Faculty Profiles - HASHIZUME Atsushi

Influence of oral contraceptive/low-dose estrogen progestin discontinuation on the incidence of alveolar osteitis after third molar extraction: a retrospective study at a single center Reviewed

Sato, K; Takenaka, K; Kouyama, N; Ishikawa-Matsumoto, Y; Wakayama, Y; Okazaki, M; Hashizume, A; Schedeit, C; Schaller, B; Hibi, H

NAGOYA JOURNAL OF MEDICAL SCIENCE Vol. 88 ( 1 ) page： 99 - 108 2026.2

Language：English Publishing type：Research paper (scientific journal) Publisher：Nagoya Journal of Medical Science

Oral contraceptive (OC)/low-dose estrogen progestin (LEP) affects both the coagulation and fibrinolytic systems and may cause alveolar osteitis (AO). However, whether OC/LEP discontinuation affects the incidence of AO has not been evaluated. The aim of this study was to investigate whether preoperative OC/LEP discontinuation influences the incidence of AO after wisdom tooth extraction in outpatients. A total of 130 women aged 18–47 years (median, 27 years) participated, and the total numbers of procedure days and teeth were 205 and 274, respectively. We compared the incidence of AOs between patients who discontinued OC/LEP before wisdom tooth extraction and those who did not. A total of 4/181 teeth (2.21%) in the discontinuation group and 7/93 (7.53%) in the continuation group exhibited AO, and Fisher’s exact test revealed a significant difference between the two groups (p=0.049). No serious adverse events, such as thrombosis, were observed. In conclusion, OC/LEP discontinuation was associated with a lower observed incidence of AO after third molar extraction.

DOI： 10.18999/nagjms.88.1.99

MRI-based analysis of facial and hypoglossal nerves in patients with spinal and bulbar muscular atrophy Reviewed

Increased HbA1c relative to actual glycemic control in patients treated with sodium-glucose cotransporter 2 inhibitors Reviewed Open Access

Mizutani, K; Uenishi, E; Onoue, T; Maeda, R; Suzuki, K; Handa, T; Kobayashi, T; Iwama, S; Miyata, T; Sugiyama, M; Hagiwara, D; Suga, H; Okazaki, M; Hashizume, A; Arima, H

JOURNAL OF DIABETES INVESTIGATION Vol. 17 ( 1 ) page： 34 - 41 2026.1

Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Diabetes Investigation

Aims/Introduction: Among patients with diabetes receiving sodium–glucose cotransporter 2 (SGLT2) inhibitors, HbA1c levels are higher than glycated albumin levels. This study therefore aimed to evaluate the discrepancy between HbA1c and glucose management indicator (GMI), an index of glucose management derived from continuous glucose monitoring, in this population. Materials and Methods: This multicenter retrospective cohort study included patients with diabetes in whom HbA1c and GMI were simultaneously measured at two Japanese institutions. Data were collected when HbA1c levels had stabilized for at least 6 months after the administration of an oral hypoglycemic agent. The primary outcome was the discrepancy between HbA1c and GMI among patients receiving SGLT2 inhibitors and those receiving other oral hypoglycemic agents. Inverse probability of treatment weighting (IPTW) was used to adjust for confounding factors. Results: In total, 136 patients were included; of these, 109 and 27 were included in the SGLT2 inhibitor group and control group, respectively. After IPTW adjustment, the discrepancy between HbA1c and GMI (HbA1c–GMI) was significantly higher in the SGLT2 inhibitor group than in the control group (β = 0.42; 95% confidence interval 0.14–0.70; P = 0.003). Conclusions: Patients receiving SGLT2 inhibitors may have increased HbA1c relative to their actual glycemic control.

DOI： 10.1111/jdi.70191

Mori, Y; Kawase, T; Yamada, S; Hashizume, A; Ito, D; Kondo, A; Obara, K; Yamamoto, M; Taoka, T; Katsuno, M

JOURNAL OF THE NEUROLOGICAL SCIENCES Vol. 480 2025.12

Bone Fragility and Fracture Characteristics in Patients With Spinal and Bulbar Muscular Atrophy. Reviewed International journal Open Access

Takahiro Kawase, Shinichiro Yamada, Yoshiyuki Kishimoto, Daisuke Ito, Shota Komori, Ayano Kondo, Madoka Iida, Itaru Kawashima, Yasuhiko Takegami, Atsushi Hashizume, Shiro Imagama, Masahisa Katsuno

