Relationship between donepezil and fracture risk in patients with dementia with Lewy bodies.

AIM: Patients with dementia with Lewy bodies (DLB) are at a high risk for falls and fractures. Although cholinesterase inhibitors reportedly are effective in suppressing the progression of cognitive symptoms in DLB patients, their effects on fracture risk remain unclarified. This study aimed to evaluate the association between donepezil use and hip fracture risk in older patients with DLB. METHODS: Using the Japanese insurance claim database, we collected the data of patients aged ≥65 years with DLB from April 2012 to March 2019. After propensity score matching, we compared the fracture rate over 3 years between DLB patients receiving donepezil and those not receiving antidementia drugs. RESULTS: Altogether, 24 022 239 individuals aged ≥65 years were newly registered from April 2012 to March 2016 and had verifiable information from 6 months before to 3 years after the registration. We identified 6634 pure-DLB patients and analyzed the data of 1182 propensity score-matched pairs. The characteristics, including age, sex, fracture history, osteoporosis, and bone mineral density test rate, of the two groups were well balanced by propensity score matching. The incidence rate of hip fracture was significantly lower in DLB patients receiving donepezil than in those not receiving antidementia drugs (0.60 vs. 1.44/100 person-years, P < 0.001), whereas that of vertebral fractures was the same. CONCLUSIONS: Donepezil administration in Japanese people aged ≥65 years with DLB was significantly associated with a decreased risk of hip fracture. Donepezil may provide new benefits to DLB patients. Geriatr Gerontol Int 2024; ••: ••-••.

Early-onset dementia and risk of hip fracture and major osteoporotic fractures.

INTRODUCTION: There is limited knowledge about early-onset dementia (EOD) on fracture risk. METHODS: Individuals ages 50 to 64 were identified from the National Database of Health Insurance Claims and Specific Health Checkups of Japan (2012 to 2019). The association between EOD and fractures and the association between cholinesterase inhibitors for EOD and fractures were evaluated using logistic regression analyses. RESULTS: We identified 13,614 EOD patients and 9,144,560 cognitively healthy individuals. The analysis revealed that EOD was associated with an increased risk of hip fractures (adjusted odds ratio, 95% confidence interval: 8.79, 7.37-10.48), vertebral fractures (1.73, 1.48-2.01), and major osteoporotic fractures (2.05, 1.83-2.30) over 3 years. The use of cholinesterase inhibitors was significantly associated with a reduction in hip fractures among EOD patients (0.28, 0.11-0.69). DISCUSSION: EOD patients have a higher risk of osteoporotic fractures than cognitively healthy individuals. The use of cholinesterase inhibitors may reduce the risk of hip fracture among EOD patients. HIGHLIGHTS: It is unknown whether early-onset dementia (EOD) increases the risk of fractures. We identified 13,614 individuals with EOD using a nationwide administrative database. Patients with EOD have a higher risk of hip, vertebral, and major osteoporotic fractures. The use of cholinesterase inhibitors may reduce hip fracture among patients with EOD.

The roles of sex hormones in the pathophysiology of age-related sarcopenia and frailty.

Background: Sarcopenia is an age-related condition characterized by a progressive and systemic decline in skeletal muscle mass, quality, and strength. The incidence of sarcopenia contains sex-specific aspects, indicating the contribution of sex hormones to its pathophysiology. This review focuses on changing trends in sarcopenia, discusses alterations in definitions and diagnostic criteria, and emphasizes the association between sarcopenia and sex hormones. Methods: A literature search was performed on PubMed for related articles published between 1997 and December 2023 using appropriate keywords. Main Findings Results: Advances in research have emphasized the significance of muscle quality and strength over muscle mass, resulting in new diagnostic criteria for sarcopenia. Androgens demonstrated anabolic effects on skeletal muscles and played a significant role in the pathophysiology of sarcopenia. In clinical settings, androgen replacement therapy has exhibited certain positive outcomes for treating sarcopenia, despite concerns about potential side effects. Conversely, estrogen is involved in skeletal muscle maintenance, but the detailed mechanisms remain unclear. Moreover, results regarding the clinical application of estrogen replacement therapy for treating sarcopenia remained inconsistent. Conclusion: The elucidation of molecular mechanisms that involve sex hormones is eagerly awaited for novel therapeutic interventions for sarcopenia.

Exercise-induced vitamin D receptor and androgen receptor mediate inhibition of IL-6 and STAT3 in muscle.

