Publications by authors named "Ekaterina Rogaeva"

202 Publications

Targeted copy number variant identification across the neurodegenerative disease spectrum.

Mol Genet Genomic Med 2022 Jun 3:e1986. Epub 2022 Jun 3.

Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mgg3.1986DOI Listing
June 2022

Genome-wide Association and Meta-analysis of Age-at-Onset in Parkinson Disease: Evidence From COURAGE-PD Consortium.

Neurology 2022 May 26. Epub 2022 May 26.

Sorbonne Université (SU) Unité Mixte de Recherche (UMR) 1127, INSERM U1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.

Background And Objectives: Considerable heterogeneity exists in the literature concerning genetic determinants of the age of onset (AAO) of Parkinson's disease (PD), which could be attributed to lack of well-powered replication cohorts. The previous largest GWAS identified nd loci on chromosome (Chr) 4 with a significant influence on AAO of PD, these have not been independently replicated. The present study aims to conduct a meta-analysis of GWAS of PD AAO and validate previously observed findings in worldwide populations.

Methods: A meta-analysis was performed on PD AAO GWAS of 30 populations of predominantly European ancestry from the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (COURAGE-PD) consortium. This was followed up by combining our study with the largest publicly available European ancestry dataset compiled by the International Parkinson disease Genomics Consortium (IPDGC).

Results: The COURAGE-PD included a cohort of 8,535 patients with PD (91.9%: Europeans, 9.1%: East-Asians). The average AAO in the COURAGE-PD dataset was 58.9 years (SD=11.6), with an under-representation of females (40.2%). The heritability estimate for AAO in COURAGE-PD was 0.083 (SE=0.057). None of the loci reached genome-wide significance (P<5x10). Nevertheless, the COURAGE-PD dataset confirmed the role of the previously published variant as genetic determinant of AAO of PD with Bonferroni-corrected nominal levels of significance (P<0.025): (rs34311866:β(SE)=0.477(0.203), P=0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (N=25,950) led to the identification of two genome-wide significant association signals on Chr 4, including the previously reported locus (rs983361:β(SE)=0.720(0.122), P=3.13x10) and a novel locus (rs4698412:β(SE)=-0.526(0.096), P=4.41x10).

Discussion: Our study further refines the genetic architecture of Chr 4 underlying the AAO of the PD phenotype through the identification of as a novel AAO PD locus. These findings open a new direction for the development of treatments to delay the onset of PD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000200699DOI Listing
May 2022

Case of a Man with Hemichorea and Behavioral Changes: "A Red Herring".

Mov Disord Clin Pract 2022 May 30;9(4):501-507. Epub 2022 Mar 30.

Division of Neurology, Department of Medicine University of Toronto Toronto Ontario Canada.

Background: Progressive supranuclear palsy (PSP)-pallido-nigro-luysian atrophy (PNLA) is a neuropathological entity thought to be a variant of classic PSP. Clinical features and pathologic hallmarks are the same in both conditions; however, age and order of symptom onset, disease duration and prognosis, and distribution and density of pathology differentiate the 2 entities.

Objectives: This study presents a PSP-PNLA case confirmed pathologically with a clinical presentation of hemichorea/ballism, spasticity, progressive hemiparesis, and a frontal behavioral syndrome with relative cognitive sparing early in the disease course.

Methods: We describe the clinical progression in this unique case supplemented with video and imaging findings in the form of magnetic resonance imaging and brain single photon emission computed tomography. Final diagnosis is via pathological analysis at autopsy.

Results: We present an elderly gentleman who manifested a clinical syndrome consisting of subacute onset of chorea that at presentation was distinctly unilateral and a frontal behavioral syndrome in the setting of mild thrombocytopenia and elevated anticardiolipin antibodies. Positive antiphospholipid antibodies resulted in an initial antemortem diagnosis of primary antiphospholipid syndrome as a cause of his chorea. Longitudinal follow-up over 5 years demonstrated a progression of clinical features with hemi-motor impersistence/chorea, disinhibition and impulsivity, and eventually corticospinal distribution weakness on the initially affected side. He required nursing home care and falls necessitated wheelchair use. Postmortem neuropathological study revealed a diagnosis of frontotemporal lobar degeneration-tau, PSP-PNLA.

Conclusions: This case broadens the phenotype of PSP-PNLA and to our knowledge is the only case presenting with unilateral chorea.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mdc3.13433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9092749PMC
May 2022

Protracted course progressive supranuclear palsy.

Eur J Neurol 2022 Apr 6. Epub 2022 Apr 6.

Edmond J. Safra Program in Parkinson's Disease, Rossy Program for PSP Research and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, Ontario, Canada.

Background And Purpose: Progressive supranuclear palsy (PSP) encompasses a broader range of disease courses than previously appreciated. The most frequent clinical presentations of PSP are Richardson syndrome (RS) and PSP with a predominant Parkinsonism phenotype (PSP-P). Time to reach gait dependence and cognitive impairment have been proposed as prognostic disease milestones. Genetic polymorphisms in TRIM11 and SLC2A13 genes have been associated with longer disease duration (DD).

Methods: Methods used include retrospective chart review, genetic single nucleotide polymorphism analyses (in three cases), and neuropathology.

Results: We identified four cases with long (>10-15 years) or very long (>15 years) DD. Stage 1 PSP tau pathology was present in two cases (one PSP-P and one undifferentiated phenotype), whereas pallidonigroluysian atrophy (PSP-RS) and Stage 4/6 (PSP-P) PSP pathology were found in the other two cases. Three cases were homozygous for the rs564309-C allele of the TRIM11 gene and the H1 MAPT haplotype. Two were heterozygous for rs2242367 (G/A) in SLC2A13, whereas the third was homozygous for the G-allele.

Conclusions: We propose a protracted course subtype of PSP (PC-PSP) based on clinical or neuropathological criteria in two cases with anatomically restricted PSP pathology, and very long DD and slower clinical progression in the other two cases. The presence of the rs564309-C allele may influence the protracted disease course. Crystallizing the concept of PC-PSP is important to further understand the pathobiology of tauopathies in line with current hypotheses of protein misfolding, seeding activity, and propagation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ene.15346DOI Listing
April 2022

CAPTURE ALS: the comprehensive analysis platform to understand, remedy and eliminate ALS.

Amyotroph Lateral Scler Frontotemporal Degener 2022 Feb 23:1-7. Epub 2022 Feb 23.

Neuroscience Axis, CHU de Québec - Université Laval, Quebec, QC, Canada.

