Publications by authors named "Atsushi Iwata"

158 Publications

18F-THK5351 PET Can Identify Core Lesions in Different Amyotrophic Lateral Sclerosis Phenotypes.

Clin Nucl Med 2021 Jun 10. Epub 2021 Jun 10.

From the Department of Neurology, Tokyo Metropolitan Geriatric Hospital Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology Department of Diagnostic Radiology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan.

Abstract: Two patients with different amyotrophic lateral sclerosis (ALS) phenotypes underwent 18F-THK5351 PET to visualize lesions undergoing astrogliosis by measuring monoamine oxidase B activity. Patient 1 was a 57-year-old man with flail leg syndrome. Elevated uptake was observed inside the motor cortex, corresponding to the leg area in a cortical homunculus. Patient 2 was a 64-year-old man with ALS-frontotemporal dementia semantic variant. Elevated uptake was observed around the left anterior temporal lobe. Both core lesions were consistent with their respective neurological features. Hence, 18F-THK5351 PET is a useful technique to assess ALS pathophysiology by visualizing the core lesions.
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http://dx.doi.org/10.1097/RLU.0000000000003755DOI Listing
June 2021

State-of-the-art of lumbar puncture and its place in the journey of patients with Alzheimer's disease.

Alzheimers Dement 2021 May 27. Epub 2021 May 27.

Eisai Inc., Neurology Business Group, Woodcliff Lake, New Jersey, USA.

Recent advances in developing disease-modifying therapies (DMT) for Alzheimer's disease (AD), and the recognition that AD pathophysiology emerges decades before clinical symptoms, necessitate a paradigm shift of health-care systems toward biomarker-guided early detection, diagnosis, and therapeutic decision-making. Appropriate incorporation of cerebrospinal fluid biomarker analysis in clinical practice is an essential step toward system readiness for accommodating the demand of AD diagnosis and proper use of DMTs-once they become available. However, the use of lumbar puncture (LP) in individuals with suspected neurodegenerative diseases such as AD is inconsistent, and the perception of its utility and safety differs considerably among medical specialties as well as among regions and countries. This review describes the state-of-the-art evidence concerning the safety profile of LP in older adults, discusses the risk factors for LP-associated adverse events, and provides recommendations and an outlook for optimized use and global implementation of LP in individuals with suspected AD.
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http://dx.doi.org/10.1002/alz.12372DOI Listing
May 2021

Predicting amyloid risk by machine learning algorithms based on the A4 screen data: Application to the Japanese Trial-Ready Cohort study.

Alzheimers Dement (N Y) 2021 24;7(1):e12135. Epub 2021 Mar 24.

Department of Neuropathology Graduate School of Medicine The University of Tokyo Tokyo Japan.

Background: Selecting cognitively normal elderly individuals with higher risk of brain amyloid deposition is critical to the success of prevention trials for Alzheimer's disease (AD).

Methods: Based on the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease study data, we built machine-learning models and applied them to our ongoing Japanese Trial-Ready Cohort (J-TRC) webstudy participants registered within the first 9 months ( = 3081) of launch to predict standard uptake value ratio (SUVr) of amyloid positron emission tomography.

Results: Age, family history, online Cognitive Function Instrument and CogState scores were important predictors. In a subgroup of J-TRC webstudy participants with known amyloid status ( = 37), the predicted SUVr corresponded well with the self-reported amyloid test results (area under the curve = 0.806 [0.619-0.992]).

Discussion: Our algorithms may be usable for automatic prioritization of candidate participants with higher amyloid risks to be preferentially recruited from the J-TRC webstudy to in-person study, maximizing efficiency for the identification of preclinical AD participants.
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http://dx.doi.org/10.1002/trc2.12135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988864PMC
March 2021

Autocorrelation-based method to identify disordered rhythm in Parkinson's disease tasks: A novel approach applicable to multimodal devices.

PLoS One 2020 8;15(10):e0238486. Epub 2020 Oct 8.

Department of Neurology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Objective: We aim to propose a novel method of evaluating the degree of rhythmic irregularity during repetitive tasks in Parkinson's disease (PD) by using autocorrelation to extract serial perturbation in the periodicity of body part movements as recorded by objective devices.

Methods: We used publicly distributed sequential joint movement data recorded during a leg agility task or pronation-supination task. The sequences of body part trajectory were processed to extract their short-time autocorrelation (STACF) matrices; the sequences of single task conducted by participants were then divided into two clusters according to their similarity in terms of their STACF representation. The Unified Parkinson's Disease Rating Scale sub-score rated for each task was compared with cluster membership to obtain the area under the curve (AUC) to evaluate the discrimination performance of the clustering. We compared the AUC with those obtained from the clustering of the raw sequence or short-time Fourier transform (STFT).

Results: In classifying the pose estimator-based trajectory data of the knee during the leg agility task, the AUC was the highest when the STACF sequence was used for clustering instead of other types of sequences with up to 0.815, being comparable to the results reported in the original analysis of the data using an approach different from ours. In addition, in classifying another dataset of accelerometer-based trajectory data of the wrist during a pronation-supination task, the AUC was again highest up to 0.785 when clustering was performed using the STACF rather than other types of sequence.

Conclusion: Our autocorrelation-based method achieved a fair performance in detecting sequences with irregular rhythm, suggesting that it might be used as another evaluation strategy that is potentially widely applicable to qualify the disordered rhythm of PD regardless of the kinds of task or the modality of devices, although further refinement is needed.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238486PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544077PMC
November 2020

CMOS Gaussian Monocycle Pulse Transceiver for Radar-Based Microwave Imaging.

IEEE Trans Biomed Circuits Syst 2020 12 31;14(6):1333-1345. Epub 2020 Dec 31.

