Characteristics of the Ontario Neurodegenerative Disease Research Initiative cohort

Sunderland, Kelly M; Beaton, Derek; Arnott, Stephen R.; Kleinstiver, Peter; Kwan, Donna; Lawrence‐Dewar, Jane M.; Ramirez, Joel; Tan, Brian; Bartha, Robert; Black, Sandra E.; Borrie, Michael; Brien, Donald C.; Casaubon, Leanne K.; Coe, Brian C.; Cornish, Benjamin; Dilliott, Allison A.; Dowlatshahi, Dar; Finger, Elizabeth; Fischer, Corinne E.; Frank, Andrew; Fraser, Julia; Freedman, Morris; Greenberg, Barry D.; Grimes, David A.; Hassan, Ayman; Hatch, Wendy; Hegele, Robert A.; Hudson, Christopher; Jog, Mandar; Kumar, Sanjeev; Lang, Anthony E.; Levine, Brian; Lou, Wendy; Mandzia, Jennifer; Marras, Connie; McIlroy, William E.; Montero‐Odasso, Manuel; Muñoz, David G.; Munoz, Douglas P.; Orange, J. B.; Park, David; Pasternak, Stephen; Pieruccini‐Faria, Frederico; Rajji, Tarek K.; Roberts, Angela; Robinson, John F.; Rogaeva, Ekaterina; Sahlas, Demetrios J.; Saposnik, Gustavo; Scott, Christopher J.; Seitz, Dallas; Shoesmith, Christen; Steeves, Thomas; Strong, Michael J.; Strother, Stephen C.; Swartz, Richard H.; Symons, Sean; Tang‐Wai, David F.; Tartaglia, Maria Carmela; Troyer, Angela K.; Turnbull, John; Zinman, Lorne; McLaughlin, Paula; Masellis, Mario; Binns, Malcolm A.; Abrahão, Agessandro; Adamo, Sabrina; Berezuk, Courtney; Black, Alanna; Breen, David P.; Bulman, Dennis E.; Chen, Ying; El‐Defrawy, Sherif; Farhan, Sali M.K.; Ghani, Mahdi; Gonder, John R.; Haddad, Seyyed Mohammad Hassan; Holmes, Melissa F.; Huang, Jeff; Leontieva, Elena; Mandelcorn, Efrem D.; Margolin, Edward; Nanayakkara, Nuwan D.; Ozzoude, Miracle; Peltsch, Alicia; Pollock, Bruce G.; Raamana, Pradeep Reddy; Rashkovan, Natalie; Yanina,; Southwell, Alisia; Sujanthan, Sujeevini; Tayyari, Faryan; Ooteghem, Karen Van; Woulfe, John; Zamyadi, Mojdeh; Zou, Guangyong

doi:10.1002/alz.12632

Cited by 18 publications

(24 citation statements)

References 51 publications

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“…Participants were excluded if they had severe cognitive impairment, aphasia, evidence of a nonvascular cause of symptoms, inability to write or severe functional disability, severe claustrophobia, or other contraindications to MRI scanning procedures or other assessments. 7 Participants with large cortical strokes (>1/3 middle cerebral artery) were excluded. 7 Ethics approval was obtained from all participating institutions and performed in accordance with the Declaration of Helsinki.…”

Section: Methodsmentioning

confidence: 99%

“… 7 Participants with large cortical strokes (>1/3 middle cerebral artery) were excluded. 7 Ethics approval was obtained from all participating institutions and performed in accordance with the Declaration of Helsinki. All participants provided informed consent, and subsequently underwent clinical evaluation, MRI, and other assessments as part of the full ONDRI protocol.…”

Section: Methodsmentioning

confidence: 99%

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Soluble Epoxide Hydrolase Derived Linoleic Acid Oxylipins, Small Vessel Disease Markers, and Neurodegeneration in Stroke

Liang

Zebarth

et al. 2023

JAHA

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Background Cerebral small vessel disease is associated with higher ratios of soluble‐epoxide hydrolase derived linoleic acid diols (12,13‐dihydroxyoctadecenoic acid [DiHOME] and 9,10‐DiHOME) to their parent epoxides (12(13)‐epoxyoctadecenoic acid [EpOME] and 9(10)‐EpOME); however, the relationship has not yet been examined in stroke. Methods and Results Participants with mild to moderate small vessel stroke or large vessel stroke were selected based on clinical and imaging criteria. Metabolites were quantified by ultra‐high‐performance liquid chromatography–mass spectrometry. Volumes of stroke, lacunes, white matter hyperintensities, magnetic resonance imaging visible perivascular spaces, and free water diffusion were quantified from structural and diffusion magnetic resonance imaging (3 Tesla). Adjusted linear regression models were used for analysis. Compared with participants with large vessel stroke (n=30), participants with small vessel stroke (n=50) had a higher 12,13‐DiHOME/12(13)‐EpOME ratio (β=0.251, P =0.023). The 12,13‐DiHOME/12(13)‐EpOME ratio was associated with more lacunes (β=0.266, P =0.028) but not with large vessel stroke volumes. Ratios of 12,13‐DiHOME/12(13)‐EpOME and 9,10‐DiHOME/9(10)‐EpOME were associated with greater volumes of white matter hyperintensities (β=0.364, P <0.001; β=0.362, P <0.001) and white matter MRI‐visible perivascular spaces (β=0.302, P =0.011; β=0.314, P =0.006). In small vessel stroke, the 12,13‐DiHOME/12(13)‐EpOME ratio was associated with higher white matter free water diffusion (β=0.439, P =0.016), which was specific to the temporal lobe in exploratory regional analyses. The 9,10‐DiHOME/9(10)‐EpOME ratio was associated with temporal lobe atrophy (β=−0.277, P =0.031). Conclusions Linoleic acid markers of cytochrome P450/soluble‐epoxide hydrolase activity were associated with small versus large vessel stroke, with small vessel disease markers consistent with blood brain barrier and neurovascular‐glial disruption, and temporal lobe atrophy. The findings may indicate a novel modifiable risk factor for small vessel disease and related neurodegeneration.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Soluble Epoxide Hydrolase Derived Linoleic Acid Oxylipins, Small Vessel Disease Markers, and Neurodegeneration in Stroke

