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 (AD) and vascular dementia (VaD), and the prospect of disease-modifying therapies have intensified efforts to find neuroimaging biomarkers for differential diagnosis, preclinical detection and monitoring 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. AD and CVD, alone or in combination, are etiologically implicated in 80% of all dementias. Mixed AD+CVD in population autopsy series is the most common substrate. Both disorders share vascular risk factors and may benefit from their control. 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 continue to explain the relationships between AD and subcortical CVD to cognition and behaviour, cross-sectionally and over time, using modern quantitative neuroimaging techniques, informed by genetic markers, and whenever possible by autopsy, 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 (FTD), and Lewy body/Parkinson’s dementia, to understand brain-behaviour relations and progression patterns.
Progress
In the last ten years of this research, we have collected a valuable archive from over 900 subjects (100 normal elderly and 800 cognitively impaired), clinically diagnosed as probable or possible AD +/- CVD, probable or possible vascular dementia/cognitive impairment, FTD and LBD+/- AD including standardized cognitive/behavioural evaluations, SPECT and MRI datasets (3DT1 and interleaved PD/ T2-weighted scans). Multimodal longitudinal follow-ups have been collecting sub-samples at one year and two years. Autopsies have been completed on 120. We have devised reliable linear and aerial brain measures and developed in-house imaging analysis techniques for regional perfusion ratios on SPECT and for simultaneous quantification of CVD and regional brain atrophy on MRI including 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. So far, we have generated 81 peer-reviewed papers on this area, with support from the CIHR, Alzheimer Society of Canada, HSFO and NIH, Alzheimer Association US and a generous donation from the LC Campbell Foundation.
Ongoing research
We are this large longitudinal cohort study (following whenever possible to autopsy) and to quantify regional brain changes in AD and CVD, both cross-sectionally and longitudinally in parallel with clinical measures, to understand their interactions and verify which measures best predict and correlate with functional and behavioural decline. More detailed assessment of executive functions has been added to better capture 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 early detection, differential diagnosis and understanding cognitive profiles in the different dementias. Based on progress to date, 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) vs lacunes (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 predictors of decline. In new initiatives using our 3T magnet, we are also adding magnetic resonance spectroscopy and fMRI to probe white matter disease and effects of recent stroke in correlation with clinic and cognitive deficits.