A single-chip Gaussian monocycle pulse (GMP) transceiver was developed for radar-based microwave imaging by the use of 65-nm complementary metal oxide semiconductor (CMOS) technology. A transmitter (TX) generates GMP signals, whose pulse widths and -3 dB bandwidths are 192 ps and 5.9 GHz, respectively. A 102.4 GS/s equivalent time sampling receiver (RX) performs the minimum jitter, input referred noise, signal-to-nose-ratio (SNR), signal-to-noise and distortion ratio (SNDR) effective number of bits (ENOB) of 0.58 ps, 0.24 mVrms, 28.4 dB, 26.6 dB and 4.1 bits, respectively. The SNR for the bandwidth of 3.6 GHz is 36.3 dB. The power dissipations of transmitter and receiver circuits are 19.79 mW and 48.87 mW, respectively. The GMP transceiver module can differentiate two phantom targets with the size of 1 cm and the spacing of 1 cm by confocal imaging.
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http://dx.doi.org/10.1109/TBCAS.2020.3029282DOI Listing
December 2020

Clinical efficacy of haematopoietic stem cell transplantation for adult adrenoleukodystrophy.

Brain Commun 2020 14;2(1):fcz048. Epub 2020 Jan 14.

Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

Accumulated experience supports the efficacy of allogenic haematopoietic stem cell transplantation in arresting the progression of childhood-onset cerebral form of adrenoleukodystrophy in early stages. For adulthood-onset cerebral form of adrenoleukodystrophy, however, there have been only a few reports on haematopoietic stem cell transplantation and the clinical efficacy and safety of that for adulthood-onset cerebral form of adrenoleukodystrophy remain to be established. To evaluate the clinical efficacy and safety of haematopoietic stem cell transplantation, we conducted haematopoietic stem cell transplantation on 12 patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy in a single-institution-based prospective study. Through careful prospective follow-up of 45 male adrenoleukodystrophy patients, we aimed to enrol patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy at early stages. Indications for haematopoietic stem cell transplantation included cerebral form of adrenoleukodystrophy or cerebello-brainstem form of adrenoleukodystrophy with Loes scores up to 13, the presence of progressively enlarging white matter lesions and/or lesions with gadolinium enhancement on brain MRI. Clinical outcomes of haematopoietic stem cell transplantation were evaluated by the survival rate as well as by serial evaluation of clinical rating scale scores and neurological and MRI findings. Clinical courses of eight patients who did not undergo haematopoietic stem cell transplantation were also evaluated for comparison of the survival rate. All the patients who underwent haematopoietic stem cell transplantation survived to date with a median follow-up period of 28.6 months (4.2-125.3 months) without fatality. Neurological findings attributable to cerebral/cerebellar/brainstem lesions became stable or partially improved in all the patients. Gadolinium-enhanced brain lesions disappeared or became obscure within 3.5 months and the white matter lesions of MRI became stable or small. The median Loes scores before haematopoietic stem cell transplantation and at the last follow-up visit were 6.0 and 5.25, respectively. Of the eight patients who did not undergo haematopoietic stem cell transplantation, six patients died 69.1 months (median period; range 16.0-104.1 months) after the onset of the cerebral/cerebellar/brainstem lesions, confirming that the survival probability was significantly higher in patients with haematopoietic stem cell transplantation compared with that in patients without haematopoietic stem cell transplantation ( = 0.0089). The present study showed that haematopoietic stem cell transplantation was conducted safely and arrested the inflammatory demyelination in all the patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy when haematopoietic stem cell transplantation was conducted in the early stages. Further studies are warranted to optimize the procedures of haematopoietic stem cell transplantation for adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy.
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http://dx.doi.org/10.1093/braincomms/fcz048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425345PMC
January 2020

Clinical Characteristics of Neuronal Intranuclear Inclusion Disease-Related Retinopathy With CGG Repeat Expansions in the NOTCH2NLC Gene.

Invest Ophthalmol Vis Sci 2020 09;61(11):27

Department of Ophthalmology, The University of Tokyo, Tokyo, Japan.

Purpose: To report the ocular characteristics of neuronal intranuclear inclusion disease (NIID)-related retinopathy with expansion of the CGG repeats in the NOTCH2NLC gene.

Methods: Seven patients from six families (aged 66-81 years) diagnosed with adult-onset NIID were studied. Ophthalmologic examinations, including the best-corrected visual acuity (BCVA), Goldmann perimetry, fundus photography, fundus autofluorescence (FAF) imaging, optical coherence tomography (OCT), and full-field electroretinography (ERGs), were performed. The expansion of the CGG repeats in the NOTCH2NLC gene was determined.

Results: All patients had an expansion of the CGG repeats (length approximately from 330-520 bp) in the NOTCH2NLC gene. The most common symptoms of the five symptomatic cases were reduced BCVA and night blindness. The other two cases did not have any ocular symptoms. The decimal BCVA varied from 0.15 to 1.2. Goldmann perimetry was constricted in all four cases tested; physiological blind spot was enlarged in two of the cases. The FAF images showed an absence of autofluorescence (AF) around the optic disc in all cases and also showed mild hypo-AF or extinguished AF in the midperiphery. In all cases, the OCT images showed an absence of the ellipsoid zone of the photoreceptors in the peripapillary region, and hyperreflective dots were also present between the retinal ganglion cell layer and outer nuclear layer. The macular region was involved in the late stage of the retinopathy. The full-field ERGs showed rod-cone dysfunction.

Conclusions: Patients with adult-onset NIID with CGG repeats expansions in the NOTCH2NLC gene had similar ophthalmologic features, including rod-cone dysfunction with progressive retinal degeneration in the peripapillary and midperipheral regions. The primary site is most likely the photoreceptors. Because the ocular symptoms are often overlooked due to dementia and occasionally precede the onset of dementia, detailed ophthalmological examinations are important for the early diagnosis of NIID-related retinopathy.
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http://dx.doi.org/10.1167/iovs.61.11.27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500143PMC
September 2020

Differences in lesion characteristics and patient background associated with the medium-term clinical outcomes of bare-metal and first-, second- and third-generation drug-eluting stents.

Heart Vessels 2021 Feb 11;36(2):211-222. Epub 2020 Sep 11.

Department of Cardiology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.

