The Nakajima Study is an ongoing population-based longitudinal cohort study that investigates cognitive decline in older Japanese people. The study was conducted in Nakajima, Nanao City, Ishikawa Prefecture, Japan. The study design has been described previously21. From 2016 to 2018, a total of 2,454 residents aged 60 or older (92.9% of the total population in this age group) participated in the dementia screening examination. To clarify whether frailty is a risk factor for cognitive impairment in older people without cognitive impairment, we excluded patients with dementia (n = 364) and MCI (n = 427). MCI and dementia were confirmed according to the clinical criteria defined by Petersen et al.22 and the Third Diagnostic and Statistical Manual of Mental Disorders, Revised Edition (DSM-III-R)23. We also excluded people who had bleeding and/or ischemic lesions on MRI, regardless of the presence or absence of neurological symptoms (n=59), no brain MRI (n=632 ) or lack of assessment of physical frailty (n = 302) (Fig. 1). Hemorrhagic and/or ischemic stroke lesions were reported by two trained neuroradiologists blind to the clinical information. People with terrible high blood pressure (blood pressure levels ≥ 180/110 mmHg) and people with leg pain while walking were excluded from physical frailty assessments.
Finally, 670 people were enrolled for the analysis (286 men, 384 women; age, mean [standard deviation, SD] is 70.1 [6.4] years).
Standard Protocol Approvals and Participant Consent
This study was conducted under the guidelines of the Declaration of Helsinki and all procedures were approved by the Kanazawa University Medical Ethics Committee (approval number 2185). We obtained written informed consent from all participants.
Structural MRI studies were performed using a 1.5 T system (ECHELON RX; Hitachi, Japan). A 3D volumetric acquisition of T1-weighted turbo field echo images was performed according to the brain MRI protocol for the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study.24 (Echo time/repetition time, 4.0/9.2 ms; tilt angle, 8°; field of view, 240 mm; acquisition matrix, 192 × 192; number of slices, 170; size of voxel, 0.9375 × 0.9375 mm; slice thickness, 1.2 mm). All T1 structural images were analyzed using FreeSurfer version 5.3 (FreeSurfer version 5.3; http://surfer.nmr.mgh.harvard.edu)25 at Tohoku University and preprocessed in the standard way. Region of interest volumes were created by FreeSurfer26, and HV and WMHV were calculated as the sum of right and left hippocampal volumes and white matter hypointensities, respectively. TBV was calculated by summing white and gray matter volumes and eTIV was used to normalize each volumetric value. In this study, we assessed three parameters, namely TBV/eTIV ratio (%), HV/eTIV ratio (%), and WMHV/eTIV ratio (%), to determine potential indices of brain atrophy , hippocampal atrophy, and severity of small vessel brain disease, respectively.
Assessment of physical frailty
This study assessed physical frailty and its phenotype according to Fried’s criteria14, namely weight loss, sluggishness, weakness, exhaustion and low physical activity. We collected data from 2016 to 2018 and assessed physical frailty using the Revised Japanese Version of Cardiovascular Health Study Criteria (Revised J-CHS Criteria)27. except exhaustion.
Weight loss was assessed by responses to the self-reported question “Have you (unintentionally) lost 2 kg or more in the past 6 months?” (“Yes” = 1 point). Slowness was defined as a comfortable walking speed 28. Low physical activity was assessed by responses to the self-reported questions “Do you do low levels of physical exercise?” and “Do you exercise or play sports at moderate levels?” (“No” to both = 1 point). Based on these definitions, we defined the fragile group as having 3 or more points, the prefragile group as having 1 or 2 points, and the robust group as having 0 points. Since only 10 people were part of the fragile group, we analyzed the fragile group with the prefragile group.
Other measures of risk factors
Each participant completed a self-administered questionnaire containing questions on socio-demographic data (age, gender and level of education), medical history (diabetes mellitus and hypertension), information on medications, smoking and drinking habits. . Completed questionnaires were reviewed by trained researchers to identify inconsistent or unanswered items. Depressive symptoms were assessed using the GDS–Short Form29, and a GDS score ≥ 6 was used to denote depressive symptoms. Blood pressure was measured three times using a sphygmomanometer, with an interval of at least 5 min. The average of the three measurements was used for further analysis. Hypertension was determined by blood pressure levels ≥ 140/90 mmHg or current use of antihypertensive agents. Body mass index (BMI, kg/m2) has been measured as an indicator of obesity. Serum high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol levels were measured enzymatically30. The ApoE phenotype was determined by isoelectric electrophoresis as described by Kamboh et al.31.
Clinical characteristics of each frailty state were compared using t-test for mean values of continuous variables, Mann-Whitney U-test for median MMSE and GDS values, and chi-square test for continuous and categorical variables. One to two tails p 32. The adjusted FDR p values (i.e. qvalues) less than 0.05 were considered statistically significant. SPSS software (version 26; SPSS Inc., Chicago, IL, USA) was used to perform all statistical analyses.