Research


Alzheimer’s disease (AD) is the most prevalent dementing disorder, affecting 18 million people worldwide. According to the Canadian Institutes of Health Research (CIHR), it is expected that over a million people will be living with AD or related dementias by 2031 in Canada, with a cost of 293 billion dollars from the health care system in 2040.

Our research focuses on quantification of the mechanisms underlying dementia using imaging biomarkers as well as translating these results into clinical applications. In order to accomplish these goals, our experiments involve in vivo, ex vivo as well as in vitro methods.

In vivo quantification of glutamatergic abnormalities in patients with early Alzheimer’s disease (Alzheimer’s Association New Investigator Award / CIHR funded: Serge Gauthier, Pedro Rosa-Neto, Jean-Paul Soucy) 

pic10Glutamate is the major excitatory neurotransmitter of the human brain and has a pivotal role in many vital processes, such as learning and memory. Recent studies have shown that the metabotropic glutamate receptor type five (mGLUR5) is of particular importance for neurodegenerative diseases, since this receptor mediates critical intracellular signaling pathways involved in memory, reward and anxiety. Indeed, some of mGLUR5 are targets of the deleterious effects of Aβ1-42 oligomers. Advances in the field of neuroimaging allow, for the first time, the estimation of mGLUR5 in living humans using Positron Emission Tomography (PET) and [11C]ABP688. The first objective of this study is to compare the binding of [11C]ABP688 using PET in several brain regions of newly diagnosed Alzheimer’s disease (AD) patients and age/gender matched controls. In addition, we will compare the degree of association between [11C]ABP688 binding with brain amyloidosis using [18F]NAV4694 for PET. We believe that the results of this study will contribute to the understanding of the neurobiology of early stages of AD, potentially revealing novel therapeutic targets for AD.

 

In vivo quantification of biomarker progression on the APP-RAT model (Alzheimer’s Association, New Investigator Award, Pedro Rosa-Neto. Sole applicant)

ratThe dynamic biomarker model of Alzheimer’s disease (AD) is primarily based on cross-sectional in vivo observations conducted in elderly normal individuals as well as in mild cognitive impairment (MCI) and AD patients. This model corroborates the amyloid cascade hypothesis, which posits that the accumulation of β –amyloid that acts as an initiating ‘upstream’ event leading to ‘downstream’ events such as neurodegeneration and subsequent cognitive impairment. We aim to determine the dynamic profile of amyloid pathology and neurodegeneration in the McGill-R-Thy1-APP rat model of AD, using imaging biomarkers for longitudinal measures (structural MRI, [11C]PIB and [18F]FDG). We predict that fibrillary amyloid accumulation will precede the functional changes in the brain and that brain atrophy and behavioral declines will be last phenotypes to be expressed in these animals.

 

Diagnostic Biomarkers for pre-dementia Alzheimer Disease (CIHR Team Grant / China-Canada Alzheimer’s Disease and Related Disorders: Serge Gauthier, Jianping Jia, Pedro Rosa-Neto, Liyong Wu, Doris Doudet, Dessa Sadovnick, Mario Masselis Robin Hsiung)

sara2Some individuals get Alzheimer’s disease (AD) at a young age (before the age of 65) due to genes inherited from one of their parents. This is called Early Onset Familial Alzheimer Disease (EOFAD). Some of these autosomal dominant genes have been identified, but in half of the families, they are still unknown. People carrying such genes show changes in their brain chemistry long before they develop symptoms. This study aims at finding as many families as possible in Canada and in China with EOFAD, studying which genes are involved in those families, and studying the brain chemistry using brain scans, spinal fluid examination, and neuropsychological tests over a period of 18 months. This study is important because it will bridge research activities in AD between Canada and China, find missing genes in EOFAD, and establish the sequence of changes in the brain of those who will get AD symptoms within 10 years.

 

Validation du 18F-Fluoroethoxybenzovesamicol (FEOBV) comme biomarque de la maladie d’Alzheimer (FRSQ-Pfizer: Marc-André Bédard, Jean-Paul Soucy, Pedro Rosa-Neto)

FEOBV3Le programme de recherche proposé ici vise à vérifier chez l’humain la sensibilité et la fiabilité avec laquelle le [18F]FEOBV peut quantifier l’intégrité des neurone cholinergiques du cerveau, et ainsi faciliter le diagnostic différentiel de même que la quantification des degrés de sévérité de la MA. En d’autre mots, nous cherchons à vérifier les propriétés du [18F]FEOBV comme biomarqueur de la MA. L’autorisation devra d’abord être obtenue de Santé Canada (SC), pour mener ces études pour la première fois chez l’humain. Il nous faudra donc préalablement étudier l’innocuité du produit non marqué, ou (-)-FEOBV, à différentes doses, chez deux espèces animales distinctes. Ce volet du programme sera mené par un laboratoire indépendant selon les exigences définies par SC (bilan des correspondances écrites en annexe). Il faut noter que cette autorisation à des fins de recherche est moins complexe à obtenir qu’une autorisation d’essai clinique (CTA) pour un produit visant la commercialisation. Une fois l’autorisation de SC obtenue, nous procèderons aux premières études TEP chez l’humain, en comparant le [18F]FEOBV avec le [11C]PiB et le [18F]FDG. Les objectifs de notre programme de recherche sont les suivants : 1. Documenter, selon les standards de SC, la toxicologie du FEOBV non marqué; 2. Obtenir de SC l’autorisation d’utiliser le [18F]FEOBV chez l’humain; 3. Montrer, chez le sujet sain, que la distribution cérébrale du [18F]FEOBV concorde avec la distribution connue des terminaisons cholinergiques; 4. Comparer la sensibilité du [18F]FEOBV à celle du [11C]PiB pour distinguer les sujets présentant un DCL de ceux atteints d’une MA légère à modérée; 5. Vérifier l’existence d’une corrélation entre la sévérité de la MA notée aux échelles cliniques et celles évaluées par chacune des trois mesures TEP ([18F]FEOBV, [11C]PiB, [18F]FDG); 6. Vérifier la sensibilité du [18F]FEOBV par rapport à celle du [18F]FDG pour quantifier l’évolution de la MA sur une durée d’un an.

 

Nouveaux outils non-invasifs pour la détection précoce de la pathologie de la maladie d’Alzheimer (FRSQ-Pfizer: Claudio Cuello, Jasna Kriz, Pedro Rosa-Neto)

pfizerWe aim to investigate potential imaging biomarkers of the early stages of Alzheimer’s disease (AD) pathology using preclinical rat and mouse models of amyloid-like pathology that were recently developed in their labs. The project will focus on monitoring the progression of synaptic neurodegeneration and inflammation (gliosis) in order to correlate neuroinflammation, synaptic degeneration and amyloid load. The project will further allow in-depth investigation of key indicators of synaptic dysfunction and inflammation by using PET procedures in an advanced rat model of AD-like amyloid pathology. This bears a minimal genetic change and thus being the closest rodent model to the human AD pathology. It is expected that by the end of the grant tenure, the investigators will have generated novel bigenic transgenic rat models, which will generate IN VIVO fluorescent signals revealing synaptic alterations and/or the presence of ongoing inflammatory processes.