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Article ; Online: DNA Methylation Clocks and Their Predictive Capacity for Aging Phenotypes and Healthspan.

Bergsma, Tessa / Rogaeva, Ekaterina

Neuroscience insights

2020 Volume 15, Page(s) 2633105520942221

Abstract: 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- ... ...

Abstract	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.
Language	English
Publishing date	2020-07-21
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2633-1055
ISSN (online)	2633-1055
DOI	10.1177/2633105520942221
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Article ; Online: The molecular spectrum of amyloid-beta (Aβ) in neurodegenerative diseases beyond Alzheimer's disease.

Ichimata, Shojiro / Yoshida, Koji / Li, Jun / Rogaeva, Ekaterina / Lang, Anthony E / Kovacs, Gabor G

Brain pathology (Zurich, Switzerland)

2023 Volume 34, Issue 1, Page(s) e13210

Abstract: This study investigated the molecular spectrum of amyloid-beta (Aβ) in neurodegenerative diseases beyond Alzheimer's disease (AD). We analyzed Aβ deposition in the temporal cortex and striatum in 116 autopsies, including Lewy body disease (LBD; N = 51), ... ...

Abstract	This study investigated the molecular spectrum of amyloid-beta (Aβ) in neurodegenerative diseases beyond Alzheimer's disease (AD). We analyzed Aβ deposition in the temporal cortex and striatum in 116 autopsies, including Lewy body disease (LBD; N = 51), multiple system atrophy (MSA; N = 10), frontotemporal lobar degeneration-TDP-43 (FTLD-TDP; N = 16), and progressive supranuclear palsy (PSP; N = 39). The LBD group exhibited the most Aβ deposition in the temporal cortex and striatum (90/76%, respectively), followed by PSP (69/28%), FTLD-TDP (50/25%), and the MSA group (50/10%). We conducted immunohistochemical analysis using antibodies targeting eight Aβ epitopes in the LBD and PSP groups. Immunohistochemical findings were evaluated semi-quantitatively and quantitatively using digital pathology. Females with LBD exhibited significantly more severe Aβ deposition, particularly Aβ
MeSH term(s)	Male ; Female ; Humans ; Alzheimer Disease/genetics ; Alzheimer Disease/pathology ; Frontotemporal Dementia ; tau Proteins ; Lewy Body Disease/pathology ; Amyloid beta-Peptides ; Multiple System Atrophy/pathology ; Apolipoproteins E/genetics
Chemical Substances	tau Proteins ; Amyloid beta-Peptides ; Apolipoproteins E
Language	English
Publishing date	2023-08-31
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1051484-3
ISSN	1750-3639 ; 1015-6305
ISSN (online)	1750-3639
ISSN	1015-6305
DOI	10.1111/bpa.13210
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Zs.A 3585: Show issues

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

Reitz, Christiane / Rogaeva, Ekaterina / Beecham, Gary W

Neurology. Genetics

2020 Volume 6, Issue 5, Page(s) e512

Abstract: 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 ... ...

Abstract	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.
Language	English
Publishing date	2020-10-06
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2818607-2
ISSN	2376-7839
ISSN	2376-7839
DOI	10.1212/NXG.0000000000000512
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Article: The Rossy Progressive Supranuclear Palsy Centre: Creation and Initial Experience.

Couto, Blas / Fox, Susan / Tartaglia, Maria Carmela / Rogaeva, Ekaterina / Antwi, Jeffrey / Bhakta, Puja / Kovacs, Gabor G / Lang, Anthony E

The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques

2023 Volume 50, Issue 6, Page(s) 845–852

Abstract: Objective: To describe the development and initial experience of a clinical research program in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) in Canada: The Rossy PSP Centre, to share the data acquisition tools adopted, and to ... ...

Abstract	Objective: To describe the development and initial experience of a clinical research program in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) in Canada: The Rossy PSP Centre, to share the data acquisition tools adopted, and to report preliminary results. Methods: Extensive demographic and longitudinal clinical information is collected every 6 months using standardized forms. Biofluids are collected for biobanking and genetic analysis, and many patients are enrolled in neuroimaging research protocols. Brain donation is an important component of the program, and standardized processing protocols have been established, including very short death to autopsy times in patients undergoing medical assistance in dying. Results: Between Oct 2019 and Dec 2021, 132 patients were screened, 91 fulfilling criteria for PSP and 19 for CBS; age 71 years; 41% female; duration 5 years, age-of-onset 66 years. The most common symptoms at onset were postural instability and falls (45%), cognitive-behavioral changes (22%), and Parkinsonism (9%). The predominant clinical phenotype was Richardson syndrome (82%). Levodopa and amantadine resulted in partial and short-lasting benefit. Conclusions: The Rossy PSP Centre has been established to advance clinical and basic research in PSP and related tauopathies. The extent of the clinical data collected permits deep phenotyping of patients and allows for future clinical and basic research. Preliminary results showed expected distribution of phenotypes, demographics, and response to symptomatic treatments in our cohort. Longitudinal data will provide insight into the early diagnosis and management of PSP. Future steps include enrollment of patients in earlier stages, development of biomarkers, and fast-tracking well-characterized patients into clinical trials.
Language	English
Publishing date	2023-01-05
Publishing country	England
Document type	Journal Article
ZDB-ID	197622-9
ISSN	0317-1671
ISSN	0317-1671
DOI	10.1017/cjn.2022.332
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Zs.A 1203: Show issues

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Article ; Online: DNA Methylation Age Acceleration as a Potential Biomarker for Early Onset of Rapid Eye Movement Sleep Behavior Disorder.

