Published papers

Objective: Effective treatments for amyotrophic lateral sclerosis (ALS) remain limited, underscoring the need to identify robust biomarkers associated with disease severity and prognosis. This study investigated whether immunoglobulin G (IgG) and immunoglobulin M (IgM) anti-glycolipid antibodies are associated with clinical manifestations of ALS, particularly decline in respiratory function. Methods: This was a retrospective observational cohort study of the patients with ALS. Among patients with definite or probable limb-onset ALS, 11 patients in the glycolipid IgG-positive group were compared with 15 patients in the IgG-negative group, and 5 patients in the glycolipid IgM-positive group were compared with 9 patients in the IgM-negative group, with adjustment for age. Associations between anti-glycolipid antibody status and respiratory function were assessed using Kaplan–Meier survival analysis and Cox proportional hazards models. Results: The time to decline of percent forced vital capacity (%FVC) below 80% and 60% was significantly shorter in the IgG-positive group than in the IgG-negative group (p = 0.002 and p = 0.025, respectively). Cox proportional hazards analysis demonstrated that IgG antibody positivity was an independent risk factor for earlier decline in %FVC to 80%. Interpretation: These findings suggest that anti-glycolipid IgG antibodies may be associated with respiratory function decline in ALS. Larger comprehensive studies will be required to validate these results and to elucidate the underlying pathophysiological mechanisms.

Background: Polydoctoring can increase the risk of care fragmentation among patients with multimorbidity, but its impact on health outcomes remains unclear. Aim: To determine the effects of polydoctoring, as measured by the regularly visited facilities (RVF) indicator, on patient outcomes among older individuals with multimorbidity. Design & setting: Data from the ongoing prospective cohort study, Kawasaki Aging and Wellbeing Project (KAWP), was utilised in this study. Among the 1026 KAWP participants aged 85–89 years, those with two or more chronic conditions were enrolled in this study. Method: Care fragmentation and polydoctoring was evaluated using the RVF, which is a new indicator that measures the number of medical facilities consistently involved in a patient’s care. Based on RVF, mortality was analysed using the Cox proportional hazards model, with adjustments for age, sex, frailty, and number of comorbidities. Results: A significant reduction in mortality rates was observed in participants with an RVF of ≥3 and 2–4 comorbidities (hazard ratio [HR] 0.43, 95% confidence interval [CI] = 0.18 to 0.99, P value = 0.048). However, no significant difference in mortality based on RVF was observed for those with ≥5 comorbidities. Notably, individuals with ≥5 comorbidities and an RVF of 0 had a significantly higher HR for death (HR 2.68, 95% CI = 1.05 to 6.84, P value = 0.039). Conclusion: In older patients with multimorbidity, polydoctoring may reduce mortality in patients with ≤4 coexisting conditions, but it does not significantly impact mortality in those with ≥5 conditions. These findings provide insights for healthcare decision making in managing older patients with multimorbidity.

Advanced pathological and genetic approaches have revealed that mutations in fused in sarcoma/translated in liposarcoma (FUS/TLS), which is pivotal for DNA repair, alternative splicing, translation and RNA transport, cause familial amyotrophic lateral sclerosis (ALS). The generation of suitable animal models for ALS is essential for understanding its pathogenesis and developing therapies. Therefore, we used CRISPR-Cas9 to generate FUS-ALS mutation in the non-classical nuclear localization signal (NLS), H517D (mouse position: H509D) and genome-edited mice. FusWT/H509D mice showed progressive motor impairment (accelerating rotarod and DigiGait system) with age, which was associated with the loss of motor neurons and disruption of the nuclear lamina and nucleoporins and DNA damage in spinal cord motor neurons. We confirmed the validity of our model by showing that nuclear lamina and nucleoporin disruption were observed in lower motor neurons differentiated from patient-derived human induced pluripotent stem cells (hiPSC-LMNs) with FUS-H517D and in the post-mortem spinal cord of patients with ALS. RNA sequence analysis revealed that most nuclear lamina and nucleoporin-linking genes were significantly decreased in FUS-H517D hiPSC-LMNs. This evidence suggests that disruption of the nuclear lamina and nucleoporins is crucial for ALS pathomechanisms. Combined with patient-derived hiPSC-LMNs and autopsy samples, this mouse model might provide a more reliable understanding of ALS pathogenesis and might aid in the development of therapeutic strategies.

