Neurodegenerative disorders
Parsing disease heterogeneity
In neuroimaging research many typically ask the question: how are these brain different from one another. However, given the development and dissemination of large publicly available datasets, we are now able to ask more complex questions about the nature of neuropsychiatric disorders and their neuroanatomical signatures. Most of these disorders are exceptionally heterogeneous in their symptomatology and in their pathological burden.
Our goal is to better understand the relationship between this heterogeneity in order to better elucidate factors that are associated with risk and resilience to neuropsychiatric disorders. Projects under this theme are currently ongoing in the study of Alzheimer’s and Parkinson’s disease.
High-resolution MRI-based biomarkers for identifying risk for Alzheimer's disease
The goal of this study is to establish minimally invasive and automated techniques as alternatives to more invasive and costly Alzheimer’s disease (AD) biomarkers by applying novel MRI-based hippocampal subfield mapping techniques (Pipitone et al., 2014; Winterburn et al., 2013) and microstructural neuroimaging techniques previously developed by our group to study brain regions known to degenerate in AD in 280 seniors who are healthy, have familial history, have MCI, and mild AD. We will use our technology to map, in unprecedented detail, the architecture of memory circuit regions known to be associated with the pathophysiology of AD (the hippocampus and its subfields, the alveus, fimbria, fornix, and the entorhinal, perirhinal, and parahippocampal cortices), as well as use measures of white matter microstructures to measure the prevalence of white matter lesions and integrity of brain myeloarchitectonics. Furthermore, we will explore the relationships between these neuroanatomical measures and well-known genetic risk factors such as the effects of APOE genotype in a subset of healthy controls, MCI and mild AD patients. This project is funded by the Weston Brain Institute to support the development of therapeutics for neurodegenerative diseases.
Deep brain stimulation
For decades, deep brain stimulation, a therapy that involves the surgical implantation of an electrode that provides electrical stimulation to deficient brain circuits has been used in the treatment of Parkinson’s disease. However, prior to the wide-spread usage of this therapy it was heavily experimented in preclinical experiments. Our goal is to better understand the brain plasticity mediated by deep brain stimulation (in clinical and preclinical experiments) that may make it an effective treatment in other neuropsychiatric disorders.
Alzheimer's disease biomarker
The goal of this study is to develop sophisticated biomarkers related to the onset of Alzheimer’s disease (AD) using MRI. Healthy seniors, seniors suffering from MCI, and seniors with a new diagnosis of AD were included in the Alzheimer’s disease biomarker (ADB) dataset. A variety of MRI images were acquired, namely : T1w 1 mm3 (MPRAGE), quantitative T1 1 mm3 (MP2RAGE), T2w 0.64 mm3 (TSE), T2* and susceptibility maps (multi-echo GRE), 3D FLAIR and BOLD sequence. Additionally, substantial demographic questionnaire as well as cognitive and neuropsychological testing were completed, namely : Mini-mental state examination (MMSE), Montreal cognitive assessment (MoCA), clinical dementia rating (CDR) scale, AD8, measure of everyday cognition (Ecog), Boston naming test, repeatable battery for the assessment of neuropsychological status (RBANS) and structured clinical interview for DSM-IV (SCID). Moreover, APOE genotyping was performed for all the individuals.
Machine-learning based prediction of Alzheimer Disease related risk
Lorem ipsum dolor sit amet, consectetur adipiscing elit. Nunc luctus tellus eleifend, gravida ante vitae, condimentum orci. Ut tempor convallis tortor quis imperdiet. Proin eget feugiat orci, ac elementum ante. Mauris vehicula mattis ipsum, vel lobortis urna convallis at. Vivamus placerat lectus vel velit venenatis, eget pulvinar urna auctor. Aenean bibendum elit cursus eros convallis, ut rutrum tellus eleifend. Mauris sit amet erat lobortis diam rutrum pellentesque. Donec ligula tellus, laoreet nec nulla eget, hendrerit tristique massa. Morbi sed nulla augue. Lorem ipsum dolor sit amet, consectetur adipiscing elit. Aenean ac urna eu enim porta volutpat. Etiam tristique non justo quis scelerisque. Donec id massa magna.
Modeling life-style risk factors in Alzheimer Disease
Up to 30% of dementia cases may be attributable to potentially modifiable lifestyle related risk factors. In fact, previous work has also found that high-fat diet (HFD)-induced obesity causes neuroanatomical changes and cognitive impairment in a mouse model of Alzheimer’s disease (AD). This project assesses the potential for rescue of three interventions following exposure to a HFD: return to a low-fat diet, voluntary exercise, or the combination of both. In order to assess the interaction of AD-like pathology with intervention, we use a triple transgenic mouse model of AD (3Tg-AD) and its wild-type counterpart. Neuroanatomical changes were monitored from 2 to 6 months using Magnetic Resonance Imaging. Object recognition and spatial memory were assessed at 6 months. It was found that HFD induced volumetric decline in regions involved in spatial cognition (e.g. the hippocampus and the entorhinal and retrosplenial cortices), but this effect was rescued by exercise. The rescue effect of return to a low-fat diet was more localized. Interestingly, the 3Tg-AD mice were benefitting less from the exercise-based rescues. This was also seen in terms of behaviour, with exercise improving spatial memory performance mostly in the WT. On the other hand, it appeared that object recognition was only improved by return to a low-fat diet, independently of genotype. Currently, we are completing immunofluorescence and stereology analysis to determine respective changes in microglia activation and inflammation.
Modelling the prion-hypothesis of misfolded proteins
Recent evidence suggests that neurodegeneration in diseases such as Alzheimer’s disease and Parkinson’s disease (PD) is mediated by the cell-to-cell spreading of pathogenic proteins; endogenous proteins that adopt a maladaptive conformation which cause them to aggregate and induce further misfolding of native proteins. Using a well-established mouse model of PD, we inject the toxic form of alpha-synuclein, the protein most abundantly found in Lewy bodies, in a known network hub related to PD, the striatum. Thereafter, we map whole brain architecture using longitudinal imaging (structural and functional) as a means of tracking brain architecture changes, and behavioural tests to examine behavioural alterations and PD-like symptom worsening, as a result of the toxic protein spreading. The results from this work may provide a means to predict the course of the complex relationship between pathology and PD-related behaviours, in an effort to better understand the mechanisms of PD, and potentially provide a test-bed for testing novel therapeutics, as well as provide insight on the mechanisms of other diseases where protein propagation is a pathogenic factor (e.g. beta-amyloid in Alzheimer’s disease).
Figure : α-Synuclei preformed fibrils in brain tissue