation, immune cells in the brain release pro-inflammatory factors. These factors were shown to increase the pathophysiological progression of AD. However, research on the effects of neuroinflammation on cognitive decline and accumulation of tau protein is limited. The longitudinal observation study conducted within the TRIAD cohort with baseline and 24-month follow-up aims to fill this knowledge gap. This interface between neuroinflammation and tau pathology presents as a novel potential target for therapeutic interventions.

Facilities

McGill University Research Centre for Studies in Aging (MCSA)

The MCSA was established in 1985 as a multi-disciplinary academic unit dedicated to gerontological research and postgraduate teaching on the mechanisms of aging as well as prevention of age-associated disorders. It has achieved international recognition for its integrative work on the neurodegeneration of the aging central nervous system and neurodegenerative diseases. The Centre’s scientists are renowned for their contributions in the fields of Alzheimer’s and Parkinson’s diseases and other cognitive disorders. The MCSA team is composed of neurologists, undergrad and grad students, post-doctoral fellows, administrative staff, research nurses and research assistants.

MCSA Crossroads

Crossroads is a new annex to the MCSA that opened on April of 2018. Clinical aspects of the research projects, including biosample collections, neuropsychological assessments and clinical assessments are conducted at this location. The research assistants at Crossroads assist in participant recruitment and scheduling of appointments for all measures of the study.

Measures

  • Physical and neurological tests: during the baseline visit conducted by a physician

  • Clinical Screening: during the baseline visit conducted by a research nurse
    • Demographics
    • Eligibility criteria
    • Family history
    • List of medication

  • Neuropsychological battery:this battery of tests is made of different memory, attention and fluency exercises, conducted by the neuropsychologist or the psychometrician.
    Tests Questionnaires
    Mini Mental State Examination (MMSE) Clinical Dementia Rating (CDR)
    Montreal Cognitive Assessment (MoCA) NPI questionnaire
    Rey Auditory Verbal Learning Test (RAVLT) Geriatric depression scale (GDS)
    Aggie Figure test Beck Depression Inventory II
    Face-Name association test Geriatric anxiety inventory (GAI)
    Brief Visuospatial Memory Test (BVMT) Apathy inventory
    Logical memory Hachinski ischemic scale
    Emotional Memory Test Subjective questionnaire
    Digit span (WAIS-III; forward and backward) Epworth sleep questionnaire
    Boston naming Sleep duration questionnaire
    Semantic verbal fluency MBI-C
    IQ (WASI-II; matrix reasoning, vocabulary) Functional activity questionnaire
    Digit symbol (WAIS-III) eCOG
    Stroop test (D-KEFS) Exercise questionnaire (GPAQ)
    Trail making Nutrition assessment
    BORB – object decision test Generalized anxiety disorder questionnaire (GAD7)
    BORB – line orientation Social support questionnaire
    Pyramids and Palm trees test
    For English speakers: sentences in English (UCSF), for French speakers: repetition du Montréal-Toulouse
    Dictation task
    Rey Osterrieth Complex Figure test (copy)
    Oral description of the picnic scene picture (Western Aphasia Battery)

  • Biosample collection: Cerebrospinal fluid (CSF), blood, urine and saliva are collected by the research nurse

  • Common Scans to all studies:
    • Magnetic Resonance Imaging (MRI): this scanner will allow us to take 3-dimensional images of the brain, thanks to magnetic fields and radio waves. This scan is necessary for co-registration purposes.
    • Positron emission tomography (PET): this isotopic scan requires the injection of a slightly radioactive product. This tracer will then bind to a specific target, depending on which tracer was chosen. A special scanning machine will then take pictures of the participant’s brain, in order to quantify each target in different regions of the brain.
      • [18F]MK6240: this tracer enables us to observe tau deposition in the brain.
      • [18F]NAV4694 : this tracer will allow us to quantify amyloid deposition in the brain

  • Scans related to specific studies:
    • [18F]PI-2620, [18F]RO-948 or [18F]AV1451: tracers for the tau protein accumulation.
    • [18F]UCB-J: this tracer enables us to observe the synaptic density, targeting a molecule present in the synaptic vesicles, protein SV2a. Neurodegenerative diseases are usually linked to neuronal loss, and so, synapses.
    • [11C]PBR28 and [18F]DPA: Tracers targeting the TSPO molecule. TSPO is a molecular target enabling the quantification of microglial activation; meaning, the amount of inflammation present in the brain. This allows us to know to which degree, as well as which regions are impacted by neuroinflammation.
    • [11C]MRT: This tracer reflects histone deacetylases (HDAC) expression, an enzyme that helps in the regulation of gene transcription. A particular type of these HDACs has been linked to important neurological diseases.