We investigated the lesion characteristics and patient background factors associated with the medium-term incidence of major adverse cardiac events (MACEs) for bare-metal stents (BMS) and 1st-, 2nd- and 3rd-generation drug-eluting stents (DES) using the PCI-Registry (FU-Registry). Between January 2003 and March 2016, 2967 cases/3508 lesions for which percutaneous coronary intervention was performed at Fukuoka University Hospital and related facilities were enrolled. Patients were divided into BMS and 1st-, 2nd- and 3rd-generation drug-eluting stent (DES) groups. The incidence of MACEs in the BMS group (26.2%) was significantly higher than those in the 1st, 2nd and 3rd DES groups (18.0%, 12.5%, and 11.0%, respectively). The incidence of MACEs in the BMS group was strongly associated with insulin use, hemodialysis, low high-density lipoprotein cholesterol, stent minimum lesion diameter, stent length, severe calcification and a small vessel diameter of less than 2.5 mm. Some of these factors showed no association with MACEs among the drug-elution groups, and only hemodialysis, arteriosclerosis obliterans and severe calcification showed a strong correlation in the 2nd DES group. In the 3rd DES group, none of the factors considered were associated with MACEs. In conclusion, in stent implantation, the number of factors associated with MACEs has gradually decreased as the stent generation increased.
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http://dx.doi.org/10.1007/s00380-020-01692-zDOI Listing
February 2021

Attempt to Predict A/T/N-Based Alzheimer's Disease Cerebrospinal Fluid Biomarkers Using a Peripheral Blood DNA Methylation Clock.

J Alzheimers Dis Rep 2020 Jul 23;4(1):287-296. Epub 2020 Jul 23.

Department of Neurology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Background: Although aging is the strongest risk factor for the development of Alzheimer's disease (AD), it remains uncertain if the blood DNA methylation clock, which reflects the effect of biological aging on DNA methylation (DNAme) status of blood cells, may be used as a surrogate biomarker for AD pathology in the central nervous system (CNS).

Objective: We aimed to develop a practical model to predict for A/T/N-based AD biomarkers as the prediction targets using the aging acceleration of blood cells.

Methods: We obtained data of North American ADNI study participants ( = 317) whose blood DNA methylation microarray (Illumina HumanMethylation EPIC Beadchips) and cerebrospinal fluid (CSF) AD biomarkers (A, t-tau, and p-tau) were recorded simultaneously. Methylation clock was calculated to conduct machine learning, in order to predict binary statuses (+ or -) for A (corresponding to the lowered CSF A), T (the elevated CSF p-tau), or N (the elevated CSF t-tau). The predictive performance of the models was evaluated by area under curve (AUC) in the test subset within ADNI.

Results: Among the 317 included samples, 194 (61.2%) were A+, 247 (77.9%) were T+, and 104 (32.8%) were N+. The degree of blood aging acceleration showed weak positive correlation with the CSF A levels, even after adjustment with genotype and other covariates. However, the contribution of aging acceleration to improve the predictive performance of models was not significant for any of A+, T+, or N+.

Conclusion: Our exploratory attempts could not demonstrate the substantial utility of the peripheral blood cells' methylation clock as a predictor for A/T/N-based CSF biomarkers of AD, and further additional work should be conducted to determine whether the blood DNAme signatures including methylation clock have substantial utility in detecting underlying amyloid, tau or neurodegeneration pathology of AD.
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http://dx.doi.org/10.3233/ADR-200205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458568PMC
July 2020

Associations between the psoas major muscle index and the presence and severity of coronary artery disease.

Medicine (Baltimore) 2020 Jul;99(28):e21086

Department of Cardiology, Fukuoka University School of Medicine.

The associations between the presence and severity of coronary artery disease (CAD) and measurements of the psoas major muscle (PMM) as assessed by multidetector row coronary computed tomography angiography (MDCT) are not known.We enrolled 793 patients who were clinically suspected to have CAD or had at least one cardiac risk factor and had undergone MDCT. The number of significantly stenosed coronary vessels (VD) and measurements of the PMM index (PMMI) were determined using MDCT.PMMI in the CAD group was significantly lower than that in the non-CAD group in males, but not females. In addition, the levels of PMMI tended to increase as the number of VD decreased in males. When male patients were divided into 2 groups according to median value of age, that is, relatively younger (53.4 ± 9.2 years) and older (72.6 ± 5.7 years) groups, the presence of CAD was independently associated with PMMI in the younger group by a multiple logistic regression analysis. The cut-off level of PMMI that gave the greatest sensitivity and specificity for the diagnosis of CAD in younger males was 8.3 cm/m (sensitivity 0.441, specificity 0.752).In conclusion, PMMI may be an imaging marker for evaluating the presence and/or severity of CAD in males, and particularly in the non-elderly.
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http://dx.doi.org/10.1097/MD.0000000000021086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360204PMC
July 2020

[Factors Influencing Brain Interstitial Fluid Concentrations of Amyloid β and Tau].

Brain Nerve 2020 May;72(5):525-531

Department of Neurology, Graduate School of Medicine, The University of Tokyo.

In patients with Alzheimer's disease, the brain interstitial space is an important place where amyloid-β oligomers and aggregates exist. Although tau aggregates are observed inside neurons, extracellular brain interstitial fluid tau has drawn attention because of increasing understanding of cell-to-cell propagation of tau aggregation. In this review, we summarize our current understanding of factors influencing brain interstitial fluid concentrations of amyloid-β and tau, mainly focusing on known epidemiological risk factors for Alzheimer's disease.
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http://dx.doi.org/10.11477/mf.1416201557DOI Listing
May 2020

Neuropsychiatric adverse events of chloroquine: a real-world pharmacovigilance study using the FDA Adverse Event Reporting System (FAERS) database.

Biosci Trends 2020 May 22;14(2):139-143. Epub 2020 Apr 22.