Background: Skeletal muscle produces interleukin-6 (IL-6) during exercise as a myokine. Although IL-6 is required for skeletal muscle regeneration, its action increases the expression of myostatin and other proteins involved in muscle atrophy, resulting in skeletal muscle atrophy. In this study, we clarified the effects exercise-induced vitamin D receptor (VDR) and androgen receptor (AR) expression on IL-6 and signal transducer and activator of transcription 3 (STAT3) in vivo and in vitro. Method: C2C12 myotubes were subjected to electric pulse stimulation (EPS) in vitro. To evaluate VDR and AR function, a VDR/AR agonist and antagonist were administered before EPS to C2C12 myotubes. C57BL6 mice underwent 4 weeks of exercise. The expression levels of proteolytic-associated genes, including CCAAT/enhancer-binding protein delta (C/EBPδ) and myostatin, were measured by quantitative real-time polymerase chain reaction, and phosphorylated and total STAT3 levels were measured by Western blot analysis. Result: The expression of VDR and AR mRNA was induced following EPS in C2C12 myotubes. IL-6 mRNA expression was also increased with a peak at 6 h after EPS and p-STAT3/STAT3 ratio reciprocally decreased. Although VDR/AR agonist administration decreased IL-6 mRNA expression and p-STAT3/STAT3 ratio, these two endpoints increased after treatment with VDR/AR antagonist, respectively. Exercise in mice also increased the expression of VDR/AR and IL-6 mRNA and decreased p-STAT3/STAT3 ratio. Conclusion: Exercise-induced VDR and AR expression results in the suppression of IL-6 mRNA and STAT3 phosphorylation in skeletal muscle.

Prescription of vitamin D was associated with a lower incidence of hip fractures.

Patients with osteoporosis are prone to fragility fractures. Evidence of the effects of active forms of vitamin D on hip fracture prevention is insufficient. We examined the association between vitamin D prescription and incidence of new fractures using the data of osteoporotic patients from the nationwide health insurance claims database of Japan. The follow-up period was 3 years after entry. The untreated patients were never prescribed vitamin D during follow-up (n = 422,454), and the treated patients had a vitamin D medication possession ratio of ≥ 0.5 at all time points (n = 169,774). Propensity score matching was implemented on these groups, yielding 105,041 pairs, and subsequently, the control and treatment groups were established and analyzed. The incidence of new fractures was significantly lower in the treatment group compared with the control group (6.25% vs. 5.69%, hazard ratio 0.936 [95% confidence interval 0.904-0.970], p < 0.001*). By site, hip fractures significantly decreased (0.89% vs. 0.42%, p < 0.001), but not vertebral and radial fractures. Subgroup analysis by vitamin D type showed a significantly lower incidence of total fractures only in alfacalcidol (hazard ratio 0.676 [95% confidence interval 0.628-0.728], p < 0.001*). The results suggest that vitamin D prescription was associated with a reduced incidence of hip fractures.

Relationship between antidementia medication and fracture prevention in patients with Alzheimer's dementia using a nationwide health insurance claims database.

This retrospective study aimed to evaluate the association between antidementia medication use and incidence of new vertebral, hip, and radial fractures in patients with Alzheimer's dementia (AD). We used the nationwide health insurance claims database of Japan from 2012 to 2019 and identified 12,167,938 patients aged ≥ 65 years who were newly registered from April 2012 to March 2016 and had verifiable data receipt from half-year before to 3 years after the registration. Among these patients, 304,658 were diagnosed with AD and we showed the prescription status of antidementia and osteoporosis medication among them. Propensity score matching was conducted for AD group with and without antidementia medication use, and 122,399 matched pairs were yielded. The incidence of hip fractures (4.0% vs. 1.9%, p < 0.001) and all clinical fractures (10.5% vs. 9.0%, p < 0.001) significantly decreased and that of radial fractures increased (0.6% vs. 1.0%, p < 0.001) in AD patients with antidementia medication use compared with AD patients without antidementia medication use. No significant difference was found in vertebral fractures (6.6% vs. 6.5%, p = 0.51). Overall, these results suggest a positive relationship between antidementia medication use and fracture prevention in patients with AD.

Validation of the questionnaire for medical checkup of old-old (QMCOO) score cutoff to diagnose frailty.

