Authors: Sugimoto, Taiki | Ono, Rei | Kimura, Ai | Saji, Naoki | Niida, Shumpei | Toba, Kenji | Sakurai, Takashi
Article Type: Research Article
Abstract: Background: Cognitive frailty (CF) is defined as simultaneous presence of physical frailty (PF) and cognitive impairment among older adults without dementia. Although white matter hyperintensities (WMH) as expressions of cerebral small vessel disease are associated with physical and cognitive decline and could manifest as CF, this association remains yet to be clarified. Objects: To clarify the association between CF and WMH among memory clinic patients. Methods: The subjects of this cross-sectional study were 121 cognitively normal (CN) and 212 mildly cognitively impaired (MCI) patients who presented to the Memory Clinic at the National Center for Geriatrics and Gerontology of Japan. …PF status was defined based on the definition proposed by Fried and colleagues. CF was defined as simultaneous presence of pre-PF or PF and MCI. WMH volumes were measured using an automatic segmentation application. Multiple liner regression analyses with adjustment for cardiovascular risk factors were performed. Results: Of all subjects, 77 (63.6%) and 22 (18.2%) CN patients and 132 (62.3%) and 65 (30.7%) MCI patients were categorized into pre-PF and PF, respectively. Multiple liner regression analysis showed that those with CF had higher WMH volumes than those without (β= 0.23). When categorized into six groups according to PF and cognitive status, the PF/CN (β= 0.15), pre-PF/MCI (β= 0.41), and PF/MCI (β= 0.34) groups had higher WMH volumes than the non-PF/CN group. Conclusions: This study showed increased WMH volumes in CF and PF, indicating that WMH could be one of the key underlying brain pathologies of CF. Show more
Keywords: Cognitive frailty, frailty syndrome, mild cognitive impairment, physical frailty, white matter hyperintensity
DOI: 10.3233/JAD-190622
Citation: Journal of Alzheimer's Disease, vol. 72, no. 2, pp. 605-612, 2019
Authors: Sugimoto, Taiki | Yoshida, Masaki | Ono, Rei | Murata, Shunsuke | Saji, Naoki | Niida, Shumpei | Toba, Kenji | Sakurai, Takashi
Article Type: Research Article
Abstract: Background: Urinary incontinence (UI) is frequently observed in patients with Alzheimer’s disease (AD). Although previous works highlight the association between frontal lobe-related function and UI, causal relationship is unclear. Objects: To clarify the longitudinal association between frontal lobe function and the incidence of UI at 1 year in patients with AD. Methods: The subjects were 215 continent AD patients who attended the Memory Clinic of the National Center for Geriatrics and Gerontology of Japan during the period from March 2011 to December 2014. The absence or presence of UI was operationally assigned by the dementia behavior disturbance scale subscale, which …was completed by the patients’ caregivers. Frontal lobe function was assessed using the Frontal Assessment Battery (FAB). Other confounding factors including demographic data, cognitive status, vitality, mood, physical performance, and use of medication (cholinesterase inhibitors, calcium channel blockers [CCBs], diuretics, alpha blockers and anticholinergic drugs) were assessed. Results: During 1-year follow up (mean: 377.4±83.7 days), the incidence of UI was 12.1% (n = 26). Patients with UI had significantly lower FAB performance at baseline (no UI versus UI = 9.3±2.8 versus 7.8±2.7). In multivariate analysis, stepwise logistic regression analysis demonstrated that FAB (odds ratio [OR] = 0.79, 95% confidence interval [CI] = 0.66–0.94) and the use of CCB (OR = 2.72, 95% CI = 1.09–6.77) were significantly associated with UI at 1 year. Conclusion: The results of study indicate that frontal lobe dysfunction is predictor for UI in patients with AD. Show more
Keywords: Alzheimer’s disease, calcium channel blocker, cholinesterase inhibitors, frontal lobe function, urinaryincontinence
DOI: 10.3233/JAD-160923
Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 567-574, 2017
Authors: Saji, Naoki | Ishihara, Yuichi | Murotani, Kenta | Uchiyama, Akira | Takeda, Akinori | Sakurai, Takashi | Matsushita, Kenji
Article Type: Research Article