This study identified the factors associated with current and quitting alcohol drinking in the Oldest Old to better understand the associated factors and mechanisms underlying drinking behaviors in this age group. Results of a questionnaire for drinking behavior in 1015 Japanese Oldest Old citizens aged 85 to 89 years revealed that 56.0% of men and 24.0% of women were current drinkers. A genome-wide association study revealed that the rs671 G > A variation, which corresponds to the aldehyde dehydrogenase 2 (ALDH2) p.E504K missense variant, was significantly associated with current drinking (odds ratio: 3.8, p = 3.33 × 10−31 ). Variable selection with 41 factors and multivariate regression logistic analysis for current drinking indicated that the rs671 genotype and sex were the most significant factors in the Oldest Old. Further analysis revealed that the rs671 genotype, alcohol-associated biomarkers, a history of heart or kidney disease, and frailty score are factors associated with quitting drinking in the Oldest Old men, whereas smoking history, walking time, and depression score were factors associated with quitting drinking in the Oldest Old women. These results indicate that the ALDH2 p.E504K variation is a major factor associated with current and quitting drinking in the Japanese Oldest Old.

INTRODUCTION: Clinical features of cognitive performance in extreme old age differ from those of pathological cognitive decline in Alzheimer's disease (AD). METHODS: We compared cognitive traits between 638 centenarians aged 100–115 years and 208 and 221 patients with AD from independent facilities. RESULTS: The presence of the apolipoprotein E (APOE) ε4 allele did not affect Mini-Mental State Examination (MMSE) scores in centenarians. Centenarians retained the ability to follow three consecutive commands, associated with their educational background and activities of daily living. Cognitive retention remained unchanged in semi-supercentenarians (aged ≥ 105 years) and supercentenarians (aged ≥110 years). A quantitative genome-wide association study (GWAS) identified two loci associated with maintaining the ability to follow three consecutive commands. DISCUSSION: This is the first study to compare cognitive traits between >600 centenarians and patients with AD. Centenarians attained higher MMSE scores for the phenotype of following three consecutive commands than patients with AD, being useful in clinical practice. Highlights: Cognitive phenotypes in centenarians differ from those in the AD groups Clinical trait to follow consecutive instructions is retained in centenarians but not in AD groups GWAS identified SNPs related to the maintained trait of MMSE in centenarians.

Background: Multimorbidity increases with age, leading to various adverse outcomes, including higher mortality, care dependency, hospitalizations, and healthcare costs. Polydoctoring, managing a patient with multimorbidity by multiple healthcare providers, can be a risk of fragmented care and increased healthcare expenditures. This study aims to identify patient-related factors contributing to polydoctoring in older adults with multimorbidity. Methods: This study is a cross-sectional study using baseline data from the Kawasaki Aging and Wellbeing Project. Participants were residents of Kawasaki City aged 85–89 years, without disability in basic activities of daily living, and being able to visit study site. The regularly visited facilities (RVF) index was employed to quantify polydoctoring. Polydoctoring was defined as having two or more RVFs. Poisson regression analysis was conducted to assess the association between polydoctoring and patient demographics, including types of chronic conditions and socioeconomic factors. Results: A total of, 968 participants with multimorbidity were analyzed. Increased RVF was significantly associated with eye diseases (rate ratio [RR] 1.27, 95% confidence interval [CI] 1.12–1.44), osteoporosis (RR 1.22, 95% CI 1.08–1.38), prostate diseases (RR 1.22, 95% CI 1.07–1.40), and osteoarthritis (RR 1.16, 95% CI 1.05–1.27). No significant correlation was found with educational status or financial hardship. Conclusion: The study indicated that certain chronic conditions are linked to increased polydoctoring among multimorbid older adults in Japan. However, most of those conditions are considered to be within a scope of family medicine/general practice. Training general practitioners to manage these conditions could reduce healthcare costs and the treatment burden, indicating a direction for future healthcare policy and medical education.