BACKGROUND: Frailty is a state of increased vulnerability to poor resolution of homeostasis following a stress. Early diagnosis and intervention of frailty are essential to prevent its adverse outcomes. However, simple diagnostic criteria have not been established. The Questionnaire for Medical Checkup of Old-Old (QMCOO) is widely used for medical checkups of older adults in Japan. In our previous report, we developed a method to score the QMCOO and showed that frailty can be diagnosed with the highest accuracy when the score cutoff was set at 3/4 points. We aimed to validate the criteria in a larger cohort. METHODS: Participants aged 65 years or over were recruited in the western region of Japan. They answered all the items of the Kihon Checklist (KCL) and the QMCOO. Based on the KCL score, they were diagnosed as robust (3 or lower), prefrail (4 to 7), or frail (8 or over). Then we tested the effectiveness to diagnose frailty using the QMCOO cutoff of 3/4 points. We also aimed to determine the score cutoff to separate robust and prefrail. RESULTS: 7,605 participants (3,458 males and 4,147 females, age 77.4 ± 6.9 years) were recruited. 3,665 participants were diagnosed as robust, 2,448 were prefrail, and 1,492 were frail based on the KCL score. The diagnosis of frailty had a sensitivity of 84.0%, specificity of 82.5%, and accuracy of 82.8% with a QMCOO score cutoff of 3/4 points, suggesting its validity. To separate robust and prefrail, both the accuracy and the Youden index were the highest with the QMCOO cutoff of 2/3 points (sensitivity, specificity, and accuracy were 63.9%, 83.4%, and 75.6%, respectively). All the questions of the QMCOO except Q12 (about smoking) were significantly related to prefrailty status after a logistic regression analysis. CONCLUSION: Diagnosis of frailty using the QMCOO score cutoff of 3/4 points was validated. Prefrailty could be diagnosed using the score cutoff of 2/3 points.

Sarcopenia phenotype and impaired muscle function in male mice with fast-twitch muscle-specific knockout of the androgen receptor.

Sarcopenia is distinct from normal muscle atrophy in that it is closely related to a shift in the muscle fiber type. Deficiency of the anabolic action of androgen on skeletal muscles is associated with sarcopenia; however, the function of the androgen receptor (AR) pathway in sarcopenia remains poorly understood. We generated a mouse model (fast-twitch muscle-specific AR knockout [fmARKO] mice) in which the AR was selectively deleted in the fast-twitch muscle fibers. In young male mice, the deletion caused no change in muscle mass, but it reduced muscle strength and fatigue resistance and induced a shift in the soleus muscles from fast-twitch fibers to slow-twitch fibers (14% increase, P = 0.02). After middle age, with the control mice, the male fmARKO mice showed much less muscle function, accompanied by lower hindlimb muscle mass; this phenotype was similar to the progression of sarcopenia. The bone mineral density of the femur was significantly reduced in the fmARKO mice, indicating possible osteosarcopenia. Microarray and gene ontology analyses revealed that in male fmARKO mice, there was downregulation of polyamine biosynthesis-related geneswhich was confirmed by liquid chromatography-tandem mass spectrometry assay and the primary cultured myofibers. None of the AR deletion-related phenotypes were observed in female fmARKO mice. Our findings showed that the AR pathway had essential muscle type- and sex-specific roles in the differentiation toward fast-twitch fibers and in the maintenance of muscle composition and function. The AR in fast-twitch muscles was the dominant regulator of muscle fiber-type composition and muscle function, including the muscle-bone relationship.

Kampo formula hochu-ekki-to (Bu-Zhong-Yi-Qi-Tang, TJ-41) ameliorates muscle atrophy by modulating atrogenes and AMPK in vivo and in vitro.

BACKGROUND: Muscle disuse results in loss of skeletal muscle mass and function. Hochu-ekki-to (TJ-41; Bu-Zhong-Yi-Qi-Tang in Chinese) is an herbal medicinal formulation used to treat patients with frailty, fatigue and appetite loss. It has been suggested that two atrogenes, atrogin-1 and muscle Ring finger 1 (MuRF1), are ubiquitin ligases involved in disuse-induced muscle atrophy and that 5' adenosine monophosphate-activated protein kinase (AMPK) is involved in skeletal muscle metabolism. Effects of TJ-41 on disuse-induced muscle atrophy are unclear. METHODS: We subjected differentiated C2C12 myotubes to serum starvation, then examined the effects of TJ-41 on atrogenes expression, AMPK activity and the morphology of the myotubes. Male C57BL/6J mice were subjected to tail-suspension to induce hindlimb atrophy. We administered TJ-41 by gavage to the control group and the tail-suspended group, then examined the effects of TJ-41 on atrogene expression, AMPK activity, and the muscle weight. RESULTS: Serum starvation induced the expression of atrogin-1 and MuRF1 in C2C12 myotubes, and TJ-41 significantly downregulated the expression of atrogin-1. Tail-suspension of the mice induced the expression of atrogin-1 and MuRF1 in skeletal muscle as well as its muscle atrophy, whereas TJ-41 treatment significantly downregulated the expression of atrogin-1 and ameliorated the loss of the muscle weight. In addition, TJ-41 also activated AMPK and inactivated Akt and mTOR in skeletal muscle in vivo. CONCLUSION: TJ-41 inhibited atrogenes in an Akt-independent manner as well as activating AMPK in skeletal muscles in vivo, further implying the therapeutic potential of TJ-41 against disuse-induced muscle atrophy and other atrogenes-dependent atrophic conditions.