Abstract: Background: Periodontal disease (PeD) is a risk factor of Alzheimer’s disease and is associated with cognitive decline in older adults. However, the relationships between subitems of neuropsychological tests and PeD have not been fully clarified. Objective: To evaluate associations between PeD and subitems of neuropsychological tests. Methods: We performed a cross-sectional analysis of data of 183 participants (women: 50%, mean age: 79 years) from a clinical study. We enrolled patients who visited our memory clinic and assessed demographics, dementia-related risk factors, neuropsychological tests, brain magnetic resonance images, and a dental screening check. We evaluated the relationships between cognitive function and …PeD using multivariable logistic regression analyses. Results: Participants with dementia were less likely to make periodical visits to the dentist, had fewer teeth, had less frequent tooth brushing habits, and were more likely to have PeD. Impaired cognitive function was significantly associated with an increasing degree of PeD. In multivariable logistic regression analyses, impaired visuospatial function and attention were associated with twice the risk of moderate or severe PeD compared with individuals with preserved visuospatial function and attention (odds ratio: 2.11, 95% confidence interval: 1.04–4.29, p = 0.037). Impaired word recall and recognition and following commands were associated with increased risk of PeD (odds ratio: 2.80, 95% confidence interval: 1.41–5.32, p = 0.003). Conclusions: Cognitive decline, such as impaired visuospatial function, attention, word recall and recognition, and inability to follow commands were independently and strongly associated with PeD. These items can be assessed easily on a daily basis. Show more
Keywords: Alzheimer’s disease, cognitive decline, dementia, oral health, periodontal disease, periodontitis
DOI: 10.3233/JAD-230742
Citation: Journal of Alzheimer's Disease, vol. 96, no. 1, pp. 369-380, 2023
Authors: Tsujimoto, Masashi | Suzuki, Keisuke | Saji, Naoki | Sakurai, Takashi | Ito, Kengo | Toba, Kenji
Article Type: Research Article
Abstract: Background: With increasingly aging societies, a comprehensive strategy for dementia research is important. The Organized Registration for the Assessment of dementia by the Nationwide General consortium toward Effective treatment (ORANGE) Registry is the first longitudinal multicenter prospective trial-ready cohort in Japan. Objective: To establish a large cohort for use in clinical trials and research in Japan. Methods: This registry, based on communities, hospitals, and nursing homes, covers three dementia stages (preclinical, mild cognitive impairment [MCI], and advanced dementia), and includes more than 30 hospitals. We analyzed enrollment and 1-year follow-up data for disease progression. Results: There were 1450 registered patients …(649 men, 801 women; mean age, 77.92±6.70 years; mean Mini-Mental State Examination [MMSE] score, 25.19±2.76). The conversion rates from MCI to dementia and MCI to normal were 14.3% and 1.1%, respectively. High Clinical Dementia Rating score (odds ratio [OR] = 11.085, 95% confidence interval [CI]:1.619–75.913, p = 0.014), low MMSE score (OR = 0.835, 95% CI: 0.761–0.917, p < 0.001), high Geriatric Depression Scale score (OR = 1.093, 95% CI: 1.005–1.189, p = 0.038), and low body mass index (OR = 0.895, 95% CI: 0.829–0.967, p = 0.005) at enrollment were significant factors for conversion. Conclusion: The ORANGE MCI Registry is an established registry that facilitates creation of trial-ready cohorts to accelerate promotion of clinical trials with low reversion rates as it originates from a hospital. One-year follow-up analysis suggested assessing various factors for conversion risk. Further analyses will be possible in future with registry expansion. We will continue to refine this registry, including how it can be used more efficiently. Show more
Keywords: Alzheimer’s disease, cognitive dysfunction, dementia, humans, longitudinal studies, preventive medicine, registries
DOI: 10.3233/JAD-220039
Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1423-1433, 2022
Authors: Kinjo, Yoshino | Saji, Naoki | Murotani, Kenta | Sakima, Hirokuni | Takeda, Akinori | Sakurai, Takashi | Ohya, Yusuke | Kusunose, Kenya
Article Type: Research Article
Abstract: Background: Recent studies have demonstrated an association between pulse wave velocity (PWV), cerebral small vessel disease (SVD), and cognitive impairment such as Alzheimer’s disease. However, the association between brachial-ankle PWV and enlarged perivascular spaces (EPVS), one component of cerebral SVD remains controversial. Objective: To investigate the relationship between brachial-ankle PWV and EPVS severity in participants without dementia. Methods: We performed a cross-sectional study of data of 74 participants from sub-analysis of ongoing research. We assessed cognitive function, brachial-ankle PWV, and brain magnetic resonance imaging (MRI) features. Using brain MRI, EPVS were separately assessed as basal ganglia (BG)-EPVS or centrum semiovale …(CSO)-EPVS on the basis of their location. The relationship between EPVS severity and brachial-ankle PWV was evaluated using multivariable ordinal logistic regression analyses. Results: We analyzed 74 participants (women: 47%, mean age: 73 years, mild cognitive impairment [MCI]: 74%). Compared with participants with normal cognition, those with MCI were more likely to have both severe BG-EPVS and severe CSO-EPVS. In multivariable analyses, high brachial-ankle PWV and age were independently associated with BG-EPVS severity (odds ratio [95% confidence interval]: 1.19 [1.02–1.38], 1.09 [1.01–1.17], respectively), whereas only age was independently associated with CSO-EPVS severity. A causal mediation analysis under a counterfactual approach revealed a significant pure natural indirect effect of brachial-ankle PWV on MCI that was mediated by BG-EPVS (estimate: 1.04, 95% CI: 1.01–1.12, p = 0.006). Conclusions: Brachial-ankle PWV was associated with BG-EPVS severity. High PWV may cause cerebrovascular pulsatility, which accelerates BG-EPVS and may worsen cognitive impairment. Show more