Senkevich, Konstantin / Pelletier, Amélie / Sato, Christine / Liu, Lang / Keil, Allison / Gan-Or, Ziv / Lang, Anthony E / Postuma, Ronald B / Rogaeva, Ekaterina

Annals of neurology

2023

Abstract: Rapid eye movement sleep behavior disorder (RBD) is the strongest prodromal marker for α-synucleinopathies. The Horvath DNA methylation age (DNAm-age) is an epigenetic clock reflecting biological aging. We found an association of DNAm-age acceleration ... ...

Abstract	Rapid eye movement sleep behavior disorder (RBD) is the strongest prodromal marker for α-synucleinopathies. The Horvath DNA methylation age (DNAm-age) is an epigenetic clock reflecting biological aging. We found an association of DNAm-age acceleration with RBD age at onset at baseline (N = 162, B = -0.68, standard error [SE] = 0.12, p = 2.59e-08) and follow-up (n = 45, B = -1.07, SE = 0.21, p = 9.73e-06). The result remained similar after accounting for genetic risk factors (eg, RBD polygenic risk score). On average, RBD patients with faster versus slow/normal epigenetic aging had a 5.2-year earlier phenoconversion, and the Cox regression analysis revealed a trend toward significance (n = 53, hazard ratio = 1.05, 95% confidence interval = 0.99-1.11, p = 0.06). Our findings suggest that DNAm-age acceleration is a potential biomarker for earlier RBD onset. ANN NEUROL 2023.
Language	English
Publishing date	2023-10-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	80362-5
ISSN	1531-8249 ; 0364-5134
ISSN (online)	1531-8249
ISSN	0364-5134
DOI	10.1002/ana.26811
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Zs.A 1370: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 478: Show issues

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Article ; Online: Does BDNF Val66Met contribute to preclinical Alzheimer's disease?

Rogaeva, Ekaterina / Schmitt-Ulms, Gerold

Brain : a journal of neurology

2016 Volume 139, Issue Pt 10, Page(s) 2586–2589

Language	English
Publishing date	2016-10
Publishing country	England
Document type	Journal Article
ZDB-ID	80072-7
ISSN	1460-2156 ; 0006-8950
ISSN (online)	1460-2156
ISSN	0006-8950
DOI	10.1093/brain/aww201
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Ui II Zs.26: Show issues

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

Ayodele, Temitope / Rogaeva, Ekaterina / Kurup, Jiji T / Beecham, Gary / Reitz, Christiane

Current neurology and neuroscience reports

2021 Volume 21, Issue 2, Page(s) 4

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Age of Onset ; Aged ; Alzheimer Disease/diagnosis ; Alzheimer Disease/epidemiology ; Alzheimer Disease/genetics ; Amyloid beta-Protein Precursor/genetics ; Humans ; Mutation ; Presenilin-1/genetics ; Presenilin-2/genetics
Chemical Substances	Amyloid beta-Protein Precursor ; Presenilin-1 ; Presenilin-2
Language	English
Publishing date	2021-01-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2057363-7
ISSN	1534-6293 ; 1528-4042
ISSN (online)	1534-6293
ISSN	1528-4042
DOI	10.1007/s11910-020-01090-y
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Zs.A 5549: Show issues

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

Zhang, Ming / Rohani, Mohammad / Montazer Haghighi, Mahdi / Sato, Christine / Rogaeva, Ekaterina / Fasano, Alfonso

The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques

2021 Volume 49, Issue 3, Page(s) 381–386

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Canada ; Essential Tremor/genetics ; Heterozygote ; Humans ; Mutation, Missense ; Pedigree
Language	English
Publishing date	2021-05-05
Publishing country	England
Document type	Journal Article
ZDB-ID	197622-9
ISSN	0317-1671
ISSN	0317-1671
DOI	10.1017/cjn.2021.104
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Article ; Online: Case of a Man with Hemichorea and Behavioral Changes: "A Red Herring".

Kleiner, Galit / Ryan, Stephen A / Bilbao, Juan / Keith, Julia / Rogaeva, Ekaterina / Black, Sandra E / Lang, Anthony E / Masellis, Mario

Movement disorders clinical practice

2022 Volume 9, Issue 4, Page(s) 501–507

Abstract: 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 ... ...

Abstract	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.
Language	English
Publishing date	2022-03-30
Publishing country	United States
Document type	Journal Article
ISSN	2330-1619
ISSN (online)	2330-1619
DOI	10.1002/mdc3.13433
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Article ; Online: Reply: Is Pathology Always the Diagnostic Gold Standard in Neurodegeneration?

Ryan, Stephen A / Masellis, Mario / Bilbao, Juan / Keith, Julia / Rogaeva, Ekaterina / Black, Sandra E / Lang, Anthony E / Kleiner, Galit

Movement disorders clinical practice

2022 Volume 9, Issue 8, Page(s) 1154–1155

Language	English
Publishing date	2022-10-03
Publishing country	United States
Document type	Journal Article
ISSN	2330-1619
ISSN (online)	2330-1619
DOI	10.1002/mdc3.13571
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