European journal of neurology Vol. 32 ( 12 ) page： e70457 2025.12

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Spinal and bulbar muscular atrophy (SBMA) is a hereditary neuromuscular disorder linked to androgen receptor gene mutations, often associated with metabolic abnormalities. We aimed to investigate the incidence of fragility fractures and the underlying mechanisms in SBMA. METHODS: Consecutive genetically confirmed SBMA patients and healthy controls (HC) were enrolled. We surveyed fracture history and assessed motor function, bone metabolism markers, and bone mineral density (BMD) using dual-energy X-ray absorptiometry. Longitudinal BMD changes were also analyzed between SBMA patients and HC. RESULTS: A total of 109 SBMA patients and 21 HC were included. Fragility fractures in SBMA patients were mainly observed in cortical bone-dominant regions. Their lower limb BMD was significantly reduced (SBMA 1.10 g/cm, HC 1.19 g/cm; p < 0.05) and further decreased overtime. Despite low bone resorption markers, bone formation markers showed no difference between the groups, suggesting that SBMA patients exhibit characteristics of low turnover osteoporosis. Serum 25-hydroxyvitamin D levels were lower in SBMA patients than in HC (15.4 ng/mL vs. 19.4 ng/mL; p < 0.01). Longitudinal analysis revealed that SBMA patients had a higher incidence of fragility fractures than HC (log-rank test, p < 0.05), with the first fragility fracture occurring 10 years after the onset of muscle weakness. Low baseline BMD was a predictor of fragility fractures (adjusted OR = 0.32; 95% CI: 0.17-0.60; p < 0.05). CONCLUSIONS: SBMA patients have a high fragility fracture incidence, particularly in cortical bone, with a progressive BMD decrease. Low bone turnover and vitamin D deficiency are associated with these fractures.

DOI： 10.1111/ene.70457

Therapeutic impact of leuprorelin acetate on spinal and bulbar muscular atrophy: pre- and post-marketing observational study. Reviewed International journal

Atsushi Hashizume, Ryoichi Hanazawa, Shinichiro Yamada, Daisuke Ito, Yoshiyuki Kishimoto, Shota Komori, Takahiro Kawase, Madoka Iida, Ayano Kondo, Yu Mori, Kazuki Obara, Mitsuya Morita, Tomotaka Yamamoto, Hiroyuki Sato, Akihiro Hirakawa, Masahisa Katsuno

Journal of neurology Vol. 272 ( 12 ) page： 772 - 772 2025.11

Language：English Publishing type：Research paper (scientific journal)

Although leuprorelin acetate, a luteinizing hormone-releasing hormone agonist, has been approved based on short-term clinical trials conducted in Japan, its long-term efficacy on physical function remains unclear. We aimed to evaluate the long-term therapeutic efficacy of leuprorelin acetate using real-world clinical data through a self-controlled trend-shift analysis. The analysis included 91 genetically confirmed patients with spinal and bulbar muscular atrophy, with follow-up data collected before and after treatment initiation. The functional outcomes assessed included the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) and modified Norris scales, grip power, and serum creatinine levels. Leuprorelin acetate significantly slowed disease progression. For instance, the annual ALSFRS-R decline rate improved from approximately 0.5 points pre-treatment to 0.2 points post-treatment. The subgroup analysis supported the potential benefit of early intervention. These findings highlight the value of leveraging patient registries and post-marketing real-world data to evaluate treatment efficacy in slowly progressive diseases, such as SBMA, where traditional randomized controlled trials are often limited by insufficient statistical power to detect therapeutic efficacy. They also underscore the need for innovative methodologies to assess post-approval drug performance, paving the way for improved clinical outcomes for neurodegenerative diseases.

DOI： 10.1007/s00415-025-13509-y

Home-based Hybrid Assistive Limb Lumbar Type Telerehabilitation in Spinocerebellar Ataxias: A Nonrandomized Open-label Trial. Reviewed International journal

Yoshiyuki Kishimoto, Shinichiro Yamada, Atsushi Hashizume, Daisuke Ito, Shota Komori, Takahiro Kawase, Ayano Kondo, Yu Mori, Kazuki Obara, Munetaka Yamamoto, Yachiyo Kuwatsuka, Masahiko Ando, Tomokazu Abe, Yoshihiro Yasunaga, Masahisa Katsuno

Cerebellum (London, England) Vol. 24 ( 6 ) page： 173 - 173 2025.11

Language：English Publishing type：Research paper (scientific journal)

