Genetic study of<scp>young‐onset</scp>dementia using targeted gene panel sequencing in Taiwan

Hsu, Jen‐Hwa; Lin, Chin-Hsien; Chen, Pei‐Lung; Lin, Kun‐Ju; Chen, Ta‐Fu

doi:10.1002/ajmg.b.32836

Cited by 7 publications

(4 citation statements)

References 44 publications

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“…in AD patients, which had been replicated by tau-PET imaging studies in vivo (Koychev et al, 2017;Baghel et al, 2019;Das et al, 2019;Zhao et al, 2019;Cho et al, 2020;Hsu et al, 2021;Seemiller et al, 2021). In our study, 31 AD patients were divided into 3 groups (i.e., mild, moderate, and severe) according to the MMSE score.…”

Section: Discussionsupporting

confidence: 59%

“…This stage pattern was derived from the histopathological staining at autopsy. Then, tau tracer could be used to describe the spatiotemporal pattern of tau deposition in AD patients, which had been replicated by tau-PET imaging studies in vivo ( Koychev et al, 2017 ; Baghel et al, 2019 ; Das et al, 2019 ; Zhao et al, 2019 ; Cho et al, 2020 ; Hsu et al, 2021 ; Seemiller et al, 2021 ). In our study, 31 AD patients were divided into 3 groups (i.e., mild, moderate, and severe) according to the MMSE score.…”

Section: Discussionmentioning

confidence: 95%

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18F-APN-1607 Tau Positron Emission Tomography Imaging for Evaluating Disease Progression in Alzheimer’s Disease

Ruan

Liu

et al. 2022

Front. Aging Neurosci.

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Purpose18F-APN-1607 is a novel tau positron emission tomography (PET) tracer characterized with high binding affinity for 3− and 4-repeat tau deposits. The aim was to analyze the spatial distribution of 18F-APN-1607 PET imaging in Alzheimer’s disease (AD) subjects with different stages and to investigate the relationship between the change of tau deposition and overall disease progression.MethodsWe retrospectively analyzed the 18F-APN-1607 PET imaging of 31 subjects with clinically and imaging defined as AD. According to the Mini-Mental State Examination (MMSE) score, patients were divided into three groups, namely, mild (≥21, n = 7), moderate (10–20, n = 16), and severe (≤9, n = 8). PET imaging was segmented to 70 regions of interest (ROIs) and extracted the standard uptake value (SUV) of each ROI. SUV ratio (SUVR) was calculated from the ratio of SUV in different brain regions to the cerebellar cortex. The regions were defined as positive and negative with unsupervised cluster analysis according to SUVR. The SUVRs of each region were compared among groups with the one-way ANOVA or Kruskal–Wallis H test. Furthermore, the correlations between MMSE score and regional SUVR were calculated with Pearson or Spearman correlation analysis.ResultsThere were no significant differences among groups in gender (χ2 = 3.814, P = 0.161), age of onset (P = 0.170), age (P = 0.109), and education level (P = 0.065). With the disease progression, the 18F-APN-1607 PET imaging showed the spread of tau deposition from the hippocampus, posterior cingulate gyrus (PCG), and lateral temporal cortex (LTC) to the parietal and occipital lobes, and finally to the frontal lobe. Between the mild and moderate groups, the main brain areas with significant differences in 18F-APN-1607 uptake were supplementary motor area (SMA), cuneus, precuneus, occipital lobule, paracentral lobule, right angular gyrus, and parietal, which could be used for early disease progression assessment (P < 0.05). There were significant differences in the frontal lobe, right temporal lobe, and fusiform gyrus between the moderate and severe groups, which might be suitable for the late-stage disease progression assessment (P < 0.05).Conclusion18F-APN-1607 PET may serve as an effective imaging marker for visualizing the change pattern of tau protein deposition in AD patients, and its uptake level in certain brain regions is closely related to the severity of cognitive impairment. These indicate the potential of 18F-APN-1607 PET for the in vivo evaluation of the progression of AD.

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Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 95%

18F-APN-1607 Tau Positron Emission Tomography Imaging for Evaluating Disease Progression in Alzheimer’s Disease

Ruan

Liu

et al. 2022

Front. Aging Neurosci.

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“…Leucine-rich repeat kinase 2 (LRRK2) is a major causative gene of late-onset familial Parkinson's disease (PD) (OMIM#607060). Remarkably, some of the clearly PD associated mutations have also been found in patients suffering from atypical PD and tauopathies [ 28 – 33 ]. Three patients in our cohort were identified to carry rare variants in the LRRK2 gene.…”