Department of Neurology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

In late March and early April 2020, the antimalarial drug, chloroquine, has been approved as an emergency treatment for the coronavirus disease 2019 (COVID-19) in the United States and in Europe. Although infrequent, neuropsychiatric symptoms have been reported in patients who received chloroquine for the treatment of malaria or autoimmune diseases. In this study, aiming to investigate these adverse events (AEs) using a large self-reporting database, we conducted a disproportionality analysis for the detection of neuropsychiatric AE signals associated with the use of chloroquine (or hydroxychloroquine), reported to FDA Adverse Event Reporting System (FAERS) database between the fourth quarter of 2012 and the fourth quarter of 2019. We included 2,389,474 AE cases, among which 520 cases developed neuropsychiatric AE following the use of chloroquine. Adjusted reporting odds ratio (ROR) for the development of each of the neuropsychiatric AEs following the use of chloroquine was calculated using a multilevel model: exposure to chloroquine was associated with a statistically significant high reporting of amnesia, delirium, hallucinations, depression, and loss of consciousness, (lower 95% confidence interval of the adjusted ROR > 1), although the degree of increase in their ROR was limited. There was no statistically significant high reporting of any other neuropsychiatric AE, including suicide, psychosis, confusion, and agitation. Current pharmacovigilance study results did not suggest any potential link between the use of chloroquine and an increased risk of suicide, psychosis, confusion, and agitation, which would be informative during the emergency use of chloroquine for the treatment of COVID-19.
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http://dx.doi.org/10.5582/bst.2020.03082DOI Listing
May 2020

Impact of visit-to-visit variability in blood pressure on coronary plaque as assessed by integrated backscatter intravascular ultrasound.

Clin Exp Hypertens 2020 Oct 21;42(7):608-613. Epub 2020 Apr 21.

Department of Cardiology, Fukuoka University School of Medicine , Fukuoka, Japan.

Introduction: Visit-to-visit variability (VVV) in blood pressure (BP) has been reported to be a strong predictor of cardiovascular disease. However, the association between VVV in BP and coronary plaque composition has not been fully elucidated.

Methods: One hundred-two consecutive patients with coronary artery disease (CAD) who underwent percutaneous coronary intervention (PCI) using integrated backscatter (IB) intravascular ultrasound (IVUS), and who had at least six clinic visits a year before PCI were included. We measured systolic and diastolic BP (SBP and DBP) at each visit and determined VVV in BP expressed as the standard deviation of the average BP. Grayscale and IB IVUS examinations were performed for the culprit lesion of a coronary artery just before PCI.

Results: There were no significant associations between the average SBP or DBP and various IVUS parameters. However, VVV in SBP was positively correlated with both the percentage (%) of atheroma volume (β = 0.23,  = .02) and % lipid volume (β = 0.53,  < .0001). VVV in DBP was positively correlated with % lipid volume (β = 0.24,  = .01), while there was no significant correlation between VVV in DBP and % atheroma volume. A  multivariable linear regression analysis showed that VVV in SBP was independently associated with % atheroma volume ( = .04) and % lipid volume ( < .001).

Conclusions: Larger VVV in SBP was significantly associated with an increased plaque burden and lipid composition at the culprit lesion of a coronary artery in CAD patients. The improvement of VVV in SBP may contribute to the regression and stabilization of coronary plaques.
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http://dx.doi.org/10.1080/10641963.2020.1756315DOI Listing
October 2020

Effect of apolipoprotein E ε4 allele on the progression of cognitive decline in the early stage of Alzheimer's disease.

Alzheimers Dement (N Y) 2020 20;6(1):e12007. Epub 2020 Mar 20.

Unit for Early and Exploratory Clinical Development The University of Tokyo Hospital Tokyo Japan.

Introduction: Possession of the apolipoprotein E () ε4 allele advances amyloid β (Aβ) deposition and symptomatic onset of Alzheimer's disease (AD), whereas its effect on the rate of cognitive decline remained controversial. We examined the effects of ε4 allele on cognition in biomarker-confirmed late mild cognitive impairment (LMCI) and mild AD subjects in the Japanese Alzheimer's Disease Neuroimaging Initiative (J-ADNI) and North American ADNI (NA-ADNI).

Methods: The "early AD" (ie, combined LMCI and mild AD) cohort of 649 subjects from J-ADNI and NA-ADNI were selected based on positivity of Aβ confirmed by amyloid positron emission tomography (PET) or cerebrospinal fluid testing. The rates of cognitive decline in the Mini Mental State Examination (MMSE), the Clinical Dementia Rating Sum of Boxes (CDR-SB), and the Alzheimer's Disease Assessment Scale-cognitive subscale 13 (ADAS-Cog) from baseline were examined using mixed-effects model. The effect of ε4 on time to conversion to dementia was also analyzed in LMCI using the Kaplan-Meier estimator and log-rank test.

Results: The rates of cognitive decline were not significantly different between ε4 carriers and ε4 non-carriers in the total early AD cohort, which were affected neither by region nor by the number of ε4 alleles. In LMCI, ε4 carriers showed almost the same progression rates as ε4 non-carriers, except for a significantly faster decline in MMSE ( = .0282). Time to conversion to demenita was not significantly different between ε4 carriers and ε4 non-carriers. In ε4-positive mild AD, the rates of decline in MMSE ( = .003) and CDR-SB ( = .0071) were slower than those in ε4 non-carriers.

Discussion: The ε4 allele had little effect on the rates of cognitive decline in the overall biomarker-confirmed early AD, regardless of region and number of ε4 alleles, with a slight variability in different clinical stages, the ε4 allele being slightly accelerative in LMCI, while decelerative in mild AD.
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http://dx.doi.org/10.1002/trc2.12007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7087431PMC
March 2020

Neuron-specific analysis of histone modifications with post-mortem brains.

Sci Rep 2020 02 28;10(1):3767. Epub 2020 Feb 28.

Department of Neurology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Histone modifications govern chromatin structures and regulate gene expression to orchestrate cellular functions in the central nervous system, where neuronal cells are postmitotic and developmentally inactive, the functional and age-dependent changes also accumulate in the epigenetic states. Because the brain is composed of several types of cells, such as the neurons, glial cells, and vascular cells, the analysis of histone modifications using bulk brain tissue might obscure alterations specific to neuronal cells. Furthermore, among the various epigenetic traits, analysis of the genome-wide distribution of DNA methylation in the bulk brain is predominantly a reflection of DNA methylation of the non-neuronal cells, which may be a potential caveat of previous studies on neurodegenerative diseases using bulk brains. In this study, we established a method of neuron-specific ChIP-seq assay, which allows for the analysis of genome-wide distribution of histone modifications specifically in the neuronal cells derived from post-mortem brains. We successfully enriched neuronal information with high reproducibility and high signal-to-noise ratio. Our method will further facilitate the understanding of neurodegeneration.
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http://dx.doi.org/10.1038/s41598-020-60775-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048733PMC
February 2020

YAP-dependent necrosis occurs in early stages of Alzheimer's disease and regulates mouse model pathology.