A hybrid assistive limb (HAL) can improve the motor performance of patients with various neurodegenerative diseases, but the efficacy of home-based rehabilitation using HAL for spinocerebellar ataxias (SCA) has yet to be elucidated. To evaluate the efficacy and safety of home-based telerehabilitation with lumbar type HAL in patients with SCA. In this non-randomized open-label single center trial, all participants underwent a 20-min home-based telerehabilitation program using the HAL lumbar type three times a week for 4 weeks. The primary outcome was the Timed Up and Go test (TUG), and secondary outcomes were the scale for the assessment and rating of ataxia (SARA), 10-m walk test, Berg Balance Scale (BBS), cerebellar cognitive affective/Schmahmann Syndrome Scale (CCAS-S), visual analogue scale, and clinical global impressions (CGI) scale. The assessments were conducted pre- and post-intervention and at 4 and 12 weeks after completion of the 4-week HAL rehabilitation. There was a non-significant mean change in TUG of - 1.3 s after the intervention (p = 0.051) but significant improvements in BBS (2.6 points; p = 0.011) and CCAS-S (3.7 points; p = 0.027). All participants completed the 4-week rehabilitation without any serious adverse events or dropout. Home-based telerehabilitation with HAL lumbar type is feasible and safe for patients with SCA. Despite its efficacy on TUG not being demonstrated, telerehabilitation improved balance and cognitive function in patients with SCA.

DOI： 10.1007/s12311-025-01926-8

Self-Organized Prediction-Classification- Superposition of Longitudinal Cognitive Decline in Alzheimer's Disease: An Application to Novel Clinical Research Methodology Reviewed

Utility of a newly created questionnaire on subtle motor symptoms in high-risk subjects with Parkinson's disease Reviewed Open Access

Tamakoshi, D; Hiraga, K; Fukushima, T; Uematsu, T; Tsuboi, T; Sato, M; Hattori, M; Satake, Y; Hashizume, A; Yamamoto, M; Shimizu, H; Wakai, M; Katsuno, M

JOURNAL OF PARKINSONS DISEASE Vol. 15 ( 6 ) page： 1086 - 1098 2025.9

Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Parkinson S Disease

BackgroundProdromes of Parkinson's disease (PD) include both motor and non-motor symptoms. Although questionnaires have been established for non-motor symptoms, no quantitative self-assessment tool has been developed to assess subtle motor symptoms during the prodromal stage.ObjectiveTo develop a self-administered questionnaire to assess subtle motor symptoms during the prodromal stage.MethodsWe created the Screening Questionnaire for Subtle Parkinsonism (SQSP). The SQSP and questionnaires on non-motor symptoms were collected from health checkup examinees. Individuals with ≥ 2 non-motor symptoms, including autonomic dysfunction, hyposmia, and REM sleep behavior disorder, were classified as high-risk, while those without these symptoms were low-risk. We also conducted comprehensive evaluations, including neurological examinations and imaging tests, on 30 patients with PD, 71 high-risk, and 24 low-risk subjects.ResultsAmong 1183 health checkup examinees, high-risk subjects had higher SQSP scores than low-risk (9 [4-15] vs. 3 [1-6]). Patients with PD had the highest SQSP scores, followed by high-risk subjects and then low-risk. SQSP scores correlated with MDS-UPDRS II and III scores and specific binding ratios of DaT-SPECT. High-risk subjects with abnormal DaT-SPECT had higher SQSP scores than those with normal imaging (9 [7-19] vs. 5.5 [2-10]). Although 26 of the 71 high-risk and 23 of the 24 low-risk subjects scored zero on the MDS-UPDRS II, most high-risk and half low-risk subjects had SQSP scores above zero.ConclusionsThe SQSP was deemed effective for assessing subtle motor symptoms during the prodromal stage of PD and identifying prodromal PD cases within the general population.

DOI： 10.1177/1877718X251361506

Sato, H; Hanazawa, R; Suzuki, K; Hashizume, A; Hirakawa, A

IEEE JOURNAL OF BIOMEDICAL AND HEALTH INFORMATICS Vol. 29 ( 8 ) page： 5922 - 5935 2025.8

Language：English Publishing type：Research paper (scientific journal) Publisher：IEEE Journal of Biomedical and Health Informatics

Progressive cognitive decline spanning across decades is characteristic of Alzheimer's disease (AD). Various predictive models have been designed to realize its early onset and study the long-term trajectories of cognitive test scores across populations of interest. Research efforts have been geared towards superimposing patients’ cognitive test scores with the long-term trajectory denoting gradual cognitive decline, while considering the heterogeneity of AD. Multiple trajectories representing cognitive assessment for the long-term have been developed based on various parameters, highlighting the importance of classifying several groups based on disease progression patterns. In this study, a novel method capable of self-organized prediction, classification, and the overlay of long-term cognitive trajectories based on short-term individual data was developed, based on statistical and differential equation modeling. Here, “self-organized” denotes a data-driven mechanism by which the prediction model adaptively configures its structure and parameters to classify individuals and estimate long-term trajectories. We validated the predictive accuracy of the proposed method on two cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Japanese ADNI. We also presented two practical illustrations of the simultaneous evaluation of risk factor associated with both the onset and the longitudinal progression of AD, and an innovative randomized controlled trial design for AD that standardizes the heterogeneity of patients enrolled in a clinical trial. These resources would improve the power of statistical hypothesis testing and help evaluate the therapeutic effect. The application of predicting the trajectory of longitudinal disease progression goes beyond AD, and is especially relevant for progressive and neurodegenerative disorders.