Keywords: Alzheimer’s disease, cerebral small vessel disease, cognitive decline, enlarged perivascular spaces, pulsatility, pulse wave velocity
DOI: 10.3233/JAD-240589
Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 627-636, 2024
Authors: Sugimoto, Taiki | Ono, Rei | Kimura, Ai | Saji, Naoki | Niida, Shumpei | Sakai, Toshihiro | Rakugi, Hiromi | Toba, Kenji | Sakurai, Takashi
Article Type: Research Article
Abstract: Background: Very few studies have investigated the impact of cognitive frailty in clinical settings, especially in memory clinic populations. Objective: To examine the impact of cognitive frailty on activities of daily living (ADL), cognitive function, and conversion to dementia among memory clinic patients with mild cognitive impairment (MCI). Methods: The subjects of this retrospective study were 248 MCI patients (mean age, 76.3±5.4 years; females, 60.9%). All subjects completed a comprehensive geriatric assessment at baseline and at least one assessment during 3-year follow-up. Frailty was defined by generating a frailty index (FI), and MCI patients with frailty (FI≥0.25) were considered to …represent cognitive frailty. As primary outcomes, the Barthel Index, Mini-Mental State Examination, and incident dementia were evaluated during follow-up. At baseline, patients were assessed for apolipoprotein E (APOE ) phenotype. A linear mixed model, as well as a Cox proportional hazards regression model with adjustment for confounding variables, was performed. Results: Of these patients, 75 (30.2%) were classified as cognitive frail. APOE ɛ 4 carriers accounted for 26.7% of those with cognitive frailty and 44.5% of those without (p = 0.008). Cognitive frail patients showed a faster ADL decline (estimate, –1.04; standard error, 0.38; p = 0.007) than patients without cognitive frailty. Cognitive frailty was not associated with cognitive decline and incident dementia. Conclusion: Our findings demonstrated cognitive frailty increases the risk of dependence but not cognitive outcomes. Cognitive frailty may have heterogeneous conditions, including APOE ɛ 4-related pathologies, which may affect the cognitive trajectories of patients with MCI. Show more
Keywords: Cognitive frailty, disability, frailty, memory clinic, mild cognitive impairment, older persons
DOI: 10.3233/JAD-191135
Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 895-903, 2020
Authors: Saji, Naoki | Murotani, Kenta | Sato, Naoyuki | Tsuduki, Tsuyoshi | Hisada, Takayoshi | Shinohara, Mitsuru | Sugimoto, Taiki | Niida, Shumpei | Toba, Kenji | Sakurai, Takashi
Article Type: Research Article
Abstract: Background: Previous studies have demonstrated associations between gut microbiota, microbial metabolites, and cognitive decline. However, relationships between these factors and neurofilament light chain (NfL; a disease-nonspecific biomarker of neural damage) remain controversial. Objective: To evaluate the associations between plasma NfL, gut microbiota, and cognitive function. Methods: We performed a cross-sectional sub-analysis of data from our prospective cohort study that was designed to investigate the relationship between gut microbiota and cognitive function. Patients who visited our memory clinic were enrolled and demographics, dementia-related risk factors, cognitive function, brain imaging, gut microbiomes, and microbial metabolites were assessed. We evaluated the relationships between …the gut microbiome, microbial metabolites, and plasma NfL. Moreover, the relationships between plasma NfL and cognitive function were assessed using multivariable logistic regression analyses. Results: We analyzed 128 participants (women: 59%, mean age: 74 years). Participants with high (above the median) plasma NfL concentrations tended to be older, women, and hypertensive and have a history of stroke, chronic kidney disease, and dementia. Plasma NfL was also associated with cerebral small vessel disease. However, plasma NfL levels were not significantly correlated with gut microbial metabolites. Multivariable analyses revealed that a higher plasma NfL concentration was independently associated with the presence of dementia (odds ratio: 9.94, 95% confidence interval: 2.75–48.2, p < 0.001). Conclusion: High plasma NfL concentration was independently associated with the presence of dementia as previously reported. However, plasma NfL levels were not significantly correlated with gut microbial metabolites in this preliminary study. Show more