Background: Serum testosterone level is a potential prognostic marker for castration-resistant prostate cancer. However, its role as a prognostic marker in cabazitaxel chemotherapy remains unclear. This study aimed to elucidate the clinical significance of serum testosterone levels before cabazitaxel chemotherapy. Methods: This single-institution, retrospective study included 47 patients with metastatic castration-resistant prostate cancer (mCRPC) who received cabazitaxel therapy. Serum testosterone levels were measured before the initiation of cabazitaxel therapy. Results: Progression-free survival and overall survival (OS) were not significantly different between patients with high and low serum testosterone levels. Analysis of patients aged <70 years revealed that those with high serum testosterone levels (total testosterone level > 0.055 ng/mL) had significantly longer OS than those with low serum testosterone levels (total testosterone level < 0.055 ng/mL, p = 0.012). Multivariate analysis revealed that low serum testosterone levels (hazard ratio [HR] = 11.874, 95% confidence interval [CI] 2.076–67.953, p = 0.005) and high prostate-specific antigen levels (HR = 18.051, 95% CI 2.462–132.347, p = 0.004) in the pretreatment phase were independent prognostic factors for OS in patients receiving cabazitaxel therapy. Conclusions: Serum testosterone level may be a prognostic marker for cabazitaxel therapy in patients with mCRPC who are younger than 70 years, and high serum testosterone levels may lead to longer survival.

Background: Care fragmentation, characterized by the uncoordinated involvement of multiple healthcare providers, leads to inefficient and ineffective healthcare, posing a significant challenge in managing patients with multimorbidity. In this context, “polydoctoring,” where patients see multiple specialists, emerges as a crucial aspect of care fragmentation. This study seeks to develop an indicator to assess polydoctoring, which can subsequently enhance the management of multimorbidity. Methods: Baseline survey data from the Kawasaki Aging and Wellbeing Project (KAWP) involving independent community-dwelling older adults aged 85–89 were utilized in this cross-sectional study. Polydoctoring measure was defined as the number of regularly visited facilities (RVFs). The association of RVF with the Fragmentation of Care Index (FCI) and the outcome measures of polypharmacy and ambulatory care costs were examined as indicators of care fragmentation. Results: The analysis comprised 968 participants, with an average of 4.70 comorbid chronic conditions; 65.3% of the participants had two or more RVFs, indicating polydoctoring. A significant correlation between RVF and FCI was observed. Modified Poisson regression analyses revealed associations between higher RVF and increased prevalence ratio of polypharmacy. Likewise, a higher RVF was associated with higher outpatient medical costs. Conclusions: RVF was significantly correlated with FCI, polypharmacy, and higher outpatient medical costs. Unlike complex indices, RVF is simple and intuitively comprehensible. Further research is needed to evaluate the impact of care fragmentation on patient outcomes, considering factors such as RVF thresholds, patient multimorbidity, and social support. Understanding the influence of polydoctoring can enhance care quality and efficiency for patients with multimorbidity.

Background: High levels of circulating adiponectin are associated with increased insulin sensitivity, low prevalence of diabetes, and low body mass index (BMI); however, high levels of circulating adiponectin are also associated with increased mortality in the 60–70 age group. In this study, we aimed to clarify factors associated with circulating high-molecular-weight (cHMW) adiponectin levels and their association with mortality in the very old (85–89 years of age) and centenarians. Methods: The study included 812 (women: 84.4%) for centenarians and 1498 (women: 51.7%) for the very old. The genomic DNA sequence data were obtained by whole-genome sequencing or DNA microarray-imputation methods. Least Absolute Shrinkage and Selection Operator (LASSO) and multivariate regression analyses were used to evaluate cHMW adiponectin characteristics and associated factors. All-cause mortality was analyzed in three quantile groups of cHMW adiponectin levels using Cox regression. Results: The cHMW adiponectin levels were increased significantly beyond 100 years of age, were negatively associated with diabetes prevalence, and were associated with SNVs in CDH13 (p=2.21 × 10-22) and ADIPOQ (p=5.72 × 10-7). Multivariate regression analysis revealed that genetic variants, BMI, and high-density lipoprotein cholesterol (HDLC) were the main factors associated with cHMW adiponectin levels in the very old, whereas the BMI showed no association in centenarians. The hazard ratios for all-cause mortality in the intermediate and high cHMW adiponectin groups in very old men were significantly higher rather than those for all-cause mortality in the low-level cHMW adiponectin group, even after adjustment with BMI. In contrast, the hazard ratios for all-cause mortality were significantly higher for high cHMW adiponectin groups in very old women, but were not significant after adjustment with BMI. Conclusions: cHMW adiponectin levels increased with age until centenarians, and the contribution of known major factors associated with cHMW adiponectin levels, including BMI and HDLC, varies with age, suggesting that its physiological significance also varies with age in the oldest old. Funding: This study was supported by grants from the Ministry of Health, Welfare, and Labour for the Scientific Research Projects for Longevity; a Grant-in-Aid for Scientific Research (No 21590775, 24590898, 15KT0009, 18H03055, 20K20409, 20K07792, 23H03337) from the Japan Society for the Promotion of Science; Keio University Global Research Institute (KGRI), Kanagawa Institute of Industrial Science and Technology (KISTEC), Japan Science and Technology Agency (JST) Research Complex Program "Tonomachi Research Complex" Wellbeing Research Campus: Creating new values through technological and social innovation (JP15667051), the Program for an Integrated Database of Clinical and Genomic Information from the Japan Agency for Medical Research and Development (No. 16kk0205009h001, 17jm0210051h0001, 19dk0207045h0001); the medical-welfare-food-agriculture collaborative consortium project from the Japan Ministry of Agriculture, Forestry, and Fisheries; and the Biobank Japan Program from the Ministry of Education, Culture, Sports, and Technology.