The absence of disease modifying treatments for amyotrophic lateral sclerosis (ALS) is in large part a consequence of its complexity and heterogeneity. Deep clinical and biological phenotyping of people living with ALS would assist in the development of effective treatments and target specific biomarkers to monitor disease progression and inform on treatment efficacy. The objective of this paper is to present the Comprehensive Analysis Platform To Understand Remedy and Eliminate ALS (CAPTURE ALS), an open and translational platform for the scientific community currently in development. CAPTURE ALS is a Canadian-based platform designed to include participants' voices in its development and through execution. Standardized methods will be used to longitudinally characterize ALS patients and healthy controls through deep clinical phenotyping, neuroimaging, neurocognitive and speech assessments, genotyping and multisource biospecimen collection. This effort plugs into complementary Canadian and international initiatives to share common resources. Here, we describe in detail the infrastructure, operating procedures, and long-term vision of CAPTURE ALS to facilitate and accelerate translational ALS research in Canada and beyond.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/21678421.2022.2041668DOI Listing
February 2022

Genomic study of a large family with complex neurological phenotype including hearing loss, imbalance and action tremor.

Neurobiol Aging 2022 05 25;113:137-142. Epub 2021 Dec 25.

Tanz Center for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada; Division of Neurology, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Neurological disorders are often associated with a variety of symptoms, which can result from the combined action of genetic variants. We conducted a whole-genome analysis of a previously unreported unique multigenerational Dutch-Canadian family with a complex phenotype presenting with a combination of hearing loss, balance issues or action tremor. Ten family members were available for genetic study. The hearing loss and balance problems are explained by a pathogenic p.P51S substitution in COCH, which is a known founder mutation in Dutch and Belgium families affected by non-syndromic progressive sensorineural hearing loss often accompanied by vestibular dysfunction. Notably, p.P51S did not co-segregate with action tremor in our and reported kindreds. In our family, all 5 patients with tremor were carriers of the extremely rare p.R247W substitution in MCM9 (minor allele frequency in European population is 0.00003), which belongs to the top 0.1% of deleterious variants in the human genome. The MCM9 locus has not been previously associated with action tremor and deserves further investigation in future functional and genetic studies of action tremor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neurobiolaging.2021.12.004DOI Listing
May 2022

Dairy Intake and Parkinson's Disease: A Mendelian Randomization Study.

Mov Disord 2022 04 8;37(4):857-864. Epub 2022 Jan 8.

Department of Neurology, Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, Larissa, Greece.

Background: Previous prospective studies highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men. It is unclear whether this association is causal or explained by reverse causation or confounding.

Objective: The aim is to examine the association between genetically predicted dairy intake and PD using two-sample Mendelian randomization (MR).

Methods: We genotyped a well-established instrumental variable for dairy intake located in the lactase gene (rs4988235) within the Courage-PD consortium (23 studies; 9823 patients and 8376 controls of European ancestry).

Results: Based on a dominant model, there was an association between genetic predisposition toward higher dairy intake and PD (odds ratio [OR] per one serving per day = 1.70, 95% confidence interval = 1.12-2.60, P = 0.013) that was restricted to men (OR = 2.50 [1.37-4.56], P = 0.003; P-difference with women = 0.029).

Conclusions: Using MR, our findings provide further support for a causal relationship between dairy intake and higher PD risk, not biased by confounding or reverse causation. Further studies are needed to elucidate the underlying mechanisms. © 2022 International Parkinson and Movement Disorder Society.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mds.28902DOI Listing
April 2022

Mendelian Randomisation Study of Smoking, Alcohol, and Coffee Drinking in Relation to Parkinson's Disease.

J Parkinsons Dis 2022 ;12(1):267-282

Department of Neurology, Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, Larissa, Greece.

Background: Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson's disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation.

Objective: To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases.

Methods: We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017).

Results: We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60-0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking.

Conclusion: Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JPD-212851DOI Listing
April 2022

Axial Impairment Following Deep Brain Stimulation in Parkinson's Disease: A Surgicogenomic Approach.

J Parkinsons Dis 2022 ;12(1):117-128

Edmond J. Safra Program in Parkinson's Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, UHN, Toronto, Ontario, Canada.

Background: Postoperative outcome following deep brain stimulation (DBS) of the subthalamic nucleus is variable, particularly with respect to axial motor improvement. We hypothesized a genetic underpinning to the response to surgical intervention, termed "surgicogenomics".

Objective: We aimed to identify genetic variants associated with clinical heterogeneity in DBS outcome of Parkinson's disease (PD) patients that could then be applied clinically to target selection leading to improved surgical outcome.

Methods: Retrospective clinical data was extracted from 150 patient's charts. Each individual was genotyped using the genome-wide NeuroX array tailored to study neurologic diseases. Genetic data were clustered based on surgical outcome assessed by comparing pre- and post-operative scores of levodopa equivalent daily dose and axial impairment at one and five years post-surgery. Allele frequencies were compared between patients with excellent vs. moderate/poor outcomes grouped using a priori defined cut-offs. We analyzed common variants, burden of rare coding variants, and PD polygenic risk score.

Results: NeuroX identified 2,917 polymorphic markers at 113 genes mapped to known PD loci. The gene-burden analyses of 202 rare nonsynonymous variants suggested a nominal association of axial impairment with 14 genes (most consistent with CRHR1, IP6K2, and PRSS3). The strongest association with surgical outcome was detected between a reduction in levodopa equivalent daily dose and common variations tagging two linkage disequilibrium blocks with SH3GL2.

Conclusion: Once validated in independent populations, our findings may be implemented to improve patient selection for DBS in PD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JPD-212730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8842751PMC
April 2022

Contribution of rare variant associations to neurodegenerative disease presentation.

NPJ Genom Med 2021 Sep 28;6(1):80. Epub 2021 Sep 28.

Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada.