Marked Cognitive and Activities of Daily Living Improvement by Shunt Embolization in a Very Old Man with Portosystemic Encephalopathy Mimicking Alzheimer Disease: A Case Report.

A 91-year-old man with chronic cognitive impairment underwent shunt embolization for portosystemic encephalopathy (PSE). He experienced intermittent episodes of impaired consciousness and decreased cognitive function and activities of daily living (ADL), for which Alzheimer disease was suspected. On admission, he was in a coma and PSE was diagnosed based on his high ammonia level and the computed tomography findings. After shunt embolization, the patient fully recovered from the impaired consciousness and experienced no recurrence. The patient's Revised Hasegawa Dementia Scale and Mini-Mental State Examination scores improved significantly from 12 and 17 to 30 and 29 points, respectively. The Barthel Index score also improved from 55/100 to 85/100, suggesting a marked improvement in ADL. PSE progresses slowly in very old patients and may mimic the clinical course of Alzheimer disease but without liver enzyme abnormalities. Therefore, it should be distinguished in every dementia case.

Effectiveness of the Questionnaire for Medical Checkup of Old-Old (QMCOO) to diagnose frailty in community-dwelling older adults.

AIM: Although frailty could be reversible by early diagnosis and interventions, it lacks definite diagnostic criteria. The Kihon Checklist is a 25-item questionnaire that diagnoses frailty with a cutoff score of 7/8. The Questionnaire for Medical Checkup of Old-Old (QMCOO) was recently established and used for medical checkups among Japanese older adults, but no method or cutoff score for diagnosing frailty has been established. Thus, we aimed to diagnose frailty using the QMCOO and to determine its cutoff score by comparing it with that of the Kihon Checklist. METHODS: We recruited 223 older adults in Yasugi City and Yonago City to answer all the questions in the Kihon Checklist and the QMCOO at the same time. Those scoring ≥8 for the Kihon Checklist (n = 38) were diagnosed as frail. We also determined the cutoff score for frailty for the QMCOO and examined which questionnaire items affected the frailty status. RESULTS: The QMCOO and the Kihon Checklist score showed a significant positive correlation (r = 0.670, P < 0.001). The area under the curve was 0.851. A cutoff score of 3/4 for the QMCOO represented the best results (sensitivity, 76.3%; specificity, 88.1%; and accuracy, 86.1%). Multiple linear regression analysis revealed that subjective health status, body weight loss, slowness, and forgetfulness still affected the frailty status. CONCLUSIONS: A cutoff score of 3/4 for the QMCOO might be effective in diagnosing frailty. Geriatr Gerontol Int 2022; 22: 127-131.

Sex-related differences in the effects of nutritional status and body composition on functional disability in the elderly.

BACKGROUND: The aim of our study was to evaluate the influence of changes of nutritional status and body composition on the results of comprehensive geriatric assessment (CGA) in inpatients of a geriatric ward. Sex differences in these relationships were also investigated. METHODS: A total of 212 elderly patients (>65 years old) admitted to the geriatric ward at the University of Tokyo hospital between 2012 and 2019 were enrolled in this study. CGA (ADL, IADL, MMSE, GDS, Vitality Index) was performed, along with assessment of body compositions (appendicular muscle mass, abdominal muscle mass, body fat mass) and blood malnutrition biomarkers (serum albumin, pre-albumin, 25-hydroxy vitamin D, zinc, hemoglobin concentrations). RESULTS: Multiple linear regression analysis showed that upper, lower limbs and abdominal muscle masses were significantly associated with the score on ADL in men. On the other hand, abdominal muscle mass was negatively associated with the scores on GDS. Body fat mass was also negatively associated with the score on IADL. In contrast, in women, multiple linear regression analysis failed to show any significant associations between body composition parameters and scores on any domains of CGA. Unlike in men, however, blood malnutrition biomarkers were significantly associated with ADL, IADL, MMSE, and Vitality Index in women. CONCLUSIONS: Our study findings revealed that the association of the nutritional status and body composition with the functional status in the elderly differs by sex. These results suggest that intensification of exercise in men and improvement of the nutritional status in women are particularly useful to maintain the functional status.

