Showing papers by "Harro Seelaar published in 2019"
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Mayo Clinic1, Erasmus University Rotterdam2, University of California, San Francisco3, University of British Columbia4, University of Western Ontario5, Karolinska Institutet6, German Center for Neurodegenerative Diseases7, University of Tübingen8, University of Rostock9, Ludwig Maximilian University of Munich10, Technische Universität München11, University of Texas Southwestern Medical Center12, King's College London13, University of Cambridge14, Northwestern University15, University of Texas Health Science Center at San Antonio16, University of Arizona17, Columbia University18, Indiana University – Purdue University Indianapolis19, Medical Research Council20, University of Pennsylvania21, University of Manchester22, University of Sydney23, United States Department of Veterans Affairs24, University of Toronto25, University Health Network26, Washington University in St. Louis27, University of Pittsburgh28, University of New South Wales29, Emory University30, University College London31
TL;DR: A possible role for genes functioning within the TBK1-related immune pathway (e.g., DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP is discovered and strongly implicates the immune pathway in FTLD/TDP pathogenesis.
Abstract: Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (p value = 4.82e − 08, OR = 2.12), and two known loci: UNC13A, led by rs1297319 (p value = 1.27e − 08, OR = 1.50) and HLA-DQA2 led by rs17219281 (p value = 3.22e − 08, OR = 1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole-genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n ≥ 3) as compared to controls (n = 0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g., DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis.
72 citations
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TL;DR: To identify novel CSF biomarkers in GRN‐associated frontotemporal dementia (FTD) by proteomics using mass spectrometry (MS) using peptide-based methods.
Abstract: Objective: To identify novel CSF biomarkers in GRN-associated frontotemporal dementia (FTD) by proteomics using mass spectrometry (MS). Methods:
Unbiased MS was applied to CSF samples from 19 presymptomatic and 9
symptomatic GRN mutation carriers and 24 noncarriers. Protein abundances
were compared between these groups. Proteins were then selected for validation
if identified by ≥4 peptides and if fold change was ≤0.5 or ≥2.0. Validation and
absolute quantification by parallel reaction monitoring (PRM), a high-resolution targeted MS method, was performed on an international cohort (n = 210)
of presymptomatic and symptomatic GRN, C9orf72 and MAPT mutation carriers. Results: Unbiased MS revealed 20 differentially abundant proteins between
symptomatic mutation carriers and noncarriers and nine between symptomatic
and presymptomatic carriers. Seven of these proteins fulfilled our criteria for
validation. PRM analyses revealed that symptomatic GRN mutation carriers had
significantly lower levels of neuronal pentraxin receptor (NPTXR), receptortype tyrosine-protein phosphatase N2 (PTPRN2), neurosecretory protein VGF,
chromogranin-A (CHGA), and V-set and transmembrane domain-containing
protein 2B (VSTM2B) than presymptomatic carriers and noncarriers. Symptomatic C9orf72 mutation carriers had lower levels of NPTXR, PTPRN2,
CHGA, and VSTM2B than noncarriers, while symptomatic MAPT mutation
carriers had lower levels of NPTXR and CHGA than noncarriers. Interpretation: We identified and validated five novel CSF biomarkers in GRN-associated
FTD. Our results show that synaptic, secretory vesicle, and inflammatory proteins are dysregulated in the symptomatic stage and may provide new insights into the pathophysiology of genetic FTD. Further validation is needed to investigate their clinical applicability as diagnostic or monitoring biomarkers.
44 citations
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TL;DR: A 65-year-old patient presenting with mild cognitive impairment, evolving in dementia with behavioral disturbances and parkinsonism is described, with an absence of typical MRI abnormalities, lack of intranuclear inclusions in glial cells, and prominent involvement of hippocampal neurons, refining the clinico-pathological spectrum of the disease.
Abstract: Neuronal intranuclear inclusion disease (NIID) is a rare heterogeneous progressive neurodegenerative disease characterized by the presence of eosinophilic hyaline intranuclear inclusions in neuronal and glial cells of the CNS, peripheral cells of the autonomic nervous system, visceral organs and skin. The clinical presentation is broadly heterogeneous and includes limb weakness, dementia, seizures, ataxia, and parkinsonism. High-intensity signal in the corticomedullary junction on brain MRI is a characteristic finding in NIID. We describe a 65-year-old patient presenting with mild cognitive impairment, evolving in dementia with behavioral disturbances and parkinsonism. Brain MRI showed mild global cortical atrophy, more pronounced in the cingulate and temporal cortex and mild leukoaraiosis, but no high-intensity signal in corticomedullary junction on diffusion weighted imaging. Neuropathological examination showed p62- and optineurin-positive neuronal intranuclear inclusions in the hippocampus and in some subcortical structures. Glial cells did not present any intranuclear inclusions, and no spongiotic changes proximal to the U-fibers or diffuse myelin pallor were disclosed in the white matter. We report on a case with pathological features of NIID showing different neuroimaging and pathological findings. We noted an absence of typical MRI abnormalities, lack of intranuclear inclusions in glial cells, and prominent involvement of hippocampal neurons, refining the clinico-pathological spectrum of the disease.