Genetic factors contribute to neurodegenerative diseases, with high heritability estimates across diagnoses; however, a large portion of the genetic influence remains poorly understood. Many previous studies have attempted to fill the gaps by performing linkage analyses and association studies in individual disease cohorts, but have failed to consider the clinical and pathological overlap observed across neurodegenerative diseases and the potential for genetic overlap between the phenotypes. Here, we leveraged rare variant association analyses (RVAAs) to elucidate the genetic overlap among multiple neurodegenerative diagnoses, including Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), mild cognitive impairment, and Parkinson's disease (PD), as well as cerebrovascular disease, using the data generated with a custom-designed neurodegenerative disease gene panel in the Ontario Neurodegenerative Disease Research Initiative (ONDRI). As expected, only ~3% of ONDRI participants harboured a monogenic variant likely driving their disease presentation. Yet, when genes were binned based on previous disease associations, we observed an enrichment of putative loss of function variants in PD genes across all ONDRI cohorts. Further, individual gene-based RVAA identified significant enrichment of rare, nonsynonymous variants in PARK2 in the FTD cohort, and in NOTCH3 in the PD cohort. The results indicate that there may be greater heterogeneity in the genetic factors contributing to neurodegeneration than previously appreciated. Although the mechanisms by which these genes contribute to disease presentation must be further explored, we hypothesize they may be a result of rare variants of moderate phenotypic effect contributing to overlapping pathology and clinical features observed across neurodegenerative diagnoses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41525-021-00243-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478934PMC
September 2021

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis.

JAMA Neurol 2021 10;78(10):1236-1248

Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.

Objective: To identify the genetic variants associated with juvenile ALS.

Design, Setting, And Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.

Main Outcomes And Measures: De novo variants present only in the index case and not in unaffected family members.

Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.

Conclusions And Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaneurol.2021.2598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406220PMC
October 2021

Amyloid-β toxicity modulates tau phosphorylation through the PAX6 signalling pathway.

Brain 2021 10;144(9):2759-2770

School of Biomedical Sciences, University of Hong Kong, Hong Kong, China.

The molecular link between amyloid-β plaques and neurofibrillary tangles, the two pathological hallmarks of Alzheimer's disease, is still unclear. Increasing evidence suggests that amyloid-β peptide activates multiple regulators of cell cycle pathways, including transcription factors CDKs and E2F1, leading to hyperphosphorylation of tau protein. However, the exact pathways downstream of amyloid-β-induced cell cycle imbalance are unknown. Here, we show that PAX6, a transcription factor essential for eye and brain development which is quiescent in adults, is increased in the brains of patients with Alzheimer's disease and in APP transgenic mice, and plays a key role between amyloid-β and tau hyperphosphorylation. Downregulation of PAX6 protects against amyloid-β peptide-induced neuronal death, suggesting that PAX6 is a key executor of the amyloid-β toxicity pathway. Mechanistically, amyloid-β upregulates E2F1, followed by the induction of PAX6 and c-Myb, while Pax6 is a direct target for both E2F1 and its downstream target c-Myb. Furthermore, PAX6 directly regulates transcription of GSK-3β, a kinase involved in tau hyperphosphorylation and neurofibrillary tangles formation, and its phosphorylation of tau at Ser356, Ser396 and Ser404. In conclusion, we show that signalling pathways that include CDK/pRB/E2F1 modulate neuronal death signals by activating downstream transcription factors c-Myb and PAX6, leading to GSK-3β activation and tau pathology, providing novel potential targets for pharmaceutical intervention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awab134DOI Listing
October 2021

White matter hyperintensities in autopsy-confirmed frontotemporal lobar degeneration and Alzheimer's disease.

Alzheimers Res Ther 2021 07 13;13(1):129. Epub 2021 Jul 13.

Cognitive & Movement Disorders Clinic, Sunnybrook Health Sciences Centre, 2075 Bayview Ave., Room A4 42, Toronto, ON, M4N 3M5, Canada.

Background: We aimed to systematically describe the burden and distribution of white matter hyperintensities (WMH) and investigate correlations with neuropsychiatric symptoms in pathologically proven Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD).

Methods: Autopsy-confirmed cases were identified from the Sunnybrook Dementia Study, including 15 cases of AD and 58 cases of FTLD (22 FTLD-TDP cases; 10 FTLD-Tau [Pick's] cases; 11 FTLD-Tau Corticobasal Degeneration cases; and 15 FTLD-Tau Progressive Supranuclear Palsy cases). Healthy matched controls (n = 35) were included for comparison purposes. Data analyses included ANCOVA to compare the burden of WMH on antemortem brain MRI between groups, adjusted linear regression models to identify associations between WMH burden and neuropsychiatric symptoms, and image-guided pathology review of selected areas of WMH from each pathologic group.

Results: Burden and regional distribution of WMH differed significantly between neuropathological groups (F = 2.67, P' = 0.029), with the FTLD-TDP group having the highest mean volume globally (8032 ± 8889 mm) and in frontal regions (4897 ± 6163 mm). The AD group had the highest mean volume in occipital regions (468 ± 420 mm). Total score on the Neuropsychiatric Inventory correlated with bilateral frontal WMH volume (β = 0.330, P = 0.006), depression correlated with bilateral occipital WMH volume (β = 0.401, P < 0.001), and apathy correlated with bilateral frontal WMH volume (β = 0.311, P = 0.009), all corrected for the false discovery rate. Image-guided neuropathological assessment of selected cases with the highest burden of WMH in each pathologic group revealed presence of severe gliosis, myelin pallor, and axonal loss, but with no distinguishing features indicative of the underlying proteinopathy.

Conclusions: These findings suggest that WMH are associated with neuropsychiatric manifestations in AD and FTLD and that WMH burden and regional distribution in neurodegenerative disorders differ according to the underlying neuropathological processes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13195-021-00869-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278704PMC
July 2021

Association of apolipoprotein E variation with cognitive impairment across multiple neurodegenerative diagnoses.

Neurobiol Aging 2021 09 24;105:378.e1-378.e9. Epub 2021 Apr 24.

Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.

For many years there has been uncertainty regarding how apolipoprotein E (APOE) E2 and E4 variants may influence overlapping features of neurodegeneration, such as cognitive impairment. We aimed to identify whether the APOE variants are associated with cognitive function across various neurodegenerative and cerebrovascular diagnoses (n = 513). Utilizing a comprehensive neuropsychology battery, multivariate multiple regression was used to assess the influence of APOE carrier status and disease cohort on performance across five cognitive domains. Irrespective of disease cohort, E4 carriers had significantly lower performance in verbal memory and visuospatial domains than those with E3/3, while E2 carriers' cognitive performance was not significantly different. However, E2 carriers with frontotemporal dementia (FTD) performed significantly worse than those with E3/3 in the attention/working memory, executive function, and visuospatial domains. Our results highlight that the influence of APOE variation on cognition is complex, in some cases varying based on diagnosis and possibly underlying disease pathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neurobiolaging.2021.04.011DOI Listing
September 2021

Occurrence of Amyotrophic Lateral Sclerosis in Type 1 Gaucher Disease.

Neurol Genet 2021 Aug 18;7(4):e600. Epub 2021 May 18.