Cognitive function has a stronger correlation with perceived age than with chronological age.

AIM: The perceived age of older adults, as measured by their facial appearance, has been shown to be a robust biomarker of aging predictive of survival, telomere length and DNA methylation, and reportedly correlates with carotid atherosclerosis and bone status. This study aimed to determine whether metrics of dementia, including general cognition, vitality, depressive state and self-supportability, have stronger correlations with perceived age than with chronological age. METHODS: This study included 124 patients who were admitted to the Department of Geriatric Medicine, The University of Tokyo Hospital, on account of being suspected of cognitive decline. The Mini-Mental State Examination, Vitality Index, Geriatric Depression Scale-15, instrumental activities of daily living and Barthel Index were carried out. Five experienced geriatricians and five experienced clinical psychologists determined the perceived age of participants based on photographs. RESULTS: The average values of the 10 raters showed excellent reliability (intraclass correlation coefficient (3, 10) = 0.941). Steiger's test revealed that perceived age showed a significantly better correlation with the Mini-Mental State Examination (female) and Vitality Index (total, female) than did chronological age, but not with Geriatric Depression Scale-15, instrumental activities of daily living or the Barthel Index. CONCLUSIONS: Perceived age was shown to be a reliable biomarker for cognitive assessment. Geriatr Gerontol Int 2020; 20: 779-784.

Updated concept of sarcopenia based on muscle-bone relationship.

Sarcopenia is an age-related loss of skeletal muscle mass and strength. It has been widely recognized that low muscle mass was essential in the diagnosis of sarcopenia, whereas recent studies have emphasized the importance of muscle strength. In practice, muscle quality as well as muscle mass might determine the strength and physical performance. A new diagnostic algorithm of sarcopenia has recently been established, in which low muscle strength is a key characteristic factor for the diagnosis of sarcopenia. Although many factors are supposed to be involved in the pathology and development of sarcopenia, precise mechanisms remain to be elucidated. Recent studies have also focused on the crosstalk between muscles and bones, including functional involvement of myokines and osteokines.

[Aging-related frailty and sarcopenia. The relationship between "inflammaging" and frailty/sarcopenia.]

Aging is associated with a rise in serum levels of inflammatory markers. This chronic, low-grade inflammation is termed as "inflammaging", which might be involved in the pathogenesis of frailty/sarcopenia. Some clinical studies suggest the relationship between inflammation and frailty/sarcopenia.

Inhibition of interleukin-6 decreases atrogene expression and ameliorates tail suspension-induced skeletal muscle atrophy.

BACKGROUND: Interleukin-6 (IL-6) is an inflammatory cytokine. Whether systemic IL-6 affects atrogene expression and disuse-induced skeletal muscle atrophy is unclear. METHODS: Tail-suspended mice were used as a disuse-induced muscle atrophy model. We administered anti-mouse IL-6 receptor antibody, beta-hydroxy-beta-methylbutyrate (HMB) and vitamin D to the mice and examined the effects on atrogene expression and muscle atrophy. RESULTS: Serum IL-6 levels were elevated in the mice. Inhibition of IL-6 receptor suppressed muscle RING finger 1 (MuRF1) expression and prevented muscle atrophy. HMB and vitamin D inhibited the serum IL-6 surge, downregulated the expression of MuRF1 and atrogin-1 in the soleus muscle, and ameliorated atrophy in the mice. CONCLUSION: Systemic IL-6 affects MuRF1 expression and disuse-induced muscle atrophy.

[Aging-related changes in motor organs and energy metabolism.]

Aging causes loss of skeletal muscle mass and strength, which is termed as sarcopenia. Aging of the neurological system may affect motor organs. Reduced muscle mass and increased fat mass induce insulin resistance, which is one of the causes for impaired glucose tolerance in the elderly.

Age-related sarcopenia and its pathophysiological bases.

Age-related loss of the skeletal muscle and its function is known as sarcopenia. Definition and diagnostic criteria for sarcopenia have been outlined as consensus statements from several study groups, including usual gait speed, grip strength, and skeletal muscle mass. Whereas underlying mechanisms and pathophysiology of sarcopenia remains to be clarified, recent studies have suggested that chronic inflammatory status as well as lifestyle-related factors in older individuals might contribute to the process and progress of sarcopenia.