Background and Objectives: Previous studies have evaluated the diagnostic effect of amyloid PET in selected research cohorts. However, these studies did not assess the clinical impact of the combination of amyloid and tau PETs. Our objective was to evaluate the association of the combination of 2 PETs with changes in diagnosis, treatment, and management in a memory clinic cohort.Methods: All participants underwent amyloid [18F]florbetaben PET and tau PET using [18F]PI-2620 or [18F]Florzolotau, which are potentially useful for the diagnosis of non-Alzheimer disease (AD) tauopathies. Dementia specialists determined a pre- and post-PET diagnosis that existed in both a clinical syndrome (cognitive normal [CN], mild cognitive impairment [MCI], and dementia) and suspected etiology, with a confidence level. In addition, the dementia specialists determined patient treatment in terms of ancillary investigations and management. Results: Among 126 registered participants, 84.9% completed the study procedures and were included in the analysis (CN [n = 40], MCI [n = 25], AD [n = 20], and non-AD dementia [n = 22]). The etiologic diagnosis changed in 25.0% in the CN, 68.0% in the MCI, and 23.8% with dementia. Overall changes in management between pre- and post-PET occurred in 5.0% of CN, 52.0% of MCI, and 38.1% of dementia. Logistic regression analysis revealed that tau PET has stronger associations with change management than amyloid PET in all participants and dementia groups. Discussion: The combination of amyloid and tau PETs was associated with changes in management and diagnosis of MCI and dementia, and the second-generation tau PET has a strong impact on the changes in diagnosis and management in memory clinics. Classification of Evidence: This study provides Class I evidence that the combination of amyloid and tau PETs was associated with changes in management and diagnosis of MCI and dementia.

Objectives: Spinal dural arteriovenous fistula (sDAVF) is a rare and often underdiagnosed spinal disease. Early diagnosis is required because the deficits are reversible and delays in treatment cause permanent morbidity. Although the abnormal vascular flow void is a critical radiographic feature of sDAVF, they are not always present. A characteristic enhancement pattern of sDAVF has been recently reported as the “missing-piece” sign which can lead to the early and correct diagnosis. Methods: We presented imaging findings, treatment decisions, and the outcome of a rare case of sDAVF, in which the “missing-piece” sign appeared atypical. Results: A 60-year-old woman developed numbness and weakness in her extremities. Spinal MRI revealed longitudinal hyperintensity in the T2-weighted image, extending from the thoracic level to medulla oblongata. At first, myelopathy with inflammation or tumor was suspected because of the lack of flow voids and vascular abnormalities in CT-angiography and MR-DSA. However, we administered intravenous methylprednisolone and her symptom got worse with the appearance of the “missing-piece” sign. Then, we successfully diagnosed sDAVF by angiography. The “missing-piece” sign was considered to derive from inconsistency of the intrinsic venous system of spinal cord, with the abrupt segments without enhancement. The same etiology was considered in our case. Conclusions: Detecting the “missing-piece” sign can lead to the correct diagnosis of sDAVF, even if the sign appeared atypical.