Nat Commun 2020 01 24;11(1):507. Epub 2020 Jan 24.

Department of Neuropathology, Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.

The timing and characteristics of neuronal death in Alzheimer's disease (AD) remain largely unknown. Here we examine AD mouse models with an original marker, myristoylated alanine-rich C-kinase substrate phosphorylated at serine 46 (pSer46-MARCKS), and reveal an increase of neuronal necrosis during pre-symptomatic phase and a subsequent decrease during symptomatic phase. Postmortem brains of mild cognitive impairment (MCI) rather than symptomatic AD patients reveal a remarkable increase of necrosis. In vivo imaging reveals instability of endoplasmic reticulum (ER) in mouse AD models and genome-edited human AD iPS cell-derived neurons. The level of nuclear Yes-associated protein (YAP) is remarkably decreased in such neurons under AD pathology due to the sequestration into cytoplasmic amyloid beta (Aβ) aggregates, supporting the feature of YAP-dependent necrosis. Suppression of early-stage neuronal death by AAV-YAPdeltaC reduces the later-stage extracellular Aβ burden and cognitive impairment, suggesting that preclinical/prodromal YAP-dependent neuronal necrosis represents a target for AD therapeutics.
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http://dx.doi.org/10.1038/s41467-020-14353-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981281PMC
January 2020

Colocalization of BRCA1 with Tau Aggregates in Human Tauopathies.

Brain Sci 2019 Dec 20;10(1). Epub 2019 Dec 20.

Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

The mechanism of neuronal dysfunction via tau aggregation in tauopathy patients is controversial. In Alzheimer's disease (AD), we previously reported mislocalization of the DNA repair nuclear protein BRCA1, its coaggregation with tau, and the possible importance of the subsequent DNA repair dysfunction. However, whether this dysfunction in BRCA1 also occurs in other tauopathies is unknown. The aim of this study was to evaluate whether BRCA1 colocalizes with tau aggregates in the cytoplasm in the brains of the patients with tauopathy. We evaluated four AD, two Pick's disease (PiD), three progressive supranuclear palsy (PSP), three corticobasal degeneration (CBD), four normal control, and four disease control autopsy brains. Immunohistochemistry was performed using antibodies against BRCA1 and phosphorylated tau (AT8). Colocalization was confirmed by immunofluorescence double staining. Colocalization of BRCA1 with tau aggregates was observed in neurofibrillary tangles and neuropil threads in AD, pick bodies in PiD, and globose neurofibrillary tangles and glial coiled bodies in PSP. However, only partial colocalization was observed in tuft-shaped astrocytes in PSP, and no colocalization was observed in CBD. Mislocalization of BRCA1 was not observed in disease controls. BRCA1 was mislocalized to the cytoplasm and colocalized with tau aggregates in not only AD but also in PiD and PSP. Mislocalization of BRCA1 by tau aggregates may be involved in the pathogenesis of PiD and PSP.
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http://dx.doi.org/10.3390/brainsci10010007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016802PMC
December 2019

Subtype-Dependent Reporting of Stroke With SGLT2 Inhibitors: Implications From a Japanese Pharmacovigilance Study.

J Clin Pharmacol 2019 Dec 2. Epub 2019 Dec 2.

Department of Neurology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Volume depletion as an adverse events (AE) caused by sodium-glucose cotransporter-2 inhibitors (SGLT2i) because of their diuretic effect may raise the concern about the risk of lacunar stroke; however, an earlier meta-analysis reported no significant increase in the incidence of stroke without clearly distinguishing stroke subtypes. Here, aiming to investigate subtype-wise reporting of stroke potentially related to SGLT2i treatment, we conducted a disproportionality analysis using the Japanese Adverse Drug Event Report database, which contains approximately 500 000 cases recorded between April 2004 and March 2019 to detect stroke as AE signals associated with SGLT2i treatment by calculating the reporting odds ratio (ROR). As a result, we identified 532 stroke event reports with the use of SGLT2i. The SGLT2i showed varying degrees of significantly higher reporting (lower 95% ROR > 1) for all ischemic stroke (ROR, 12.7), thrombosis (ROR, 21.7), lacunar infarction (ROR, 48.9), and embolism (ROR, 2.51), but no significantly higher reporting for hemorrhagic stroke. Current pharmacovigilance results showed that the RORs for stroke following SGLT2i use differ greatly depending on the stroke subtypes. It suggests the need for an observational cohort study to be conducted to investigate the incidence of each stroke subtype as the effect of SGLT2i.
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http://dx.doi.org/10.1002/jcph.1561DOI Listing
December 2019

Rituximab improves not only back stiffness but also "stiff eyes" in stiff person syndrome: Implications for immune-mediated treatment.

J Neurol Sci 2020 Jan 2;408:116506. Epub 2019 Nov 2.

Department of Neurology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan; Department of Cell Physiology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, Japan.

Objective: Stiff person syndrome (SPS) is usually characterized by truncal muscle rigidity and episodic painful spasms, but it sometimes appears with ocular symptoms called "stiff eyes". We recorded saccade movements in an SPS patient manifesting with "stiff eyes" conditions with slow saccade velocity and evaluated the effect of immunotherapy including rituximab on saccade parameters.

Methods: We repeatedly conducted saccade eye recordings using video-based eye tracking system on a 42-year-old male SPS patient with slow saccade. The velocity and onset latency of visual guided saccades (VGS) were measured at each recording. Because VGS velocity is affected by saccade amplitude, estimated peak velocity (Vmax) was also calculated by taking the relationship between the velocity and the amplitude of saccade into account.

Results: The mean VGS velocity improved significantly after two courses of rituximab administration compared with its lowest value. The estimated Vmax decreased as the clinical manifestations worsened, but it increased after rituximab administration. Other neurological symptoms in this patient such as muscle rigidity and gait instability also improved after the treatment.