Liang

Zebarth

et al. 2023

JAHA

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“…Research ethics board approval was obtained from each of the 11 participating sites. Descriptions of the inclusion/exclusion criteria of ONDRI participants were previously reported (Farhan et al, 2017 ; Sunderland et al, 2022 ). All participants provided informed written consent.…”

Section: Methodsmentioning

confidence: 99%

“…Clinical diagnoses and demographic data were obtained during participant screening and baseline assessment. When possible, participants provided clinical longitudinal follow‐up assessment yearly, for up to 3 years (Farhan et al, 2017 ; Sunderland et al, 2022 ).…”

Section: Methodsmentioning

confidence: 99%

Targeted copy number variant identification across the neurodegenerative disease spectrum

Dilliott

Zhang

Wang

et al. 2022

Molec Gen & Gen Med

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Background Although genetic factors are known to contribute to neurodegenerative disease susceptibility, there remains a large amount of heritability unaccounted for across the diagnoses. Copy number variants (CNVs) contribute to these phenotypes, but their presence and influence on disease state remains relatively understudied. Methods Here, we applied a depth of coverage approach to detect CNVs in 80 genes previously associated with neurodegenerative disease within participants of the Ontario Neurodegenerative Disease Research Initiative ( n = 519). Results In total, we identified and validated four CNVs in the cohort, including: (1) a heterozygous deletion of exon 5 in OPTN in an Alzheimer's disease participant; (2) a duplication of exons 1–5 in PARK7 in an amyotrophic lateral sclerosis participant; (3) a duplication of >3 Mb, which encompassed ABCC6 , in a cerebrovascular disease (CVD) participant; and (4) a duplication of exons 7–11 in SAMHD1 in a mild cognitive impairment participant. We also identified 43 additional CNVs that may be candidates for future replication studies. Conclusion The identification of the CNVs suggests a portion of the apparent missing heritability of the phenotypes may be due to these structural variants, and their assessment is imperative for a thorough understanding of the genetic spectrum of neurodegeneration.

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“…This was an analysis of a prospective, multi-center, observational study known as the Ontario Neurodegenerative Disease Research Initiative (ONDRI; Farhan et al, 2017 ). Baseline characteristics of the full ONDRI cohort are summarized in a study by Sunderland and colleagues ( Sunderland et al, 2022 ). Participants diagnosed with FTLD-related syndromes or ALS were recruited from the Toronto Western Hospital (Toronto, Canada), Sunnybrook Hospital (Toronto, Canada), Baycrest Hospital (Toronto, Canada), Parkwood Institute (London, Canada), and Élisabeth Bruyère Continuing Care (Ottawa, Canada), between 2014 and 2018.…”

Section: Methodsmentioning

confidence: 99%

Retinal nerve fiber layer in frontotemporal lobar degeneration and amyotrophic lateral sclerosis

Wong

Hudson²,

Snook³

et al. 2022

Front. Neurosci.

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PurposeTauopathy and transactive response DNA binding protein 43 (TDP-43) proteinopathy are associated with neurodegenerative diseases. These proteinopathies are difficult to detect in vivo. This study examined if spectral-domain optical coherence tomography (SD-OCT) can differentiate in vivo the difference in peripapillary retinal nerve fibre layer (pRNFL) thickness and macular retinal thickness between participants with presumed tauopathy (progressive supranuclear palsy) and those with presumed TDP-43 proteinopathy (amyotrophic lateral sclerosis and semantic variant primary progressive aphasia).Study designProspective, multi-centre, observational study.Materials and methodspRNFL and macular SD-OCT images were acquired in both eyes of each participant using Heidelberg Spectralis SD-OCT. Global and pRNFL thickness in 6 sectors were analyzed, as well as macular thickness in a central 1 mm diameter zone and 4 surrounding sectors. Linear mixed model methods adjusting for baseline differences between groups were used to compare the two groups with respect to pRNFL and macular thickness.ResultsA significant difference was found in mean pRNFL thickness between groups, with the TDP-43 group (n = 28 eyes) having a significantly thinner pRNFL in the temporal sector than the tauopathy group (n = 9 eyes; mean difference = 15.46 μm, SE = 6.98, p = 0.046), which was not significant after adjusting for multiple comparisons. No other significant differences were found between groups for pRNFL or macular thickness.ConclusionThe finding that the temporal pRNFL in the TDP-43 group was on average 15.46 μm thinner could potentially have clinical significance. Future work with larger sample sizes, longitudinal studies, and at the level of retinal sublayers will help to determine the utility of SD-OCT to differentiate between these two proteinopathies.

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Characteristics of the Ontario Neurodegenerative Disease Research Initiative cohort

Cited by 18 publications

References 51 publications

Soluble Epoxide Hydrolase Derived Linoleic Acid Oxylipins, Small Vessel Disease Markers, and Neurodegeneration in Stroke

Soluble Epoxide Hydrolase Derived Linoleic Acid Oxylipins, Small Vessel Disease Markers, and Neurodegeneration in Stroke

Targeted copy number variant identification across the neurodegenerative disease spectrum

Retinal nerve fiber layer in frontotemporal lobar degeneration and amyotrophic lateral sclerosis

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