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Areas of focus

In vivo brain mapping in the dementias: Longitudinal brain-behaviour studies with a focus on cerebrovascular disease

Background

The advent of new symptomatic treatments for Alzheimer’s disease (AD) and vascular dementia and the prospect of disease-modifying therapies have intensified efforts to find neuroimaging biomarkers for differential diagnosis, preclinical detection, and monitoring of disease progression and therapies. In this rapidly moving field, longitudinal brain-behaviour correlation studies are needed to understand disease heterogeneity in clinical presentation and patterns of decline. In vivo brain mapping techniques allow quantification of brain profiles and dynamic changes in brain structure and function over time.

An important emerging concept is that the interplay between AD and cerebrovascular disease (CVD) may contribute to variability of cognitive and functional decline. Alzheimer’s disease and CVD, alone and in combination, are etiologically implicated in 80% of all dementias. Mixed AD and CVD in population autopsy series is the most common substrate. Both disorders share vascular risk factors and may benefit from controlling these factors. Computerized imaging analysis capitalizes on the topographical selectivity of different degenerative processes to quantify in vivo markers of dementia and of the brain at risk.

Goals

A primary goal of this study is to explain the relationships between AD and subcortical CVD and cognition and behaviour, in cross sections and over time. We are using modern quantitative neuroimaging techniques informed by genetic markers and, whenever possible, by autopsy, thereby exploiting access to appropriate subject pools from our large tertiary cognitive neurology and regional stroke prevention clinics.

Another goal is to track the other major neurodegenerative dementias, frontotemporal degeneration and Lewy body/Parkinson’s dementia, to understand brain-behaviour relations and progression patterns.

Progress

For the last 17 years, a cohesive, expert, multidisciplinary team has been conducting the Sunnybrook Dementia Study. They have recruited from our memory clinic a real-world cohort of 970 patients with mild to moderate dementia, 125 patients with mild cognitive impairment and 130 normal controls across the four common dementias. This cohort undergoes standardized quantitative structural magnetic resonance imaging (MRI); single-photon emission computed tomography (SPECT); detailed neuropsychological, behavioural and functional evaluation; and blood sampling for Apolipoprotein E and other genetic characterization. The goal was two-year follow-up, with one-year follow-up achieved in 60%; two-year, in 30%; and greater than three years, in 16%.

Although not specifically funded, autopsies were obtained in 155 subjects, generating new insights into co-pathologies, disease mimicry by different neurodegenerative disorders and genetic causes. In a series of papers, we have developed a reliable, customized, computerized imaging pipeline that captures better this complex reality for each individual in vivo. We have devised reliable linear and serial brain measures and in-house imaging analysis techniques for regional perfusion ratios on SPECT, and for simultaneous quantification of CVD and regional brain atrophy on MRI. These measures include reliable tissue volumetrics, parcellation and quantification of subcortical hyperintensities. Diffusion tensor imaging and single-voxel MR spectroscopy have also been acquired in a subset. We are also applying statistical parametric mapping (SPECT data), voxel-based morphometry and fluid co-registration for serial measures.

The study has resulted in 145 peer-reviewed publications and 20 invited publications to date, many with junior investigators as first author. The study was supported by the Canadian Institutes of Health Research, Alzheimer Society of Canada, Heart and Stroke Foundation, National Institutes of Health, Alzheimer’s Association and by a generous donation from the LC Campbell Foundation.

Ongoing research

We have a large longitudinal cohort study (following whenever possible to autopsy) to quantify regional brain changes in AD and CVD, both as cross-sections and longitudinally. In parallel with clinical measures, we seek to understand the interactions between AD and CVD and verify which measures best predict and correlate with functional and behavioural decline. More detailed assessment of executive functions has been added to capture better frontal-subcortical dysfunction and allow fractionation of frontal functions though specialized analysis. We are also measuring mobility and computerized gait parameters as a new, previously neglected domain of cognitive competency. We are investigating the utility of atrophy patterns for the early detection, differential diagnosis and understanding of cognitive profiles in the different dementias. Based on our progress, we are testing specific hypotheses about correlations of behaviour and cognition with the following:

  • lesion volumes versus localization (e.g., thalamic, cholinergic pathways, association tracts)
  • incidental hyperintensities (venous insufficiency) versus lacunae (arteriolar occlusive disease)
  • carotid artery tortuosity.

