Abstract 5
Category: Clinical Science
At the end of the session, participants will be able to:
- To demonstrate the involvement of the HLA locus in PSP.
- To demonstrate that certain pathological and clinical phenotypes in PSP are associated with different
COI Disclosure:
None to disclose.
Forrest SL1,2,3, Zaheer SS3,4, Kim A1, Tanaka H1, Chasiotis H1, Li J1, Dasari S1, Kalyaanamoorthy S1, Fox SH3,4,7, Wang J8,9, Rogaeva E1, Fox S3,7, Tartaglia MC1,2,3,7, Lang AE1,3,4,7, Kovacs GG1-7.
1Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada
2Krembil Brain Institute, University Health Network, Toronto, M5T 0S8, Ontario, Canada
3Rossy Centre for PSP, Toronto Western Hospital, Toronto, M5T 2S8, Ontario, Canada
4Edmond J. Safra Program in Parkinson’s Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, M5T 2S8, Toronto, Ontario, Canada
5Laboratory Medicine Program, University Health Network, Toronto, Canada; Department of Chemistry, Faculty of Science, University of Waterloo, ON, Canada.
6Department of Chemistry, Faculty of Science, University of Waterloo, ON, Canada.
7Division of Neurology, University of Toronto, Toronto, M5T 1A8, Ontario, Canada
8Laboratory Medicine Program, University Health Network, Toronto, Canada
9Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
Presenter
I am a Senior Scientific Associate IV at the Tanz Centre for Research in Neurodegenerative Disease (CRND), University of Toronto. I completed my PhD in Neuroscience from The University of Sydney in 2013 and commenced postdoctoral training in the Discipline of Pathology, The University of Sydney. During this time, I acquired a deep knowledge of the cellular abnormalities characteristic of frontotemporal dementia (FTD) and related disorders, ageing and a range of neurodegenerative diseases. I have established national and international collaborations, and have been a member of international consortia that validated a novel age-related tauopathy. I am currently co-lead and coordinator of a large multicentre study, involving >25 research centres and brain banks from 9 countries, to correlate the anatomical distribution and severity of pathology in a recently described glial-predominant tauopathy. In 2020, I was recruited by the Dementia Research Centre as the Neuropathology Group Leader to facilitate the development of a neuropathology program of research combining human neurodegenerative
diseases and transgenic animal models of dementia and movement disorders. In 2022, I was recruited to the Tanz CRND to focus on human neurodegenerative diseases, in particular those with tau proteinopathies.
My research focuses on the neuropathology and disease mechanisms underlying FTD, ageing and a range of neurodegenerative disorders. In particular, my work involves the investigation of protein abnormalities
and cell types affected to determine the selective regional and cellular vulnerability in these disorders, and associated clinicopathological correlations.
Target Audience:
Pathologists, Residents, Medical Students
CanMEDS:
Communicator, Collaborator, Leader, Scholar, Professional
Does the HLA locus has relevance in progressing supranuclear palsy?
Abstract
Objectives: To investigate the role of human leukocyte antigen (HLA) haplotypes in progressive supranuclear palsy (PSP) and evaluate its relation to clinical and pathological diversity.
Relevance: PSP is a neurodegenerative 4-repeat tauopathy characterized by atypical parkinsonism and cognitive-behavioral changes. The HLA locus has not been investigated in PSP, but has been implicated in autoimmune and some neurological diseases.
Methods: First, HLA haplotyping was performed in 44 PSP cases compared to a Canadian deceased donor pool. Binding predictions were used to explore relation of HLA molecules and tau peptides. Second, 32 autopsy-confirmed PSP cases were grouped by HLA haplotypes: and systematic analysis of inflammatory cells (T and B cells, microglia) and phosphorylated-tau was performed. Statistical analysis considering confounding factors and machine learning was used evaluate the effect of HLA haplotypes on pathology variables.
Observations: The DQB106:01 allele showed an odds ratio of 2.94 (95% CI 1.01–8.55, p=0.047), and the narcolepsy-associated haplotype had an odds ratio of 2.59 (95% CI 1.39–4.83, p=0.0025). HLA-Tau peptide binding predictions confirmed strong tau peptide binding to alleles DQA101:02-DQB106:02 and DQA101:03-DQB1*06:01, but not to the PSP-protofilament fold. We observed differences of the constellations of neuropathological variables between HLA haplotype groups. Machine learning identified inflammatory markers and neuropathological ratios as strong predictors of HLA haplotypes (clustering accuracy: 86.96% and 91.30%), with clinical symptom sequences and neuropathological ratios achieving prediction accuracies of 80.00% and 71.43%, respectively.
Conclusions: These findings highlight HLA haplotype-dependent neuroinflammatory and pathological variations in PSP, suggesting potential for patient stratification in immune-modulating therapy trials.