Study Groups

The TRIAD cohort consists of study participants belonging to distinct populations, including cognitively unimpaired, mild cognitive impairment, Alzheimer’s disease, as well as atypical dementia. Each of these populations has a fundamental role in our investigation of biomarkers of aging and dementia in the human brain. Since all of our studies involve positron emission tomography (PET) and magnetic resonance imaging (MRI), we exclude individuals who are unable to undergo these procedures from our cohort. In addition, we are unable to include individuals who have any uncontrolled systemic or neurological diseases and people who are unable to give consent.

Cognitively healthy individuals

The cognitively healthy population consists of participants who do not exhibit any cognitive symptoms. These individuals do not meet the criteria for mild cognitive impairment or any form of dementia, nor any psychiatric disorder. The TRIAD cohort recruits both young (between 20 and 45 years of age) and elderly (between 55 and 85 years of age) subjects into the cognitively healthy group. The aim of this population is (1) to serve as a control group for comparison purposes in our studies of aging and dementia biomarkers and (2) study the pre-symptomatic phase of Alzheimer’s disease.

Mild cognitive impairment (MCI)

The mild cognitive impairment (MCI) population includes participants who exhibit cognitive symptoms, which include memory loss as well as problems with thinking, judgment, and language, but who do not meet the criteria for dementia. Cognitive symptoms in MCI are more significant than normal age-related changes in cognition, but typically are not sufficient to affect daily activities. The cognitive impairment should not be explained by any other disease or condition, nor by the use of certain medications. MCI diagnosis is determined through neuropsychological evaluation, MRI and PET scans and is confirmed during the weekly clinical meeting. Subtypes of MCI exist, including amnesic mild cognitive impairment (aMCI), in which episodic memory in particular is impaired. The aim of this population is to study biomarkers in an intermediate stage of dementia as a diagnosis of MCI is associated with a higher likelihood of progression to dementia.

Alzheimer’s Disease (AD)

The Alzheimer’s disease (AD) population consists of individuals who have been diagnosed with Alzheimer’s disease by a clinician. Alzheimer’s disease patients present with a progressive decline in memory and other cognitive functions which significantly impacts daily activities, which is typically accompanied by behavioral or neuropsychiatric symptoms. AD diagnosis is determined by a clinician and involves neuropsychological testing as well as brain imaging tests. Aside from typical Alzheimer’s disease, the AD population may include individuals who have been diagnosed with variant forms of Alzheimer’s disease, including early onset Alzheimer’s disease (EOAD), posterior cortical atrophy (PCA), and primary progressive aphasia (PPA). The early onset Alzheimer’s disease subgroup includes individuals who develop Alzheimer’s disease symptoms before the age of 65, and is in many cases explained by genetic risk factors (i.e. familial Alzheimer’s disease). Individuals with PCA show marked degeneration of cerebral cortex in the posterior region of the brain, and symptoms particularly affect visual function. Individuals with PPA primarily have a significant impairment in language. This subgroup includes individuals who are diagnosed with the logopenic variant of PPA, which is associated with slower speech and difficulties with word retrieval. The AD population, including its various subgroups, is crucial in investigating how various biomarkers present in different types of AD and dementia, as well as how they interact in different stages of the disease.

Atypical Dementia

The atypical dementia population includes individuals who do not meet the criteria for Alzheimer’s disease and instead present with conditions including frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and vascular dementia (vD). Diagnosis of these disorders is determined by the clinician who refers us the patients. Individuals with FTD, sometimes referred to as Pick’s disease, FTD is associated with deterioration in behavior, personality, and language, as well as disturbances in motor functions in some cases. In particular, the most common form of FTD, behavioral variant of frontotemporal dementia (bvFTD), is characterized by significant alterations in behavioral, judgment, and empathy, as well as by symptoms such as apathy, impulsivity, and lack of restraint based on social norms. PSP, sometimes referred to as Steele–Richardson–Olszewski syndrome, is a condition which primarily affects balance and eye movements, as well as sleep. CBD is characterized by a significant impairment in motor functioning. vD describes individuals whose cognitive symptoms are caused by impaired blood flow to the brain, typically due to a stroke. Patients with vD typically experience cognitive decline in a step-like manner, as opposed to gradually as in typical Alzheimer’s disease. The aim of the atypical dementia population is primarily to examine the differences in the presentation of biomarkers in these various forms of dementia, which helps to improve the differentiation and diagnosis of these disorders.