Conclusion: Slow saccade in a "stiff eyes" patient improved after rituximab administration. Our study also indicated that the saccade eye recording is useful for evaluating the clinical condition of SPS when it is complicated with ocular symptoms.
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http://dx.doi.org/10.1016/j.jns.2019.116506DOI Listing
January 2020

Quantifying normal and parkinsonian gait features from home movies: Practical application of a deep learning-based 2D pose estimator.

PLoS One 2019 14;14(11):e0223549. Epub 2019 Nov 14.

Department of Neurology, Graduate School of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan.

Objective: Gait movies recorded in daily clinical practice are usually not filmed with specific devices, which prevents neurologists benefitting from leveraging gait analysis technologies. Here we propose a novel unsupervised approach to quantifying gait features and to extract cadence from normal and parkinsonian gait movies recorded with a home video camera by applying OpenPose, a deep learning-based 2D-pose estimator that can obtain joint coordinates from pictures or videos recorded with a monocular camera.

Methods: Our proposed method consisted of two distinct phases: obtaining sequential gait features from movies by extracting body joint coordinates with OpenPose; and estimating cadence of periodic gait steps from the sequential gait features using the short-time pitch detection approach.

Results: The cadence estimation of gait in its coronal plane (frontally viewed gait) as is frequently filmed in the daily clinical setting was successfully conducted in normal gait movies using the short-time autocorrelation function (ST-ACF). In cases of parkinsonian gait with prominent freezing of gait and involuntary oscillations, using ACF-based statistical distance metrics, we quantified the periodicity of each gait sequence; this metric clearly corresponded with the subjects' baseline disease statuses.

Conclusion: The proposed method allows us to analyze gait movies that have been underutilized to date in a completely data-driven manner, and might broaden the range of movies for which gait analyses can be conducted.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223549PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855634PMC
March 2020

Treadmill Exercise Suppresses Cognitive Decline and Increases White Matter Oligodendrocyte Precursor Cells in a Mouse Model of Prolonged Cerebral Hypoperfusion.

Transl Stroke Res 2020 06 12;11(3):496-502. Epub 2019 Oct 12.

Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, MGH East 149-2401, Charlestown, MA, 02129, USA.

Clinical evidence suggests that patients with subcortical ischemic vascular dementia (SIVD) perform better at cognitive tests after exercise. However, the underlying mechanism for this effect is largely unknown. Here, we examined how treadmill exercise changes the cognitive function and white matter cellular pathology in a mouse model of SIVD. Prolonged cerebral hypoperfusion was induced in 2-month-old male C57BL/6J mice by bilateral common carotid artery stenosis. A week later, the mice were randomly divided into a group that received 6-week treadmill exercise and a sedentary group for observation. In multiple behavioral tests (Y-maze, novel object recognition, and Morris water maze tests), the treadmill exercise training was shown to ameliorate cognitive decline in the hypoperfused SIVD mice. In addition, immunohistological analyses confirmed that there was a larger population of oligodendrocyte precursor cells in the subventricular zone of exercised versus sedentary mice. Although further investigations are needed to confirm a causal link between these findings, our study establishes a model and cellular foundation for investigating the mechanisms through which exercise preserves cognitive function in SIVD.
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http://dx.doi.org/10.1007/s12975-019-00734-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298669PMC
June 2020

Hereditary Antithrombin Deficiency Presenting with Deep Venous Thrombosis During the Second Pregnancy.

Intern Med 2020 Jan 26;59(2):235-239. Epub 2019 Sep 26.

Department of Cardiology, Fukuoka University School of Medicine, Japan.

A 37-year-old woman developed deep venous thrombosis (DVT) of the left lower extremity at 8 weeks of gestation during her second pregnancy. There was no personal or family history of thrombosis. She received intravenous heparin, but heparin resistance was noted. The plasma antithrombin activity decreased to 45% in the acute phase, and it remained low postpartum. Her mother also had low plasma antithrombin activity (46%), and genetic testing revealed a heterozygous SERPINC1 mutation. Even without a family history of thrombosis, we should suspect hereditary antithrombin deficiency in patients with initial DVT and perform thorough investigation.
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http://dx.doi.org/10.2169/internalmedicine.3268-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008054PMC
January 2020

Neurological and related adverse events in immune checkpoint inhibitors: a pharmacovigilance study from the Japanese Adverse Drug Event Report database.

J Neurooncol 2019 Oct 26;145(1):1-9. Epub 2019 Aug 26.

Department of Neurology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Introduction: Immune checkpoint inhibitors (ICPI), a breakthrough immunotherapy for cancer, can cause serious neurological adverse events (AEs). We aimed to investigate the characteristics of the neurological and related AEs associated with ICPI treatment, using a large pharmacovigilance database from Japan.

Methods: We conducted disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database containing 566,698 patient cases recorded between April 2004 and March 2019, to detect neurological and related AE signals associated with ICPI treatment by calculating reporting odds ratio (ROR).

Results: Among 7604 cases with ICPI usage, we identified 583 cases (7.67%) with a significantly high reporting of neurological and related AEs (lower 95% of the ROR > 1), including myasthenia gravis (MG), inflammatory myositis, non-infectious encephalitis/myelitis, non-infectious meningitis, hypophysitis/hypopituitarism, and peripheral neuropathy including Guillain-Barre syndrome (GBS). Among the ICPI subtypes, when compared to nivolumab as a reference, number of hypophysitis, hypopituitarism, and meningitis reports from the use of ipilimumab and number of encephalitis/myelitis and meningitis reports from the use of anti-programmed cell death-ligand-1 (PD-L1) agents were significantly higher. Additionally, time to AE onset of symptoms post administration was short in meningitis (median 21 days), MG (median 28 days), myositis (median 28 days), and encephalitis/myelitis (median 32.5 days), while it was longer in peripheral neuropathy (median 42 days), hypophysitis (median 94 days), and hypopituitarism (median 112 days).

Conclusions: Our results showed characteristic features of neurological and related AEs associated with each ICPI subtype, reported in a large number of Japanese patients. This would help in prompt identification and treatment of neurological AEs associated with ICPI treatment.
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http://dx.doi.org/10.1007/s11060-019-03273-1DOI Listing
October 2019

Identification of prognostic factors to predict cognitive decline of patients with early Alzheimer's disease in the Japanese Alzheimer's Disease Neuroimaging Initiative study.