Section: Resultsmentioning

confidence: 99%

Comprehensive genetic screening of early-onset dementia patients in an Austrian cohort-suggesting new disease-contributing genes

et al. 2023

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Early-onset dementia (EOD), with symptom onset before age 65, has a strong genetic burden. Due to genetic and clinical overlaps between different types of dementia, whole-exome sequencing (WES) has emerged as an appropriate screening method for diagnostic testing and novel gene-finding approaches. We performed WES and C9orf72 repeat testing in 60 well-defined Austrian EOD patients. Seven patients (12%) carried likely disease-causing variants in monogenic genes, PSEN1, MAPT, APP, and GRN. Five patients (8%) were APOE4 homozygote carriers. Definite and possible risk variants were detected in the genes TREM2, SORL1, ABCA7 and TBK1. In an explorative approach, we cross-checked rare gene variants in our cohort with a curated neurodegeneration candidate gene list and identified DCTN1, MAPK8IP3, LRRK2, VPS13C and BACE1 as promising candidate genes. Conclusively, 12 cases (20%) carried variants relevant to patient counseling, comparable to previously reported studies, and can thus be considered genetically resolved. Reduced penetrance, oligogenic inheritance and not yet identified high-risk genes might explain the high number of unresolved cases. To address this issue, we provide complete genetic and phenotypic information (uploaded to the European Genome-phenome Archive), enabling other researchers to cross-check variants. Thereby, we hope to increase the chance of independently finding the same gene/variant-hit in other well-defined EOD patient cohorts, thus confirming new genetic risk variants or variant combinations.

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“…In the literature review, rare variants in genes such as MAPT, GRN, C9orf72, CHCHD10, VCP, TBK1, OPTN, SQSTM1, SIGMAR1, TARDBP, UBQLN2, FUS, CCNF, and CYLD were identified in Chinese FTD populations [ 8 , 28 – 36 ]. The genetic spectrum of the major FTD cohorts previously reported in China is shown in (Fig.…”

Section: Resultsmentioning

confidence: 99%

Genetic and clinical landscape of Chinese frontotemporal dementia: dominance of TBK1 and OPTN mutations

Nan,

Kim,

Chu

et al. 2024

Alz Res Therapy

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Background Our study aims to evaluate the genetic and phenotypic spectrum of Frontotemporal dementia (FTD) gene variant carriers in Chinese populations, investigate mutation frequencies, and assess the functional properties of TBK1 and OPTN variants. Methods Clinically diagnosed FTD patients underwent genetic analysis through exome sequencing, repeat-primed polymerase chain reaction, and Sanger sequencing. TBK1 and OPTN variants were biologically characterized in vitro using immunofluorescence, immunoprecipitation, and immunoblotting analysis. The frequencies of genes implicated in FTD in China were analyzed through a literature review and meta-analysis. Results Of the 261 Chinese FTD patients, 61 (23.4%) carried potential causative variants in FTD-related genes, including MAPT (n = 17), TBK1 (n = 7), OPTN (n = 6), GRN (n = 6), ANXA11 (n = 4), CHMP2B (n = 3), C9orf72 GGGGCC repeats (n = 2), CYLD (n = 2), PRNP (n = 2), SQSTM1 (n = 2), TARDBP (n = 2), VCP (n = 1), CCNF (n = 1), CHCHD10 (n = 1), SIGMAR1 (n = 1), CHCHD2 (n = 1), FUS (n = 1), TMEM106B (n = 1), and UBQLN2 (n = 1). 29 variants can be considered novel, including the MAPT p.D54N, p.E342K, p.R221P, p.T263I, TBK1 p.E696G, p.I37T, p.E232Q, p.S398F, p.T78A, p.Q150P, p.W259fs, OPTN p.R144G, p.F475V, GRN p.V473fs, p.C307fs, p.R101fs, CHMP2B p.K6N, p.R186Q, ANXA11 p.Q155*, CYLD p.T157I, SQSTM1 p.S403A, UBQLN2 p.P509H, CCNF p.S160N, CHCHD10 p.A8T, SIGMAR1 p.S117L, CHCHD2 p.P53fs, FUS p.S235G & p.S236G, and TMEM106B p.L144V variants. Patients with TBK1 and OPTN variants presented with heterogeneous clinical phenotypes. Functional analysis demonstrated that TBK1 I37T and E232Q mutants showed decreased autophosphorylation, and the OPTN phosphorylation was reduced by the TBK1 I37T mutant. The OPTN-TBK1 complex formation was enhanced by the TBK1 E696G mutant, while OPTN R144G and F475V mutants exhibited reduced recruitment to autophagosomes compared to the wild-type. The overall frequency of TBK1 and OPTN in Chinese FTD patients was 2.0% and 0.3%, respectively. Conclusions Our study demonstrates the extensive genetic and phenotypic heterogeneity of Chinese FTD patients. TBK1 mutations are the second most frequent cause of clinical FTD after MAPT in the Chinese.

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Genetic study ofyoung‐onsetdementia using targeted gene panel sequencing in Taiwan

Cited by 7 publications

References 44 publications

18F-APN-1607 Tau Positron Emission Tomography Imaging for Evaluating Disease Progression in Alzheimer’s Disease

18F-APN-1607 Tau Positron Emission Tomography Imaging for Evaluating Disease Progression in Alzheimer’s Disease

Comprehensive genetic screening of early-onset dementia patients in an Austrian cohort-suggesting new disease-contributing genes

Genetic and clinical landscape of Chinese frontotemporal dementia: dominance of TBK1 and OPTN mutations

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