Keywords: Biomarkers, cerebral small vessel disease, cognitive decline, dementia, gut microbiota
DOI: 10.3233/JAD-215141
Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1323-1335, 2022
Authors: Saji, Naoki | Saito, Yoshihiro | Yamashita, Tomoya | Murotani, Kenta | Tsuduki, Tsuyoshi | Hisada, Takayoshi | Sugimoto, Taiki | Niida, Shumpei | Toba, Kenji | Sakurai, Takashi
Article Type: Research Article
Abstract: Background: Previous studies have demonstrated associations between gut microbiota, microbial metabolites, and cognitive decline. However, relationships between these factors and lipopolysaccharides (LPS; molecules of the outer membrane of gram-negative bacteria) remain controversial. Objective: To evaluate associations between plasma LPS, gut microbiota, and cognitive function. Methods: We performed a cross-sectional sub-analysis of data of 127 participants (women: 58%, mean age: 76 years) from our prospective cohort study regarding the relationship between gut microbiota and cognitive function. We enrolled patients who visited our memory clinic and assessed demographics, dementia-related risk factors, cognitive function, brain imaging, gut microbiomes, and microbial metabolites. We evaluated …relationships between cognitive decline and plasma LPS using multivariable logistic regression analyses. Results: Plasma LPS concentration increased with increasing degree of cognitive decline and total cerebral small vessel disease (SVD) score (Kruskal-Wallis test; p = 0.016 and 0.007, respectively). Participants with high plasma LPS concentrations tended to have lower concentrations of gut microbial metabolites, such as lactic acid and acetic acid, and were less likely to consume fish and shellfish (44.7% versus 69.6%, p = 0.027) than those with low plasma LPS concentrations. Multivariable analyses revealed that plasma LPS concentration was independently associated with the presence of mild cognitive impairment in participants without dementia (odds ratio: 2.09, 95% confidence interval: 1.14–3.84, p = 0.007). Conclusion: In this preliminary study, plasma LPS concentration was associated with both cognitive decline and cerebral SVD and significantly correlated with beneficial gut microbial metabolites. Plasma LPS may be a risk factor for cognitive decline. Show more
Keywords: Biomarkers, cerebral small vessel disease, cognitive decline, dementia, gut microbiota
DOI: 10.3233/JAD-215653
Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1947-1957, 2022
Authors: Sugimoto, Taiki | Nakamura, Akinori | Kato, Takashi | Iwata, Kaori | Saji, Naoki | Arahata, Yutaka | Hattori, Hideyuki | Bundo, Masahiko | Ito, Kengo | Niida, Shumpei | Sakurai, Takashi | MULNIAD study group
Article Type: Research Article
Abstract: Background: Weight loss is frequently observed in patients with Alzheimer’s disease (AD); however, the underlying mechanisms are not well understood. Objects: To clarify the associations between nutritional status and AD-related brain changes using Pittsburgh Compound-B (PiB)-PET, fluorodeoxyglucose (FDG)-PET, and structural MRI. Methods: The subjects were 34 amyloid-β (Aβ)-positive individuals with mild cognitive impairment or early AD (prodromal/early AD), and 55 Aβ-negative cognitively normal (CN) subjects who attended the Multimodal Neuroimaging for AD Diagnosis (MULNIAD) study. Nutritional status of the subjects was assessed by body mass index and waist to height ratio (waist circumference/height). The associations between nutritional status and brain …changes were examined by multiple regression analysis using statistical parametric mapping. Results: In the prodromal/early AD group, nutritional status was significantly positively correlated with regional cerebral glucose metabolism (rCGM) in the medial prefrontal cortices, while different topographical associations were seen in the CN group, suggesting these changes were AD-specific. Aβ deposition and gray matter volume were not significantly associated with nutritional status. Sub-analysis in the prodromal/early AD group demonstrated that fat mass index, but not fat-free mass index, was positively correlated with rCGM in the medial prefrontal areas. Conclusion: This present study provides preliminary results suggesting that hypometabolism in the medial prefrontal areas is specifically associated with AD-related weight loss, and decrease in fat mass may have a key role. Show more
Keywords: Alzheimer’s disease, composition, 18F fluorodeoxyglucose, Pittsburgh Compound B, magnetic resonance imaging, nutritional status, positron-emission tomography
DOI: 10.3233/JAD-170257
Citation: Journal of Alzheimer's Disease, vol. 60, no. 1, pp. 225-233, 2017