Krembil Research Institute (L.M.O., L.V.K.), Toronto Western Hospital, University Health Network, Ontario; Djavad Mowafaghian Centre for Brain Health (T.R.), Division of Neurology, Department of Medicine, University of British Columbia, Vancouver; Mark Feedman and Judy Jacobs Program for Gaucher Disease (G.A.M.N., D. Amato, L.V.K.), Mount Sinai Hospital; Fred A. Litwin Family Centre for Genetic Medicine (G.A.M.N., D.-L.N.), Department of Medicine, Mount Sinai Hospital and Toronto General Hospital, University Health Network, University of Toronto, Ontario; Department of Human Genetics (J.P.R., P.A.D., G.A.R., Z.G.-O.), Montreal Neurological Institute and Hospital (J.P.R., P.A.D., G.A.R., Z.G.-O.), and Department of Neurology and Neurosurgery (P.A.D., G.A.R., Z.G.-O.), McGill University, Quebec; Tanz Centre for Research in Neurodegenerative Diseases (M.Z., E.A.R., L.V.K.), University of Toronto, Ontario, Canada; Shanghai First Rehabilitation Hospital (M.Z.), School of Medicine, Clinical Center for Brain and Spinal Cord Research (M.Z.), and Institute for Advanced Study (M.Z.), Tongji University, Shanghai, China; Department of Neurology (D. Arkadir, M.G.), Hadassah Medical Center, Hebrew University, Jerusalem, Israel; Ellen and Martin Prosserman Centre for Neuromuscular Diseases (C.B.), Division of Neurology, Department of Medicine, Toronto General Hospital, University Health Network, University of Toronto; London Health Sciences Centre (C.L.S.), London, Ontario, Canada; Gaucher Unit (A.Z.), Shaare Zedek Medical Center, Hadassah Medical School, Hebrew University, Jerusalem, Israel; Division of Neurology (L.Z.), Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto; and Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic (L.V.K.), Division of Neurology, Department of Medicine, Toronto Western Hospital, University Health Network, University of Toronto, Ontario, Canada.

Objective: To report the association between type 1 Gaucher disease (GD1) and amyotrophic lateral sclerosis (ALS) in 3 unrelated families and to explore whether variants influence the risk of ALS.

Methods: We conducted retrospective chart reviews of patients with GD1 or their family members diagnosed with ALS. To further investigate whether there is an association between ALS and GD, we performed exploratory analyses for the presence of variants in 3 ALS cohorts from Toronto (Canada), Montreal (Canada), and Project MinE (international), totaling 4,653 patients with ALS and 1,832 controls.

Results: We describe 2 patients with GD1 and 1 obligate mutation carrier (mother of GD1 patient) with ALS. We identified 0 and 8 carriers in the Toronto and Montreal cohorts, respectively. The frequencies of variants in patients with ALS in the Montreal and Project MinE cohorts were similar to those of Project MinE controls or Genome Aggregation Database population controls.

Conclusions: The occurrence of ALS in biallelic or monoallelic mutation carriers described here, in addition to common pathogenic pathways shared by GD1 and ALS, suggests that variants could influence ALS risk. However, analyses of variants in ALS cohorts did not reveal a meaningful association. Examination of larger cohorts and neuropathologic studies will be required to elucidate whether patients with GD1 are indeed at increased risk for ALS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXG.0000000000000600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130998PMC
August 2021

Whole-Genome Study of a Multigenerational Family with Essential Tremor.

Can J Neurol Sci 2022 05 5;49(3):381-386. Epub 2021 May 5.

Division of Neurology, Department of Medicine, University of Toronto, Toronto, Canada.

Background: Essential tremor (ET) is a common movement disorder with ˜5% prevalence in individuals above the age of 65, but in rare cases, it arises during childhood. Growing evidence suggests the role of cerebellum in the disease mechanism. ET is highly heritable, however, poor replication of risk loci point to its significant heterogeneity. Thus, it is important to genetically investigate kindreds with a strong aggregation of ET.

Methods: We conducted a clinical and whole-genome investigation of a large Caucasian Canadian family, in which six out of eight patients are affected by childhood-onset ET in four consecutive generations. Eight family members were available for study, including three patients affected by ET. Whole-genome sequencing (WGS) was conducted for the four most informative individuals, followed by Sanger sequencing in the entire kindred.

Results: We searched for rare variants absent in the eldest unaffected individual, but present in the patients (two siblings and their third-degree relative). Our stringent whole-genome filtering approach revealed a rare heterozygous p. Arg90Gln substitution in TCP10L (rs151233771) in all three investigated patients. Sanger sequencing confirmed the p. Arg90Gln variant and revealed its absence in the rest of the family members.

Conclusions: Whole-genome data of the family with ET resulted in a single candidate gene mapped to 21q22.11 locus (TCP10L) with the highest brain expression in cerebellum. Our study encourages future replication studies to validate the genetic link between TCP10L and ET, and suggests the p. Arg90Gln variant for functional investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/cjn.2021.104DOI Listing
May 2022

Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease.

Ann Neurol 2021 07 17;90(1):76-88. Epub 2021 May 17.

23andMe, Inc., Sunnyvale, CA.

Objective: The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease.

Methods: We performed the first genomewide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers.

Results: A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; p value = 2.5E-08, beta = 1.27, SE = 0.23, risk allele: C) met genomewide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: p value = 1.1E-07; age-at-onset top variant: p value = 9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset.

Interpretation: This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. ANN NEUROL 2021;90:82-94.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.26094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252519PMC
July 2021

Combined epigenetic/genetic study identified an ALS age of onset modifier.

Acta Neuropathol Commun 2021 04 23;9(1):75. Epub 2021 Apr 23.

Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Ave., Toronto, ON, M5T 0S8, Canada.

