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Yuta Kojima

Bio: Yuta Kojima is an academic researcher from Kyoto Prefectural University of Medicine. The author has contributed to research in topics: Echogenicity & Ultrasound. The author has an hindex of 3, co-authored 9 publications receiving 36 citations.

Papers
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Journal ArticleDOI
TL;DR: In this article, the diagnostic and prognostic significance of neurofilament light chain (NfL), TAR DNA-binding protein 43 (TDP-43), and total tau (t-tau) in cerebrospinal fluid (CSF) and plasma of patients with ALS was investigated.
Abstract: Objective To determine the diagnostic and prognostic significance of neurofilament light chain (NfL), TAR DNA-binding protein 43 (TDP-43), and total tau (t-tau) in cerebrospinal fluid (CSF) and plasma of patients with amyotrophic lateral sclerosis (ALS) and to investigate whether the combined use of those biomarker candidates can improve their diagnostic performance. Methods This was a single-center, prospective, longitudinal study. CSF and plasma samples were collected at the time of enrollment from a discovery cohort of 29 patients with ALS and 29 age-matched controls without neurodegenerative disease. In a validation cohort, there were 46 patients with ALS, and 46 control (not age-matched) patients with motor weakness resulting from neuromuscular diseases. NfL, TDP-43, and t-tau levels in CSF and plasma were measured using ultrasensitive single molecule assay (Simoa) technology. Results The following findings were reproducibly observed among the discovery and validation cohorts: increased levels of CSF NfL, plasma NfL, and CSF TDP-43 in ALS compared with control groups; shorter survival associated with higher levels of CSF and plasma NfL. When the CSF NfL and CSF TDP-43 levels were combined, the areas under the ROC curves (AUC) were slightly improved relative to AUCs for each biomarker alone. Interpretation CSF and plasma NfL may not only serve as diagnostic biomarkers but also provide a measure of disease progression. CSF TDP-43 is also useful as a diagnostic biomarker of ALS, but has no prognostic value. The combined use of CSF NfL and CSF TDP-43 may be a useful biomarker for the diagnosis of ALS.

27 citations

01 Dec 2019
TL;DR: To determine the diagnostic and prognostic significance of neurofilament light chain (NfL), TAR DNA‐binding protein 43 (TDP‐43), and total tau (t‐tau) in cerebrospinal fluid and plasma of patients with amyotrophic lateral sclerosis and to investigate whether the combined use of those biomarker candidates can improve their diagnostic performance.
Abstract: Objective To determine the diagnostic and prognostic significance of neurofilament light chain (NfL), TAR DNA-binding protein 43 (TDP-43), and total tau (t-tau) in cerebrospinal fluid (CSF) and plasma of patients with amyotrophic lateral sclerosis (ALS) and to investigate whether the combined use of those biomarker candidates can improve their diagnostic performance. Methods This was a single-center, prospective, longitudinal study. CSF and plasma samples were collected at the time of enrollment from a discovery cohort of 29 patients with ALS and 29 age-matched controls without neurodegenerative disease. In a validation cohort, there were 46 patients with ALS, and 46 control (not age-matched) patients with motor weakness resulting from neuromuscular diseases. NfL, TDP-43, and t-tau levels in CSF and plasma were measured using ultrasensitive single molecule assay (Simoa) technology. Results The following findings were reproducibly observed among the discovery and validation cohorts: increased levels of CSF NfL, plasma NfL, and CSF TDP-43 in ALS compared with control groups; shorter survival associated with higher levels of CSF and plasma NfL. When the CSF NfL and CSF TDP-43 levels were combined, the areas under the ROC curves (AUC) were slightly improved relative to AUCs for each biomarker alone. Interpretation CSF and plasma NfL may not only serve as diagnostic biomarkers but also provide a measure of disease progression. CSF TDP-43 is also useful as a diagnostic biomarker of ALS, but has no prognostic value. The combined use of CSF NfL and CSF TDP-43 may be a useful biomarker for the diagnosis of ALS.

17 citations

Journal ArticleDOI
TL;DR: In this paper, the characteristics of the motor unit (MU) firing rate in Charcot-Marie-Tooth disease type 1A (CMT1A) patients and its longitudinal change using high-density surface-EMG and MU decomposition analysis were investigated.