Alzheimers Dement (N Y) 2019 7;5:364-373. Epub 2019 Aug 7.

Eisai Co., Ltd., Koishikawa, Bunkyo-ku, Tokyo, Japan.

Introduction: The objective of this study was to determine the factors including neuropsychological test performances and cerebrospinal fluid (CSF) biomarkers which can predict disease progression of early Alzheimer's disease (AD) in a Japanese population.

Methods: The group classification on early AD population in both Japanese Alzheimer's Disease Neuroimaging Initiative (J-ADNI) and North American ADNI (NA-ADNI) was performed using the inclusion criteria including brain amyloid positivity on positron emission tomography or CSF. Participants with early AD from each cohort were stratified into two groups based on a cutoff 1.0 of Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) change at month 24 (m24): participants in "progress group" have CDR-SB change ≥ 1.0 and participants in "stable group" have CDR-SB change < 1.0. Then, we performed identification of prognostic factors from baseline items including neuropsychological scores (Assessment Scale-Cognitive Subscale[ADAS-cog 13], Mini-Mental State Examination (MMSE), CDR, FAQ, and Geriatric Depression Scale ), CSF markers (t-tau, p-tau, and beta-amyloid 1-42), vital signs (body weight, pulse rate, etc.,), by using two statistical approaches, Welch's t-test and simple linear regression by ordinary least squares. Comparisons between participants with J-ADNI and participants with NA-ADNI were also performed.

Results: Trends of CDR-SB changes were very similar between J-ADNI and NA-ADNI early AD population enrolled in this study. Baseline levels of CSF t-tau, p-tau, Mini-Mental State Examination, FAQ, and ADAS-cog13 were identified as prognostic factors in both J-ADNI and NA-ADNI. Based on a detailed subscale analysis on ADAS-cog13, four subscales (Q1: word recall, Q3: construction, Q4: delayed word recall, and Q8: word recognition) were identified as prognostic factors in both J-ADNI and NA-ADNI.

Discussion: Characterizing population with early AD can provide benefits for promoting efficiency in conducting AD clinical trials for disease-modifying treatments. Thus, implementing these prognostic factors into clinical trials may be potentially a good method to enrich participants with early AD who are suitable for evaluating treatment effects.
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http://dx.doi.org/10.1016/j.trci.2019.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698925PMC
August 2019

Visualizing modules of coordinated structural brain atrophy during the course of conversion to Alzheimer's disease by applying methodology from gene co-expression analysis.

Neuroimage Clin 2019 25;24:101957. Epub 2019 Jul 25.

Department of Neurology, Graduate School of Medicine, University of Tokyo, Japan. Electronic address:

Objective: We aimed to identify modularized structural atrophy of brain regions with a high degree of connectivity and its longitudinal changes associated with the progression of Alzheimer's disease (AD) using weighted gene co-expression network analysis (WGCNA), which is an unsupervised hierarchical clustering method originally used in genetic analysis.

Methods: We included participants with late mild cognitive impairment (MCI) at baseline from the Japanese Alzheimer's Disease Neuroimaging Initiative (J-ADNI) study. We imputed normalized and Z-transformed structural volume or cortical thickness data of 164 parcellated brain regions/structures based on the calculations of the FreeSurfer software. We applied the WGCNA to extract modules with highly interconnected structural atrophic patterns and examined the correlation between the identified modules and clinical AD progression.

Results: We included 204 participants from the baseline dataset, and performed a follow-up with 100 in the 36-month dataset of MCI cohort participants from the J-ADNI. In the univariate correlation or variable importance analysis, baseline atrophy in temporal lobe regions/structures significantly predicted clinical AD progression. In the WGCNA consensus analysis, co-atrophy modules associated with MCI conversion were first distributed in the temporal lobe and subsequently extended to adjacent parietal cortical regions in the following 36 months.

Conclusions: We identified coordinated modules of brain atrophy and demonstrated their longitudinal extension along with the clinical course of AD progression using WGCNA, which showed a good correspondence with previous pathological studies of the tau propagation theory. Our results suggest the potential applicability of this methodology, originating from genetic analyses, for the surrogate visualization of the underlying pathological progression in neurodegenerative diseases not limited to AD.
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http://dx.doi.org/10.1016/j.nicl.2019.101957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700430PMC
September 2020

Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease.

Nat Genet 2019 08 22;51(8):1222-1232. Epub 2019 Jul 22.

Department of Neurology, The University of Tokyo Hospital, Tokyo, Japan.

Noncoding repeat expansions cause various neuromuscular diseases, including myotonic dystrophies, fragile X tremor/ataxia syndrome, some spinocerebellar ataxias, amyotrophic lateral sclerosis and benign adult familial myoclonic epilepsies. Inspired by the striking similarities in the clinical and neuroimaging findings between neuronal intranuclear inclusion disease (NIID) and fragile X tremor/ataxia syndrome caused by noncoding CGG repeat expansions in FMR1, we directly searched for repeat expansion mutations and identified noncoding CGG repeat expansions in NBPF19 (NOTCH2NLC) as the causative mutations for NIID. Further prompted by the similarities in the clinical and neuroimaging findings with NIID, we identified similar noncoding CGG repeat expansions in two other diseases: oculopharyngeal myopathy with leukoencephalopathy and oculopharyngodistal myopathy, in LOC642361/NUTM2B-AS1 and LRP12, respectively. These findings expand our knowledge of the clinical spectra of diseases caused by expansions of the same repeat motif, and further highlight how directly searching for expanded repeats can help identify mutations underlying diseases.
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http://dx.doi.org/10.1038/s41588-019-0458-zDOI Listing
August 2019

Anomalous origin of the coronary artery coursing between the great vessels presenting with a cardiovascular event (J-CONOMALY Registry).

Eur Heart J Cardiovasc Imaging 2020 02;21(2):222-230

Department of Cardiovascular Medicine, Fukushima Medical University, 1 Hikariga-oka, Fukushima City 960-1295, Japan.