Amyotrophic lateral sclerosis (ALS) is a representative neurological disease that is known to devastate entire motor neurons within a period of just a few years. Discoveries of the specific pathologies of relevant RNA-binding proteins, including TAR DNA-binding protein-43 (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS), and the causative genes of both familial and sporadic ALS have provided crucial information that could lead to a cure. In recent ALS research the GGGGCC-repeat expansion in the C9orf72 gene was identified as one of the most important pathological findings, suggesting the significance of both nuclear dysfunction due to dipeptide repeat proteins (DPRs) and RNA toxicity (such as pathological alterations of non-coding RNAs). In research on model animals carrying ALS-related molecules, the determination of whether a factor is protective or toxic has been controversial. Herein, we review the findings regarding NEAT1 RNA and C9orf72 GGGGCC repeats associated with ALS, from the viewpoint of conversion from the protective stage in the nucleus in early-phase ALS to late-phase induction of cell death. This review will provide insights for the development of RNA effectors as novel ALS treatments.

Objective This study aimed to identify associations between multimorbidity and subjective health outcomes among the very old persons, after adjusting for coexisting conditions such as frailty and depression. Study setting and participants This was an observational cross-sectional study involving 1012 independent, community-dwelling very old persons (507 men, 505 women; aged 85-89 years) in Kawasaki city, Japan. Outcome measures The primary outcome was the cross-sectional associations between multimorbidity and poor self-rated health (SRH) and life satisfaction using binary logistic regression. The secondary outcome was the association of subjective health with each chronic condition. Results The prevalence of multimorbidity (≥2 conditions) was 94.7%, and the average number of chronic conditions was 4.47±1.9. Multimorbidity was significantly associated with poor SRH in the adjusted model only when six or more chronic conditions were present (OR 4.80; 95% CI 1.34 to 17.11; p=0.016). Cerebrovascular disease, heart disease, respiratory disease, connective tissue disease and arthritis showed significant associations with poor SRH after multivariate adjustment. Sex-specific analysis replicated associations between multimorbidity with six or more conditions and SRH in both men and women, while the diseases with the greatest impact on SRH differed between men and women. Most conditions were not associated with low satisfaction with life scale, with the exception of arthritis (OR 1.92, 95% CI 1.32 to 2.78, p=0.001). Conclusions Multimorbidity is prevalent in the independent, community-dwelling very old persons and is associated with poor SRH when six or more conditions are present; conditions causing mobility limitations, such as cerebrovascular disease, connective tissue disease and arthritis, have a negative impact on SRH. Trial registration number UMIN000026053.

Due to the recent rapid increase in the number of elderly people in the world, health management and maintenance in elderly people have become important issues. Centenaria, who are older than 100 years, tend to stay independent in their daily life with maintenance of cognitive function until the later stage of their life compared with elderly people who die earlier. In this review, we summarize the characteristics of centenarians, the genetic risk and protective factors for longevity, and intersections between research on centenarians and dementia research.

The apolipoprotein E4 (APOE ε4) allele has attracted attention as an age-related genetic factor, both in neurology and gerontology. To understand the effects of the APOE ε4 allele on mortality in elderly individuals, we combined Japanese prospective cohort studies comprising 535 very old individuals (85–99 years of age) and 930 centenarians (over 100 years of age) and analyzed the association between mortality rates and candidate factors, including the APOE ε4 allele. APOE genotyping revealed an inverse correlation between the APOE ε4 allele carrier rate and age. Additionally, APOE ε4 allele carrier rate in centenarian men was significantly lower than that in centenarian women. The association analysis between APOE ε4 allele carriers and all-cause mortality indicated that APOE ε4 carriers showed significantly higher mortality rates than the APOE ε4 noncarriers among men in the very old group. Further analysis using Cox proportional hazard models indicated that cause-specific mortalities, including pneumonia and severe dementia, were associated with APOE ε4 carriers. These findings indicate that the APOE ε4 allele shows phenotypic male-specific adverse effects in the very old, which would explain the high mortality rate observed in this group, resulting in a low APOE ε4 allele carrier rate in centenarian men.