Age at onset of amyotrophic lateral sclerosis (ALS) is highly variable (eg, 27-74 years in carriers of the GC-expansion in C9orf72). It might be influenced by environmental and genetic factors via the modulation of DNA methylation (DNAm) at CpG-sites. Hence, we combined an epigenetic and genetic approach to test the hypothesis that some common single nucleotide polymorphisms (SNPs) at CpG-sites (CpG-SNPs) could modify ALS age of onset. Our genome-wide DNAm analysis suggested three CpG-SNPs whose DNAm levels are significantly associated with age of onset in 249 ALS patients (q < 0.05). Next, genetic analysis validated the association of rs4970944 with age of onset in the discovery (n = 469; P = 0.025) and replication (n = 4160; P = 0.007) ALS cohorts. A meta-analysis of the cohorts combined showed that the median onset in AA-carriers is two years later than in GG-carriers (n = 4629; P = 0.0012). A similar association was observed with its tagging SNPs, implicating a 16 Kb region at the 1q21.3 locus as a modifier of ALS age of onset. Notably, rs4970944 genotypes are also associated with age of onset in C9orf72-carriers (n = 333; P = 0.025), suggesting that each A-allele delays onset by 1.6 years. Analysis of Genotype-Tissue Expression data revealed that the protective A-allele is linked with the reduced expression of CTSS in cerebellum (P = 0.00018), which is a critical brain region in the distributed neural circuits subserving motor control. CTSS encodes cathepsin S protein playing a key role in antigen presentation. In conclusion, we identified a 16 Kb locus tagged by rs4970944 as a modifier of ALS age of onset. Our findings support the role of antigen presenting processes in modulating age of onset of ALS and suggest potential drug targets (eg, CTSS). Future replication studies are encouraged to validate the link between the locus tagged by rs4970944 and age of onset in independent ALS cohorts, including different ethnic groups.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40478-021-01183-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066440PMC
April 2021

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture.

Nat Genet 2021 03 15;53(3):294-303. Epub 2021 Feb 15.

Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London, UK.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-021-00785-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946812PMC
March 2021

Early-Onset Alzheimer's Disease: What Is Missing in Research?

Curr Neurol Neurosci Rep 2021 01 19;21(2). Epub 2021 Jan 19.

The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA.

Purpose Of Review: Early-onset Alzheimer's disease (EOAD), defined as Alzheimer's disease (AD) occurring before age 65, is significantly less well studied than the late-onset form (LOAD) despite EOAD often presenting with a more aggressive disease progression. The aim of this review is to summarize the current understanding of the etiology of EOAD, their translation into clinical practice, and to suggest steps to be taken to move our understanding forward.

Recent Findings: EOAD cases make up 5-10% of AD cases but only 10-15% of these cases show known mutations in the APP, PSEN1, and PSEN2, which are linked to EOAD. New data suggests that these unexplained cases following a non-Mendelian pattern of inheritance is potentially caused by a mix of common and newly discovered rare variants. However, only a fraction of this genetic variation has been identified to date leaving the molecular mechanisms underlying this type of AD and their association with clinical, biomarker, and neuropathological changes unclear. While great advancements have been made in characterizing EOAD, much work is needed to disentangle the molecular mechanisms underlying this type of AD and to identify putative targets for more precise disease screening, diagnosis, prevention, and treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11910-020-01090-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815616PMC
January 2021

The Intersection between COVID-19, the Gene Family of ACE2 and Alzheimer's Disease.

Neurosci Insights 2020 22;15:2633105520975743. Epub 2020 Nov 22.

Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada.

We reviewed factors that might influence COVID-19 outcomes (eg, neurological symptoms), including the link to Alzheimer's disease. Since the virus triggers COVID-19 infection through binding to ACE2, we focused on the gene family, including . Both ACE2 and ACE are involved in the renin-angiotensin system (RAS). In general, ACE causes inflammation and vasoconstriction, while ACE2 leads to anti-inflammation activity and vasodilation. The disturbed balance between these counter-regulatory pathways could influence susceptibility to COVID-19. Notably, dysregulation of the RAS-equilibrium contributes to Alzheimer's disease. Differences in the incidence and symptoms of COVID-19 in diverse populations could be attributed to variability in the human genome. For example, and variations could modify the outcome of COVID-19 in different populations. It would be important to conduct genome-wide studies to detect variants influencing COVID-19 presentation, with a special focus on variants affecting immune-related pathways and expression of RAS-related genes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2633105520975743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686598PMC
November 2020

Late-onset vs nonmendelian early-onset Alzheimer disease: A distinction without a difference?

Neurol Genet 2020 Oct 6;6(5):e512. Epub 2020 Oct 6.

Taub Institute for Research on Alzheimer's Disease and the Aging Brain (C.R.), Gertrude H. Sergievsky Center (C.R.), Department of Neurology (C.R.), and Department of Epidemiology (C.R.), College of Physicians and Surgeons, Columbia University, New York, NY; Tanz Centre for Research in Neurodegenerative Disease (E.R.), University of Toronto, ON, Canada; and The John P. Hussman Institute for Human Genomics (G.W.B.), University of Miami, FL.

There is mounting evidence that only a small fraction of early-onset Alzheimer disease cases (onset <65 years) are explained by known mutations. Even multiplex families with early onset often also have late-onset cases, suggesting that the commonly applied categorization of Alzheimer disease into early- and late-onset forms may not reflect distinct underlying etiology. Nevertheless, this categorization continues to govern today's research and the design of clinical trials. The aim of this review is to evaluate this categorization by providing a comprehensive, critical review of reported clinical, neuropathologic, and genomic characteristics of both onset-based subtypes and explore potential overlap between both categories. The article will lay out the need to comprehensively assess the phenotypic, neuropathologic, and molecular variability in Alzheimer disease and identify factors explaining the observed significant variation in onset age in persons with and without known mutations. The article will critically review ongoing large-scale genomic efforts in Alzheimer disease research (e.g., Alzheimer Disease Sequencing Project, Dominantly Inherited Alzheimer Network, Alzheimer Disease Neuroimaging Initiative) and their shortcomings to disentangle the delineation of unexplained nonmendelian early-onset from late-onset and mendelian forms of Alzheimer disease. In addition, it will outline specific approaches including epigenetic research through which a comprehensive characterization of this delineation can be achieved.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXG.0000000000000512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673282PMC
October 2020

, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts.

Neurology 2020 12 17;95(24):e3288-e3302. Epub 2020 Sep 17.