DOI： 10.1109/JBHI.2025.3546020

Longitudinal transitions in frailty and health-related quality of life investigated by a 5-year community study Reviewed

Diffuse but Non-homogeneous Brain Atrophy: Identification of Specific Brain Regions and Their Correlation with Clinical Severity in Rett Syndrome. Reviewed International journal Open Access

Hajime Narita, Jun Natsume, Takeshi Suzuki, Tadashi Shiohama, Masahiro Kawaguchi, Masaki Okazaki, Atsushi Hashizume, Shinji Naganawa, Yuji Ito, Hiroyuki Yamamoto, Tomohiko Nakata, Hiroyuki Kidokoro, Yoshiyuki Takahashi, Satoru Takahashi, Keita Tsujimura

Brain & development Vol. 47 ( 3 ) page： 104348 - 104348 2025.6

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Rett syndrome is a genetic neurodevelopmental disorder that predominantly affects girls. While microcephaly is a common feature, there is limited information on the detailed structural changes in the brain. This study aimed to identify regional brain volume abnormalities and explore the correlation between brain volume and clinical characteristics. METHODS: We compared the regional brain volumes of 20 female children with Rett syndrome to those of 25 healthy female children. Additionally, we assessed the correlation between regional brain volume, Clinical Severity Scores, and epilepsy status. RESULTS: Significantly smaller volumes were observed in all brain regions, including the cerebral cortex, cerebral white matter, subcortical gray matter, cerebellum, and brainstem. Within the cortical regions, volume reduction was prominent in the left precentral, right lateral occipital, left precuneus, left inferior parietal, and right medial orbitofrontal cortices. After correcting for intracranial volumes, volume reduction was more prominent in the cerebral cortices than in the cerebral white matter. Small volumes were consistently observed, regardless of age. Negative correlations were observed between the volumes of multiple regions and the Clinical Severity Scores. There were no correlations among regional brain volume, seizure control, or duration of epilepsy. CONCLUSION: The mechanism underlying the cortical-dominant volume reduction remains unclear; however, it may be caused by altered synapse development associated with methyl-CpG-binding protein 2 gene abnormalities. Characteristic impairments in visual recognition and deterioration of motor function in Rett syndrome may be associated with significant volume reduction in specific cortical regions, such as the lateral occipital cortex, precuneus, and precentral gyrus.

DOI： 10.1016/j.braindev.2025.104348

Oishi, R; Segi, N; Okazaki, M; Ito, S; Ouchida, J; Yamauchi, I; Seki, T; Takegami, Y; Ishizuka, S; Hashizume, A; Hasegawa, Y; Imagama, S; Nakashima, H

SCIENTIFIC REPORTS Vol. 15 ( 1 ) page： 15162 2025.4

Language：English Publishing type：Research paper (scientific journal) Publisher：Scientific Reports

The purpose of this study was to determine the association between frailty and quality of life (QOL) in a five-year longitudinal cohort of community-dwelling middle-aged and older adults and determine how to identify health-related QOL changes. This study included 124 volunteers (67 women; mean 65 years at baseline) who underwent health checkups in 2014 and 2019. The association between frailty status (robust, prefrail, frail), according to the Japanese Cardiovascular Health Study criteria, and health-related QOL, measured with the SF-36 questionnaire, were investigated. Five-year changes in frailty status were categorized into improved, maintained, and worsened groups. The baseline prevalence of prefrailty and frailty were 44.4% and 7.2%, respectively. Five years later, the frailty of 20 participants improved, 66 maintained frailty status, and frailty worsened in 38 participants. Significant trends toward higher scores on the physical component summary (PCS), role/social component summary (RCS), and subscales of physical functioning, role-physical, vitality, social functioning, and role-emotional were detected across groups with improvements in their frailty status from 2014 to 2019. The fully adjusted multivariable regression model revealed significantly higher PCS scores (β, 12.9; 95% confidence interval (CI), 6.0 to 19.9) and RCS scores (β, 13.6; 95% CI, 6.6 to 20.6) compared with the worsened group. In conclusion, this longitudinal cohort study demonstrates that frailty status is not static and improvements or maintenance of frailty are associated with better physical and social QOL outcomes. Addressing frailty early may reverse or mitigate its impact and improve the overall well-being of older adults.

DOI： 10.1038/s41598-025-99843-7