9 citations

Journal ArticleDOI
29 Nov 2021-PLOS ONE
TL;DR: In this article, the diagnostic and prognostic performance of neurofilament light chain (NfL), TAR DNA-binding protein 43 (TDP-43), and total tau (t-tau) in cerebrospinal fluid (CSF) and plasma as ALS biomarkers was investigated by uni-and multivariate analyses.
Abstract: Objectives We previously reported the diagnostic and prognostic performance of neurofilament light chain (NfL), TAR DNA-binding protein 43 (TDP-43), and total tau (t-tau) in cerebrospinal fluid (CSF) and plasma as amyotrophic lateral sclerosis (ALS) biomarkers. The present study aimed to elucidate associations between clinical characteristics and the markers as well as mutual associations of the markers in ALS patients using the same dataset. Methods NfL, TDP-43, and t-tau levels in CSF and plasma in 75 ALS patients were analyzed. The associations between those markers and clinical details were investigated by uni- and multivariate analyses. Correlations between the markers were analyzed univariately. Results In multivariate analysis of CSF proteins, the disease progression rate (DPR) was positively correlated with NfL (β: 0.51, p = 0.007) and t-tau (β: 0.37, p = 0.03). Plasma NfL was correlated with age (β: 0.53, p = 0.005) and diagnostic grade (β: -0.42, p = 0.02) in multivariate analysis. Plasma TDP-43 was correlated negatively with split hand index (β: -0.48, p = 0.04) and positively with % vital capacity (β: 0.64, p = 0.03) in multivariate analysis. Regarding mutual biomarker analysis, a negative correlation between CSF-NfL and TDP-43 was identified (r: -0.36, p = 0.002). Conclusions Elevated NfL and t-tau levels in CSF may be biomarkers to predict rapid DPR from onset to sample collection. The negative relationship between CSF NfL and TDP-43 suggests that elevation of CSF TDP-43 in ALS is not a simple consequence of its release into CSF during neurodegeneration. The negative correlation between plasma TDP-43 and split hand index may support the pathophysiological association between plasma TDP-43 and ALS.

8 citations

Journal ArticleDOI
TL;DR: This study aimed to elucidate the longitudinal changes in nerve ultrasound parameters of adult Charcot–Marie–Tooth disease type 1A (CMT1A) patients.
Abstract: BACKGROUND This study aimed to elucidate the longitudinal changes in nerve ultrasound parameters of adult Charcot-Marie-Tooth disease type 1A (CMT1A) patients. METHODS Fifteen adult patients with CMT1A prospectively underwent nerve ultrasound and clinical assessment (CMT neuropathy score [CMTNS]) at baseline and 5 y later. Nerve cross-sectional area (CSA) and echogenicity were measured in the median and sural nerves. Changes in ultrasound parameters and CMTNS and correlation between changes of ultrasound parameters and CMTNS were analyzed. RESULTS Median and sural nerve CSAs did not change over 5 y, although CMTNS increased (P < .01). Nerve echogenicity in the sural nerve decreased over 5 y (P = .045). No correlations between changes in nerve ultrasound parameters and CMTNS were identified. CONCLUSIONS No longitudinal changes in nerve size was detected in adult CMT1A. Exploring the factors that determine nerve size in childhood CMT1A may lead to the development of treatments.

8 citations


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TL;DR: A systematic review and meta-analysis of studies conducted to evaluate the diagnostic utility of TDP-43 detected in the cerebrospinal fluid of patients with FTD-ALS spectrum disorder suggests promise for the use of CSF TDP -43 as a biomarker for ALS.
Abstract: Frontotemporal dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) are incurable, progressive and fatal neurodegenerative diseases with patients variably affected clinically by motor, behavior, and cognitive deficits. The accumulation of an RNA-binding protein, TDP-43, is the most significant pathological finding in approximately 95% of ALS cases and 50% of FTD cases, and discovery of this common pathological signature, together with an increasing understanding of the shared genetic basis of these disorders, has led to FTD and ALS being considered as part of a single disease continuum. Given the widespread aggregation and accumulation of TDP-43 in FTD-ALS spectrum disorder, TDP-43 may have potential as a biomarker in these diseases. We therefore conducted a systematic review and meta-analysis to evaluate the diagnostic utility of TDP-43 detected in the cerebrospinal fluid (CSF) of patients with FTD-ALS spectrum disorder. From seven studies, our results demonstrate that patients with ALS have a statistically significantly higher level of TDP-43 in CSF (effect size 0.64, 95% CI: 0.1–1.19, p = 0.02). These data suggest promise for the use of CSF TDP-43 as a biomarker for ALS.

58 citations

Journal ArticleDOI
TL;DR: This review covers mutations in DNAJB6, DNAJB2, αB-crystallin (CRYAB, HSPB5), HSPb1, HspB3, H SPB8, and BAG3, and discusses the molecular mechanisms by which they cause neuromuscular disease.
Abstract: Skeletal muscle and the nervous system depend on efficient protein quality control, and they express chaperones and cochaperones at high levels to maintain protein homeostasis. Mutations in many of these proteins cause neuromuscular diseases, myopathies, and hereditary motor and sensorimotor neuropathies. In this review, we cover mutations in DNAJB6, DNAJB2, αB-crystallin (CRYAB, HSPB5), HSPB1, HSPB3, HSPB8, and BAG3, and discuss the molecular mechanisms by which they cause neuromuscular disease. In addition, previously unpublished results are presented, showing downstream effects of BAG3 p.P209L on DNAJB6 turnover and localization.