Fractional anisotropy and disruptions of association tracts are also being correlated with cognitive patterns and decline. Advanced statistical techniques, such as partial least squares, will help clarify brain-behaviour relationships as well as predictors of decline. In new initiatives using our 3T magnet, we are adding MR spectroscopy and functional MRI to probe white matter disease and effects of recent stroke in correlation with clinical and cognitive deficits.

Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease resulting in paralysis and death. The Sunnybrook ALS clinic is the largest in Canada and one of the largest in the world, with about 250 new patients diagnosed with ALS annually and two to three patient deaths per week. The clinic includes a multidisciplinary team of dedicated health care professionals to help patients and family members throughout the course of this terminal disease.

The Sunnybrook ALS clinic also serves important academic roles at the University of Toronto. The clinic has formed the Canadian ALS Research Network (CALS), a nonprofit alliance of academic ALS clinics dedicated to testing promising therapeutics. Sunnybrook’s ALS clinic has become a Canadian leader in clinical research studies. It has initiated the first Canada-wide, investigator-initiated study testing a promising therapeutic for patients with ALS. A second investigator-initiated study is planned for early 2014 across Canada with Sunnybrook’s ALS clinic once again taking the lead.

The Canadian ALS Research Network has also been successful in promoting and facilitating a number of investigator-initiated epidemiological, quality of life and best practice studies. This includes an ALS Canada-supported initiative to establish a Canadian ALS registry; a study supported by the Public Health Agency of Canada to determine national ALS incidence and prevalence rates; and the development and validation of quality of life measures in ALS. The development of Canadian best practice guidelines for patients with ALS is underway. A Canadian Institutes of Health Research grant was recently obtained for a collaborative imaging study in ALS and will use CALS infrastructure and investigators.

Infrastructure from CALS has also been used to assist in the sharing of blood and tissue samples from patients with ALS to help determine disease pathophysiology and identify novel genes underlying familial forms of ALS. This initiative started at the University of Toronto with a seed grant from the division of neurology and the ALS Society of Canada. In collaboration with Drs. Janice Robertson (molecular biology), Ekaterina Rogaeva (genetics), Gerold Schmitt-Ulms (proteomics) and Juan Bilbao (neuropathology), we have established a collection of blood, cerebrospinal fluid, brain and spinal cord tissue from patients with ALS, combined with comprehensive clinical phenotype data.

This collection has provided an essential resource for numerous projects, including the correlation of clinical and neuropathological features with changes in expression in microRNA and protein for candidate genes, and for searching for unique cerebrospinal fluid biomarkers. Data from more than 1,000 ALS patients have been entered into the database; we now have one of the largest collections of ALS blood, brain and spinal cord samples globally, which we share with Canadian and international collaborators. This collection and collaboration has produced numerous research projects and publications. Most notable are the identification of a novel mutation in a family of patients with ALS and an important contribution to a groundbreaking international effort that found the most common ALS mutation to date. This finding was published in Neuron.

Studies are underway investigating the utility of stem cell transplantation into preclinical models of ALS using novel ultrasound techniques and the potential role of immunization in familial forms of ALS.

The training and mentoring of health care professionals is also a priority of the ALS clinic. Along with medical residents and fellows from numerous training specialties, including neurology, respirology, physiatry, psychiatry, internal medicine, anesthesia and palliative care, students from the faculties of medicine, speech language pathology, nursing and occupational therapy also train at the clinic.