From the Institute of Neurology (B.C., D.A.K., J.H., P.A.L., R.F.), School of Pharmacy (C.M.), and UCL Movement Disorders Centre (J.H.), University College London; School of Pharmacy (C.M., P.A.L.), University of Reading, Whiteknights; Neurogenetics Laboratory (M.B.-Q., C.W., J.M.P.), National Hospital for Neurology and Neurosurgery, London, UK; Aptima Clinic (Miquel Aguilar), Terrassa; Memory Disorders Unit, Department of Neurology (I.A., M.D.-F., P.P.), University Hospital Mutua de Terrassa, Barcelona; Hospital Universitario Central de Asturias (V.A., M.M.-G.), Oviedo, Spain; NORMENT (O.A.), Institute of Clinical Medicine, University of Oslo, Norway; Regional Neurogenetic Centre (Maria Anfossi, Livia Bernardi, A.C.B., M.E.C., Chiara Cupidi, F.F., Maura Gallo, R.M., N.S.), ASPCZ, Lamezia Terme; Department of Neuroscience, Psychology, Drug Research and Child Health (S.B., B.N., I.P., S.S.), University of Florence; Molecular Markers Laboratory (Luisa Benussi, Giuliano Binetti, R.G.), IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; Sheffield Institute for Translational Neuroscience (SITraN), Department of Neuroscience (D.B.), University of Sheffield, UK; Research Center and Memory Clinic (M.B., I.H., S.M.-G., Agustín Ruiz), Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya (UIC), Barcelona, Spain; Centre for Neurodegenerative Disorders (B.B., A.P.), Department of Clinical and Experimental Sciences, University of Brescia, Italy; Department of Clinical Neurosciences (Lucy Bowns, T.E.C., J.B.R.), Cambridge University, UK; Department of Neurology (Geir Bråthen, S.B.S.), University Hospital of Trondheim, Norway; Dept NVS, Division of Neurogeriatrics (H.-H.C., C.G., B.K., L.Ö.), Karolinska Institutet, Bioclinicum Solna, Sweden; Department of Neurology (J.C., O.D.-I., I.I.-G., A.L.), IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Spain; Anne Rowling Regenerative Neurology Clinic (S.C., G.J.T.H., S.P.) and Centre for Clinical Brain Sciences (S.P.), University of Edinburgh, UK; NeuroGenomics and Informatics, Department of Psychiatry (Carlos Cruchaga), Washington University, St. Louis, MO; Cognitive Impairment Center (M.E.D.B., Maurizio Gallucci) and Immunohematology and Transfusional Medicine Service (E.D., A.V.), Local Health Authority n.2 Marca Trevigiana, Treviso, Italy; Department of Psychiatry and Psychotherapy (J.D.-S., C.R.), School of Medicine, Technical University of Munich, Germany; Department of Neurology (D.F., M.G.K.) and Clinical Institute of Medical Genetics (A.M., B.P.), University Medical Center Ljubljana, Slovenia; Dino Ferrari Center (D.G., Elio Scarpini, M.S.), University of Milan, Italy; Cognitive Neuroscience Lab, Think and Speak Lab (J.H.G.), Shirley Ryan Ability Lab, Chicago, IL; Department of Pathology and Laboratory Medicine (Murray Grossman, EunRan Suh, J.Q.T., V.M.V.D.), Center for Neurodegenerative Diseases, Perelman School of Medicine at the University of Pennsylvania, Philadelphia; UCL Dementia Research Institute (J.H.), London; Reta Lila Weston Institute (J.H.), UCL Queen Square Institute of Neurology, UK; Institute for Advanced Study (J.H.), The Hong Kong University of Science and Technology, China; Royal Edinburgh Hospital (G.J.T.H.), UK; Taub Institute for Research on Alzheimer's Disease and the Aging Brain (E.D.H.), Columbia University, New York, NY; Department of Neurology, Memory and Aging Center (A.K., B.M., J.Y.), University of California, San Francisco; UCL Genomics (M.K., G.K.M., Y.P.), UCL Great Ormond Street Institute of Child Health, London, UK; Geriatric Center Frullone ASL Napoli 1 Centro (G.M.), Napoli, Italy; Department of Neurology (M.O.M., J.v.R., J.C.V.S.), Erasmus Medical Center, Rotterdam, the Netherlands; Rona Holdings (P.M.), Silicon Valley, CA; Newcastle Brain Tissue Resource, Institute of Neuroscience (C.M.M.), Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK; Department of Neurology (C.N.), Skåne University Hospital, Malmö, Sweden; Fondazione Policlinico Universitario A. Gemelli IRCCS (V.N.), Rome, Italy; Division of Neuroscience & Experimental Psychology (S.P.-B., A.M.T.R., S.R., J.C.T.), University of Manchester, UK; Amsterdam University Medical Center (Y.A.L.P.), VU University Medical Center, the Netherlands; Cardiovascular Research Unit (A.A.P.), IRCCS Multimedica, Milan; Neurology I, Department of Neuroscience (I.R., Elisa Rubino), University of Torino; NeurOMICS laboratory (G.M., Antonella Rendina, E.V.), Institute of Biochemistry and Cell Biology (IBBC), CNR Napoli, Italy; Manchester Centre for Clinical Neurosciences (A.M.T.R., J.S., J.C.T.), Salford Royal NHS Trust, Manchester, UK; Tanz Centre for Research in Neurodegenerative Diseases (Ekaterina Rogaeva), University of Toronto, Canada; Department of Biotechnology (B.R.), Jožef Stefan Institute, Ljubljana, Slovenia; Division of Neurology V and Neuropathology (G.R., F.T.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy; Alzheimer's Disease and Other Cognitive Disorders Unit (R.S.-V.), Hospital Clínic of Barcelona, Spain; Clinical Memory Research Unit, Department of Clinical Sciences Malmö (C.N., A.F.S.), and Division of Clinical Sciences Helsingborg, Department of Clinical Sciences Lund (M.L.W.), Lund University, Sweden; Neurodegenerative Brain Diseases Group (J.V.d.Z., C.V.B.), Center for Molecular Neurology, VIB, Antwerp, Belgium; Medical Research Council Centre for Neuropsychiatric Genetics and Genomics (V.E.-P.), Division of Psychological Medicine and Clinical Neurosciences and Dementia Research Institute, Cardiff University, UK; Instituto de Investigación Sanitaria del Principado de Asturias (V.A.), Oviedo, Asturias; Fundació per la Recerca Biomèdica i Social Mútua Terrassa (I.A., M.D.-F., P.P.), Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) (M.B., J.C., O.D.-I., I.H., I.I.-G., A.L., S.M.-G., Agustín Ruiz), Instituto de Salud Carlos III, Madrid, Spain; MRC Cognition and Brain Sciences Unit (Lucy Bowns, T.E.C., J.B.R.), Cambridge University, UK; Department of Neuromedicine and Movement Science (Geir Bråthen, S.B.S.), Norwegian University of Science and Technology, Trondheim, Norway; Unit for Hereditary Dementias (H.-H.C., C.G., B.K., L.Ö.), Theme Aging, Karolinska University Hospital, Solna, Sweden; Medical Faculty (D.F., M.G.K.), University of Ljubljana, Slovenia; Fondazione IRCCS Ca'Granda (D.G., Elio Scarpini, M.S.), Ospedale Policlinico, Milan, Italy; Penn Center for Frontotemporal Degeneration (Murray Grossman), Philadelphia, PA; Universidad de Oviedo (M.M.-G.), Asturias, Spain; IRCCS Fondazione Don Carlo Gnocchi (B.N., S.S.), Florence; Istituto di Medicina Genomica (V.N.), Università Cattolica del sacro Cuore, Rome, Italy; Amsterdam Neuroscience (Y.A.L.P.), the Netherlands; Department of Medicine and Surgery (A.A.P.), University of Salerno, Baronissi (SA), Italy; Faculty of Chemistry and Chemical Technology (B.R.), University of Ljubljana, Slovenia; Institud d'Investigacions Biomèdiques August Pi i Sunyer (R.S.-V.), Barcelona, Spain; Department of Biomedical Sciences (J.V.d.Z., C.V.B.), University of Antwerp, Belgium; and Department of Comparative Biomedical Sciences (P.A.L.), The Royal Veterinary College, London, UK.