55 citations

Journal ArticleDOI
TL;DR: There is much still to learn in the fluid biomarker field in FTD, but the creation of large multinational cohorts is facilitating better powered studies and will pave the way for larger omics studies, including proteomics, metabolomics and lipidomics, as well as investigations of multimodal biomarker combinations across fluids, brain imaging and other domains.
Abstract: The frontotemporal dementia (FTD) spectrum of neurodegenerative disorders includes a heterogeneous group of conditions. However, following on from a series of important molecular studies in the early 2000s, major advances have now been made in the understanding of the pathological and genetic underpinnings of the disease. In turn, alongside the development of novel methodologies for measuring proteins and other molecules in biological fluids, the last 10 years have seen a huge increase in biomarker studies within FTD. This recent past has focused on attempting to develop markers that will help differentiate FTD from other dementias (particularly Alzheimer’s disease (AD)), as well as from non-neurodegenerative conditions such as primary psychiatric disorders. While cerebrospinal fluid, and more recently blood, markers of AD have been successfully developed, specific markers identifying primary tauopathies or TDP-43 proteinopathies are still lacking. More focus at the moment has been on non-specific markers of neurodegeneration, and in particular, multiple studies of neurofilament light chain have highlighted its importance as a diagnostic, prognostic and staging marker of FTD. As clinical trials get under way in specific genetic forms of FTD, measures of progranulin and dipeptide repeat proteins in biofluids have become important potential measures of therapeutic response. However, understanding of whether drugs restore cellular function will also be important, and studies of key pathophysiological processes, including neuroinflammation, lysosomal function and synaptic health, are also now becoming more common. There is much still to learn in the fluid biomarker field in FTD, but the creation of large multinational cohorts is facilitating better powered studies and will pave the way for larger omics studies, including proteomics, metabolomics and lipidomics, as well as investigations of multimodal biomarker combinations across fluids, brain imaging and other domains. Here we provide an overview of the past, present and future of fluid biomarkers within the FTD field.

53 citations

Journal ArticleDOI
TL;DR: How NFs are impacting research and clinical management in ALS and other MNDs is discussed and how NFs may provide a useful tool for the early enrolment of patients in clinical trials is discussed.
Abstract: Motor neuron diseases (MNDs) are etiologically and biologically heterogeneous diseases. The pathobiology of motor neuron degeneration is still largely unknown, and no effective therapy is available. Heterogeneity and lack of specific disease biomarkers have been appointed as leading reasons for past clinical trial failure, and biomarker discovery is pivotal in today’s MND research agenda. In the last decade, neurofilaments (NFs) have emerged as promising biomarkers for the clinical assessment of neurodegeneration. NFs are scaffolding proteins with predominant structural functions contributing to the axonal cytoskeleton of myelinated axons. NFs are released in CSF and peripheral blood as a consequence of axonal degeneration, irrespective of the primary causal event. Due to the current availability of highly-sensitive automated technologies capable of precisely quantify proteins in biofluids in the femtomolar range, it is now possible to reliably measure NFs not only in CSF but also in blood. In this review, we will discuss how NFs are impacting research and clinical management in ALS and other MNDs. Besides contributing to the diagnosis at early stages by differentiating between MNDs with different clinical evolution and severity, NFs may provide a useful tool for the early enrolment of patients in clinical trials. Due to their stability across the disease, NFs convey prognostic information and, on a larger scale, help to stratify patients in homogenous groups. Shortcomings of NFs assessment in biofluids will also be discussed according to the available literature in the attempt to predict the most appropriate use of the biomarker in the MND clinic.

53 citations

Journal ArticleDOI
TL;DR: This Review highlights novel advancements in the involvement of small extracellular vesicles (EVs) as propagators of neuropathology, biomarkers and potential therapeutics in neurodegenerative diseases.
Abstract: Neurodegenerative diseases are characterised by the irreversible degeneration of neurons in the central or peripheral nervous systems. These include amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD) and prion diseases. Small extracellular vesicles (sEVs), a type of EV involved in cellular communication, have been well documented as propagating neurodegenerative diseases. These sEVs carry cargo, such as proteins and RNA, to recipient cells but are also capable of promoting protein misfolding, thus actively contributing to the progression of these diseases. sEV secretion is also a compensatory process for lysosomal dysfunction in the affected cells, despite inadvertently propagating disease to recipient cells. Despite this, sEV miRNAs have biomarker potential for the early diagnosis of these diseases, while stem cell-derived sEVs and those generated through exogenous assistance demonstrate the greatest therapeutic potential. This Review will highlight novel advancements in the involvement of sEVs as propagators of neuropathology, biomarkers and potential therapeutics in neurodegenerative diseases.

37 citations