19 citations
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Erasmus University Rotterdam1, University of Pennsylvania2, University of California, San Francisco3, VU University Amsterdam4, Technische Universität München5, Lund University6, University of Brescia7, University College London8, German Center for Neurodegenerative Diseases9, University of Lisbon10, Katholieke Universiteit Leuven11, Delft University of Technology12, Leiden University13
TL;DR: Cerebrospinal fluid NfL is a promising biomarker in the diagnostic process of SD, although it has limited cross-sectional monitoring or prognostic abilities.
Abstract: Background Semantic dementia (SD) is a
neurodegenerative disorder characterised by
progressive language problems falling within the
clinicopathological spectrum of frontotemporal lobar
degeneration (FTLD). The development of diseasemodifying agents may be facilitated by the relative
clinical and pathological homogeneity of SD, but we
need robust monitoring biomarkers to measure their
efficacy. In different FTLD subtypes, neurofilament
light chain (NfL) is a promising marker, therefore we
investigated the utility of cerebrospinal fluid (CSF) NfL
in SD.
Methods This large retrospective multicentre study
compared cross-sectional CSF NfL levels of 162
patients with SD with 65 controls. CSF NfL levels of
patients were correlated with clinical parameters
(including survival), neuropsychological test scores and
regional grey matter atrophy (including longitudinal
data in a subset).
Results CSF NfL levels were significantly higher in
patients with SD (median: 2326 pg/mL, IQR: 1628–
3593) than in controls (577 (446–766), p<0.001).
Higher CSF NfL levels were moderately associated
with naming impairment as measured by the Boston
Naming Test (r
s
=−0.32, p=0.002) and with smaller
grey matter volume of the parahippocampal gyri
(r
s
=−0.31, p=0.004). However, cross-sectional CSF NfL
levels were not associated with progression of grey
matter atrophy and did not predict survival.
Conclusion CSF NfL is a promising biomarker in the
diagnostic process of SD, although it has limited crosssectional monitoring or prognostic abilities.
18 citations
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TL;DR: Human homologue of yeast UV excision repair protein Rad23b (HR23B) inclusions are found in a number of neurodegenerative diseases and it is hypothesized that HR23B may play a role in C9ORF72 pathogenesis, possibly by aberrant ERAD functioning.
Abstract: Human homologue of yeast UV excision repair protein Rad23b (HR23B) inclusions are found in a number of neurodegenerative diseases, including frontotemporal dementia (FTD), Huntington's disease (HD), spinocerebellar ataxia type 3 and 7 (SCA3/7), fragile X associated tremor/ataxia syndrome (FXTAS) and Parkinson's disease (PD). Here, we describe HR23B pathology in C9ORF72 linked FTD and amyotrophic lateral sclerosis (ALS) cases. HR23B presented in neuropils, intranuclear inclusions and cytoplasmic and perinuclear inclusions and was predominantly found in cortices (frontal, temporal and motor), spinal cord and hippocampal dentate gyrus. HR23B co-localized with poly-GA-, pTDP-43- and p62-positive inclusions in frontal cortex and in hippocampal dentate gyrus, the latter showing higher co-localization percentages. HR23B binding partners XPC, 20S and ataxin-3, which are involved in nucleotide excision repair (NER) and the ubiquitin-proteasome system (UPS), did not show an aberrant distribution. However, C9ORF72 fibroblasts were more sensitive for UV-C damage than healthy control fibroblasts, even though all factors involved in NER localized normally to DNA damage and the efficiency of DNA repair was not reduced. HR23Bs other binding partner NGly1/PNGase, involved in ER-associated degradation (ERAD) of misfolded proteins, was not expressed in the majority of neurons in C9FTD/ALS brain sections compared to non-demented controls. Our results suggest a difference in HR23B aggregation and co-localization pattern with DPRs, pTDP-43 and p62 between different brain areas from C9FTD/ALS cases. We hypothesize that HR23B may play a role in C9ORF72 pathogenesis, possibly by aberrant ERAD functioning.
9 citations
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TL;DR: This study suggests that rare variants in EIF2AK3 may be associated with disease risk in AD, and sequenced 19 exomes from 8 Dutch families with a high AD burden to identify this gene as a candidate gene.
7 citations