You are here

Read publications written by the Ontario Neurodegenerative Disease Research Initiative (ONDRI) team.

Title: The Ontario Neurodegenerative Disease Research Initiative (ONDRI)

Authors: Sali M. K. Farhan, Robert Bartha, Sandra E. Black, Dale Corbett, Elizabeth Finger, Morris Freedman, Barry Greenberg, David A. Grimes, Robert A. Hegele, Chris Hudson, Peter W. Kleinstiver, Anthony E. Lang, Mario Masellis, William E. McIlroy, Paula M. McLaughlin, Manuel Montero-Odasso, David G. Munoz, Douglas P. Munoz, Stephen Strother, Richard H. Swartz, Sean Symons, Maria Carmela Tartaglia, Lorne Zinman, and Michael J. Strong

Synopsis: Because individuals develop dementia as a manifestation of neurodegenerative or neurovascular disorder, there is a need to develop reliable approaches to their identification. We are undertaking an observational study (Ontario Neurodegenerative Disease Research Initiative [ONDRI]) that includes genomics, neuroimaging, and assessments of cognition as well as language, speech, gait, retinal imaging, and eye tracking. Disorders studied include Alzheimer’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson’s disease, and vascular cognitive impairment. Data from ONDRI will be collected into the Brain-CODE database to facilitate correlative analysis. ONDRI will provide a repertoire of endophenotyped individuals that will be a unique, publicly available resource.

Title: The ONDRISeq panel: custom-designed next-generation sequencing of genes related to neurodegeneration

Authors: Sali MK Farhan, Allison A Dilliott, Mahdi Ghani, Christine Sato, Eric Liang, Ming Zhang, Adam D McIntyre, Henian Cao, Lemuel Racacho, John F Robinson, ONDRI Investigators, Michael J Strong, Mario Masellis, Peter St George-Hyslop, Dennis E Bulman, Ekaterina Rogaeva, and Robert A Hegele

Synopsis: The ONDRI Genomics subgroup is investigating the genetic basis of neurodegeneration. We have developed a custom next-generation-sequencing-based panel, ONDRISeq that targets 80 genes known to be associated with neurodegeneration. We processed DNA collected from 216 individuals diagnosed with one of the five diseases, on ONDRISeq. All runs were executed on a MiSeq instrument and subjected to rigorous quality control assessments. We also independently validateda subset of the variant calls using NeuroX (a genome-wide array for neurodegenerative disorders), TaqMan allelic discrimination assay, or Sanger sequencing. ONDRISeq consistently generated high-quality genotyping calls and on average, 92% of targeted bases are covered by at least 30 reads. We also observed 100% concordance for the variants identified via ONDRISeq and validated by other genomic technologies. We were successful in detecting known as well as novel rare variants in 72.2% of cases although not all variants are disease-causing. Using ONDRISeq, we also found that the APOE E4 allele had a frequency of 0.167 in these samples. Our optimised workflow highlights next-generation sequencing as a robust tool in elucidating the genetic basis of neurodegenerative diseases by screening multiple candidate genes simultaneously.

Title: Thr175-phosphorylated tau induces pathologic fibril formation via GSK3b-mediated phosphorylation of Thr231 in vitro

Authors: Alexander J. Moszczynski, May Gohar, Kathryn Volkening, Cheryl Leystra-Lantz, Wendy Strong, Michael J. Strong

Abstract: We have previously shown that amyotrophic lateral sclerosis with cognitive impairment can be characterized by pathologic inclusions of microtubule-associated protein tau (tau) phosphorylated at Thr175 (pThr175) in association with GSK3b activation. We have now examined whether pThr175 induces GSK3b activation and whether this leads to pathologic fibril formation through Thr231 phosphorylation. Seventy-two hours after transfection of Neuro2A cells with pseudophosphorylated green fluorescent protein-tagged 2N4R tau (Thr175Asp), phosphorylated kinase glycogen synthase kinase 3 beta (active GSK3b) levels were significantly increased as was pathologic fibril formation and cell death. Treatment with each of 4 GSK3b inhibitors or small hairpin RNA knockdown of GSK3b abolished fibril formation and prevented cell death. Inhibition of Thr231 phosphorylation (Thr231Ala) prevented pathologic tau fibril formation, regardless of Thr175 state, whereas Thr231Asp (pseudophosphorylated at Thr231) developed pathologic tau fibrils. Ser235 mutations did not affect fibril formation, indicating an unprimed mechanism of Thr231 phosphorylation. These findings suggest a mechanism of tau pathology by which pThr175 induces GSK3b phosphorylation of Thr231 leading to fibril formation, indicating a potential therapeutic avenue for amyotrophic lateral sclerosis with cognitive impairment.

Title: Motor Phenotype in Neurodegenerative Disorders: Gait and Balance Platform Study Design Protocol for the Ontario Neurodegenerative Research Initiative (ONDRI)

Authors: Montero-Odasso M, Pieruccini-Faria F, Bartha R, Black SE, Finger E, Freedman M, Greenberg B, Grimes DA, Hegele R, Hudson C, Kleinstiver PW, Lang AE, Masellis M, McLaughlin PM,Munoz DP, Strother S, Swartz RH, Symons S, Tartaglia MC, Zinman L, Strong MJ, ONDRI Investigators, McIlroy W

Background: The association of cognitive and motor impairments in Alzheimer's disease and other neurodegenerative diseases is thought to be related to damage in the common brain networks shared by cognitive and cortical motor control processes. These common brain networks play a pivotal role in selecting movements and postural synergies that meet an individual's needs. Pathology in this "highest level" of motor control produces abnormalities of gait and posture referred to as highest-level gait disorders. Impairments in cognition and mobility, including falls, are present in almost all neurodegenerative diseases, suggesting common mechanisms that still need to be unraveled.

Objective: To identify motor-cognitive profiles across neurodegenerative diseases in a large cohort of patients.

Methods: Cohort study that includes up to 500 participants, followed every year for three years, across five neurodegenerative disease groups: Alzheimer's disease/mild cognitive impairment, frontotemporal degeneration, vascular cognitive impairment, amyotrophic lateral sclerosis, and Parkinson's disease. Gait and balance will be assessed using accelerometers and electronic walkways, evaluated at different levels of cognitive and sensory complexity, using the dual-task paradigm.

Results: Comparison of cognitive and motor performances across neurodegenerative groups will allow the identification of motor-cognitive phenotypes through the standardized evaluation of gait and balance characteristics.

Conclusions: As part of the Ontario Neurodegenerative Research Initiative (ONDRI), the gait and balance platform aims to identify motor-cognitive profiles across neurodegenerative diseases. Gait assessment, particularly while dual-tasking, will help dissect the cognitive and motor contribution in mobility and cognitive decline, progression to dementia syndromes, and future adverse outcomes including falls and mortality.