Objective: We sought to characterize expansions in relation to genetic ancestry and age at onset (AAO) and to use these measures to discriminate the behavioral from the language variant syndrome in a large pan-European cohort of frontotemporal lobar degeneration (FTLD) cases.

Methods: We evaluated expansions frequency in the entire cohort (n = 1,396; behavioral variant frontotemporal dementia [bvFTD] [n = 800], primary progressive aphasia [PPA] [n = 495], and FTLD-motor neuron disease [MND] [n = 101]). We then focused on the bvFTD and PPA cases and tested for association between expansion status, syndromes, genetic ancestry, and AAO applying statistical tests comprising Fisher exact tests, analysis of variance with Tukey post hoc tests, and logistic and nonlinear mixed-effects model regressions.

Results: We found pathogenic expansions in 4% of all cases (56/1,396). Expansion carriers differently distributed across syndromes: 12/101 FTLD-MND (11.9%), 40/800 bvFTD (5%), and 4/495 PPA (0.8%). While addressing population substructure through principal components analysis (PCA), we defined 2 patients groups with Central/Northern (n = 873) and Southern European (n = 523) ancestry. The proportion of expansion carriers was significantly higher in bvFTD compared to PPA (5% vs 0.8% [ = 2.17 × 10; odds ratio (OR) 6.4; confidence interval (CI) 2.31-24.99]), as well as in individuals with Central/Northern European compared to Southern European ancestry (4.4% vs 1.8% [ = 1.1 × 10; OR 2.5; CI 1.17-5.99]). Pathogenic expansions and Central/Northern European ancestry independently and inversely correlated with AAO. Our prediction model (based on expansions status, genetic ancestry, and AAO) predicted a diagnosis of bvFTD with 64% accuracy.

Conclusions: Our results indicate correlation between pathogenic expansions, AAO, PCA-based Central/Northern European ancestry, and a diagnosis of bvFTD, implying complex genetic risk architectures differently underpinning the behavioral and language variant syndromes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000010914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836664PMC
December 2020

DNA Methylation Clocks and Their Predictive Capacity for Aging Phenotypes and Healthspan.

Neurosci Insights 2020 21;15:2633105520942221. Epub 2020 Jul 21.

Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada.

The number of age predictors based on DNA methylation (DNAm) profile is rising due to their potential in predicting healthspan and application in age-related illnesses, such as neurodegenerative diseases. The cumulative assessment of DNAm levels at age-related CpGs (DNAm clock) may reflect biological aging. Such DNAm clocks have been developed using various training models and could mirror different aspects of disease/aging mechanisms. Hence, evaluating several DNAm clocks together may be the most effective strategy in capturing the complexity of the aging process. However, various confounders may influence the outcome of these age predictors, including genetic and environmental factors, as well as technical differences in the selected DNAm arrays. These factors should be taken into consideration when interpreting DNAm clock predictions. In the current review, we discuss 15 reported DNAm clocks with consideration for their utility in investigating neurodegenerative diseases and suggest research directions towards developing a more optimal measure for biological aging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2633105520942221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376380PMC
July 2020

Parkinson's Disease, NOTCH3 Genetic Variants, and White Matter Hyperintensities.

Mov Disord 2020 11 23;35(11):2090-2095. Epub 2020 Jun 23.

Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, Ontario, Canada.

Background: White matter hyperintensities (WMH) on magnetic resonance imaging may influence clinical presentation in patients with Parkinson's disease (PD), although their significance and pathophysiological origins remain unresolved. Studies examining WMH have identified pathogenic variants in NOTCH3 as an underlying cause of inherited forms of cerebral small vessel disease.

Methods: We examined NOTCH3 variants, WMH volumes, and clinical correlates in 139 PD patients in the Ontario Neurodegenerative Disease Research Initiative cohort.

Results: We identified 13 PD patients (~9%) with rare (<1% of general population), nonsynonymous NOTCH3 variants. Bayesian linear modeling demonstrated a doubling of WMH between variant negative and positive patients (3.1 vs. 6.9 mL), with large effect sizes for periventricular WMH (d = 0.8) and lacunes (d = 1.2). Negative correlations were observed between WMH and global cognition (r = -0.2).

Conclusion: The NOTCH3 rare variants in PD may significantly contribute to increased WMH burden, which in turn may negatively influence cognition. © 2020 International Parkinson and Movement Disorder Society.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mds.28171DOI Listing
November 2020

DNA methylation age acceleration is associated with ALS age of onset and survival.

Acta Neuropathol 2020 05 7;139(5):943-946. Epub 2020 Mar 7.

Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Ave., Toronto, ON, M5T 2S8, Canada.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-020-02131-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181538PMC
May 2020

Interaction of APOE4 alleles and PET tau imaging in former contact sport athletes.

Neuroimage Clin 2020 13;26:102212. Epub 2020 Feb 13.

Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard avenue, Toronto, ON M5T 0S8, Canada; Institute of Medical Science, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada; Division of Neurology, Toronto Western Hospital, University Health Network, 399 Bathurst St., Toronto, ON, M5T 2S8, Canada; Canadian Concussion Center, Toronto Western Hospital, Krembil Neuroscience Centre, University Health Network, 399 Bathurst St., Toronto, ON, M5T 2S8, Canada. Electronic address:

Background: Genetic polymorphisms like apolipoprotein E (APOE) and microtubule-associated protein tau (MAPT) genes increase the risk of neurodegeneration.