Aims: Anomalous origin of the coronary artery (AOCA) with an inter-arterial course (IAC) between the great vessels poses a risk for a life-threatening cardiovascular event. We assessed, in a registry-based study, the clinical features, treatment strategies, and prognoses of life-threatening cardiovascular events ensuant to AOCA.

Methods And Results: Included were 65 AOCA patients (48 men/17 women, aged 41 ± 23 years) from 40 clinical centres who had experienced sudden cardiac arrest (SCA) (n = 30), acute myocardial infarction (AMI) (n = 5), angina (n = 23), or syncope (n = 7). The anomalous vessel was the right coronary artery in 72% of patients and left coronary artery in 28%; the ostium was slit-like in 42%. Coronary luminal narrowing ≥75% was absent in patients with SCA or syncope (86% and 57%, respectively), but occlusion or narrowing was seen in those with AMI (100%) or angina (52%). Age ≤40 years, male sex, sporting activity, absence of prodromal symptoms, acutely angled (≤30°) take-off from the aorta, and absence of luminal narrowing of the IAC segment were associated with SCA in this patient group. Coronary vasospasm was inducible in 12 of 17 patients without coronary narrowing. Management included surgical revascularization (n = 26) percutaneous coronary intervention (n = 9), and medical treatment (n = 26). Four SCA patients died while hospitalized; no others died during the median 5.0 (range, 1.8-7.0)-year follow-up period.

Conclusions: In patients with AOCA, age ≤40 years, male sex, sporting activity, and an acute take-off angle appear to be risk factors for SCA. Appropriate management can be beneficial. Confirmation in a large-scale study is warranted.
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http://dx.doi.org/10.1093/ehjci/jez076DOI Listing
February 2020

Estimating acceleration time point of respiratory decline in ALS patients: A novel metric.

J Neurol Sci 2019 Aug 30;403:7-12. Epub 2019 May 30.

Department of Neurology, Graduate School of Medicine, University of Tokyo, Japan.

Objective: We aimed to derive and assess a novel metric for respiratory decline: the timing of acceleration of respiratory functional decline during the course of the disease in patients with amyotrophic lateral sclerosis (ALS).

Methods: In this single-center retrospective study, we reviewed consecutive definite/probable ALS patients, diagnosed and followed up at our hospital. We recorded serial slow vital capacity (percentage of predicted slow vital capacity; %VC) since diagnosis for all patients. These serial %VC data were fitted with logistic function of the time since diagnosis, and 'acceleration point' was calculated as the week in which the second derivative of the fitted logistic function had the minimum value.

Results: We included 62 patients with ALS, whose serial %VC data had been recorded for a median of 8 times over a median of 94.3 weeks. The calculated acceleration time-point was the time-point at which the %VC is becoming 0.789 times of maximum %VC, and had a strong association with the period since diagnosis to the administration of nutritional/respiratory support (p < 0.001). Bulbar-type ALS or lower Body Mass Index at diagnosis, both are well-known ALS prognostic factors, were also associated with more rapid arrival of the acceleration time-point.

Conclusions: We introduced the time-point of acceleration in the vital capacity decline during disease progression as a novel metric for ALS respiratory decline. Although we could not build a practically-available clinical model that directly predicts acceleration time-point due to the limited sample size, our metric may be used as one of the helpful indicators in the management during earlier disease course of ALS, such as to be careful for the potentially approaching acceleration time-point when the %VC is decreasing to approximately 0.789 times of initial %VC.
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http://dx.doi.org/10.1016/j.jns.2019.05.031DOI Listing
August 2019

Atherosclerotic Coronary Artery Disease in Patients With Cardiometabolic Syndrome.

Cardiol Res 2019 Apr 11;10(2):69-73. Epub 2019 Apr 11.

Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.

Major risk factors for cardiovascular disease (CVD) include aging, gender, smoking, family history and cardiometabolic syndrome. The relative residual risks for CVD after statin treatment for primary and secondary prevention have been reported by several large-scale randomized clinical trials. Statin treatment appears to prevent one-third of the onset and progression of CVD, but not the remaining two-thirds. There are three major problems regarding the residual risk of CVD: 1) Insufficient reduction of low-density lipoprotein cholesterol levels; 2) Low levels of high-density lipoprotein cholesterol and elevated triglyceride; and 3) Insufficient control of other risk factors (high blood pressure, obesity, metabolic syndrome, type 2 diabetes, etc.). Thus, a multifaceted preventive approach should be needed to prevent CVD after statin treatment.
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http://dx.doi.org/10.14740/cr857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469909PMC
April 2019

Functional evaluation of PDGFB-variants in idiopathic basal ganglia calcification, using patient-derived iPS cells.

Sci Rep 2019 04 5;9(1):5698. Epub 2019 Apr 5.

Laboratory of Medical Therapeutics and Molecular Therapeutics, Gifu Pharmaceutical University, Gifu, Japan.

Causative genes in patients with idiopathic basal ganglia calcification (IBGC) (also called primary familial brain calcification (PFBC)) have been reported in the past several years. In this study, we surveyed the clinical and neuroimaging data of 70 sporadic patients and 16 families (86 unrelated probands in total) in Japan, and studied variants of PDGFB gene in the patients. Variant analyses of PDGFB showed four novel pathogenic variants, namely, two splice site variants (c.160 + 2T > A and c.457-1G > T), one deletion variant (c.33_34delCT), and one insertion variant (c.342_343insG). Moreover, we developed iPS cells (iPSCs) from three patients with PDGFB variants (c.160 + 2T > A, c.457-1G > T, and c.33_34 delCT) and induced endothelial cells. Enzyme-linked immunoassay analysis showed that the levels of PDGF-BB, a homodimer of PDGF-B, in the blood sera of patients with PDGFB variants were significantly decreased to 34.0% of that of the control levels. Those in the culture media of the endothelial cells derived from iPSCs of patients also significantly decreased to 58.6% of the control levels. As the endothelial cells developed from iPSCs of the patients showed a phenotype of the disease, further studies using IBGC-specific iPSCs will give us more information on the pathophysiology and the therapy of IBGC in the future.
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http://dx.doi.org/10.1038/s41598-019-42115-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450963PMC
April 2019