Methods: 38 former players (age 52.63±14.02) of contact sports underwent neuroimaging, biofluid collection, and comprehensive neuropsychological assessment. The [F-18]AV-1451 tracer signal was compared in the cortical grey matter between APOE4 allele carriers and non-carriers as well as carriers of MAPT H1H1 vs non-H1H1. Participants were then divided into the high (N = 13) and low (N = 13) groups based on cortical PET tau standard uptake value ratios (SUVRs) for comparison.

Findings: Cortical grey matter PET tau SUVR values were significantly higher in APOE4 carriers compared to non-carriers (p = 0.020). In contrast, there was no significant difference in SUVR between MAPT H1H1 vs non-H1H1 carrier genes (p = 1.00). There was a significantly higher APOE4 allele frequency in the high cortical grey matter PET tau group, comparing to low cortical grey matter PET tau group (p = 0.048). No significant difference in neuropsychological function was found between APOE4 allele carriers and non-carriers.

Interpretation: There is an association between higher cortical grey matter tau burden as seen with [F-18]AV-1451 PET tracer SUVR, and the APOE4 allele in former professional and semi-professional players at high risk of concussions. APOE4 allele may be a risk factor for tau accumulation in former contact sports athletes at high risk of neurodegeneration.

Funding: Toronto General and Western Hospital Foundations; Weston Brain Institute; Canadian Consortium on Neurodegeneration in ageing; Krembil Research Institute. There was no role of the funders in this study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nicl.2020.102212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037542PMC
March 2021

Neuropathologic description of mutated amyotrophic lateral sclerosis.

Neurol Genet 2020 Feb 13;6(1):e394. Epub 2020 Jan 13.

Laboratory Medicine and Molecular Diagnostics (J.L.K., A.G., S.A.), Division of Anatomical Pathology, Sunnybrook Health Sciences Centre, University of Toronto; Department of Medicine (E.S., L.Z.), Division of Neurology, Sunnybrook Health Sciences Centre, University of Toronto, Ontario, Canada; School of Medicine and Institute for Advanced Study (M.Z.), Tongji University, Shanghai, China; and Tanz Centre for Research in Neurodegenerative Diseases (M.Z., P. McGoldrick, P. McKeever, J.R., E.R.), University of Toronto, Ontario, Canada.

Objective: To present the postmortem neuropathologic report of a patient with a mutation exhibiting an amyotrophic lateral sclerosis (ALS) clinical phenotype.

Methods: A 54-year-old man without significant medical history or family history presented with arm weakness, slowly progressed over 19 years to meet the El Escorial criteria for clinically probable ALS with bulbar and respiratory involvement, and was found to have a p.R15L mutation. Postmortem neuropathologic examination took place including immunohistochemical staining with CHCHD10, and double immunofluorescence combining CHCHD10 with TDP43 and neurofilament was performed and the results were compared with normal controls and sporadic ALS cases.

Results: Postmortem examination of the mutation carrier showed severe loss of hypoglossal and anterior horn motor neurons, mild corticospinal tract degeneration, and a relative lack of TDP43 immunopathology. CHCHD10 immunohistochemistry for the 3 controls and the 5 sporadic ALS cases showed strong neuronal cytoplasmic and axonal labeling, with the mutation carrier also having numerous CHCHD10 aggregates within their anterior horns. These aggregates may be related to the CHCHD10 aggregates recently described to cause mitochondrial degeneration and disease in a tissue-selective toxic gain-of-function fashion in a CHCHD10 knock-in mouse model. The CHCHD10 aggregates did not colocalize with TDP43 and were predominantly extracellular on double immunofluorescence labeling with neurofilament.

Conclusions: The neuropathology of CHCHD10 mutated ALS includes predominantly lower motor neuron degeneration, absent TDP43 immunopathology, and aggregates of predominantly extracellular CHCHD10, which do not contain TDP43.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXG.0000000000000394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6975173PMC
February 2020

Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies.

Acta Neuropathol Commun 2020 01 29;8(1). Epub 2020 Jan 29.

Neurology Service, University of Coimbra Hospital, Coimbra, Portugal.

Dementia with Lewy bodies (DLB) is a clinically heterogeneous disorder with a substantial burden on healthcare. Despite this, the genetic basis of the disorder is not well defined and its boundaries with other neurodegenerative diseases are unclear. Here, we performed whole exome sequencing of a cohort of 1118 Caucasian DLB patients, and focused on genes causative of monogenic neurodegenerative diseases. We analyzed variants in 60 genes implicated in DLB, Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and atypical parkinsonian or dementia disorders, in order to determine their frequency in DLB. We focused on variants that have previously been reported as pathogenic, and also describe variants reported as pathogenic which remain of unknown clinical significance, as well as variants associated with strong risk. Rare missense variants of unknown significance were found in APP, CHCHD2, DCTN1, GRN, MAPT, NOTCH3, SQSTM1, TBK1 and TIA1. Additionally, we identified a pathogenic GRN p.Arg493* mutation, potentially adding to the diversity of phenotypes associated with this mutation. The rarity of previously reported pathogenic mutations in this cohort suggests that the genetic overlap of other neurodegenerative diseases with DLB is not substantial. Since it is now clear that genetics plays a role in DLB, these data suggest that other genetic loci play a role in this disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40478-020-0879-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990558PMC
January 2020

Genetic and epigenetic study of an Alzheimer's disease family with monozygotic triplets.

Brain 2019 11;142(11):3375-3381

Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Ave, Toronto, ON, Canada.

Age at onset of Alzheimer's disease is highly variable, and its modifiers (genetic or environmental) could act through epigenetic changes, such as DNA methylation at CpG sites. DNA methylation is also linked to ageing-the strongest Alzheimer's disease risk factor. DNA methylation age can be calculated using age-related CpGs and might reflect biological ageing. We conducted a clinical, genetic and epigenetic investigation of a unique Ashkenazi Jewish family with monozygotic triplets, two of whom developed Alzheimer's disease at ages 73 and 76, while the third at age 85 has no cognitive complaints or deficits in daily activities. One of their offspring developed Alzheimer's disease at age 50. Targeted sequencing of 80 genes associated with neurodegeneration revealed that the triplets and the affected offspring are heterozygous carriers of the risk APOE ε4 allele, as well as rare substitutions in APP (p.S198P), NOTCH3 (p.H1235L) and SORL1 (p.W1563C). In addition, we catalogued 52 possibly damaging rare variants detected by NeuroX array in affected individuals. Analysis of family members on a genome-wide DNA methylation chip revealed that the DNA methylation age of the triplets was 6-10 years younger than chronological age, while it was 9 years older in the offspring with early-onset Alzheimer's disease, suggesting accelerated ageing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awz289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821163PMC
November 2019
-->