Participants
We enrolled 2962 elderly participants with normonatremia (SNa 136-145 mEq/) and 75 with hyponatremia (SNa 130-135 mEq/L) aged ≥ 70 years who visited the National Center for Geriatrics and Gerontology (NCGG) for assessment of memory disorder between September 2010 and November 2017. None of the participants had any severe symptoms such as nausea, vomiting, confusion, or seizures, and all were able to carry out at least 1 of the following 3 physical function tests: grip strength (GS), walking speed (WS), and the one-leg standing (OLS) test. To eliminate pseudohyponatremia and the effect of disease on physical or cognitive function, the following inclusion criteria were adopted: (1) no history of stroke; (2) no pseudohyponatremia (TP ≤ 8.0, Glu ≤ 400, TH < 500, and T-cho ≤ 280); and (3) not taking medication for Parkinson’s disease (e.g., L-dopa, dopamine agonist, trihexyphenidyl, and amantadine).
The study was approved by the NCGG Ethics Committee. All participants provided informed consent before enrollment in the study.
Clinical Measures
The following self-reported and caregiver-reported measures were obtained based on previous studies(4, 6, 8-10): age, sex, and years of education, alcohol consumption, body mass index (BMI), history of cardiac disease, diabetes, liver disease, lung disease, depression, chronic kidney disease (CKD), cancer, dementia diagnosis, joint pain, visual impairment, hearing impairment, diuretic use, antibiotics use (e.g., clarithromycin, levofloxacin, and minocycline hydrochloride), proton pump inhibitor use, non-steroidal anti-inflammatory drug (NSAID) or acetaminophen use, antiepileptic use (e.g., sodium valproate, and carbamazepine), antipsychotic use (e.g., risperidone, haloperidol, and aripiprazole), noradrenergic and specific serotonergic antidepressant (NaSSA) use, selective serotonin reuptake inhibitor (SSRI) or serotonin noradrenaline reuptake inhibitor (SNRI) use, benzodiazepine use (e.g., alprazolam, brotizolam, etizolam, and flunitrazepam), and frequency of physical activity. Those who consumed > 60.0 g/day of alcohol were defined as heavy drinkers. No exercise per week was defined as inactivity. Potassium, calcium, brain natriuretic peptide, estimated glomerular filtration rate, C-reactive protein (CRP), hemoglobin (Hb), thyroid-stimulating hormone, and vitamin B12 were checked from their blood samples. Anemia was defined their serum Hb was < 11.0g/dL. Hypothyroidism was defined as a serum thyroid-stimulating hormone level of 10 μIU/mL or less. Vitamin B12 deficiency was defined as a serum vitamin B12 level of < 200 pg/mL.
Assessment of SMM, physical function, and sarcopenia
Body weight and SMM were assessed using a multi-frequency body composition analyzer (MC-180 Multi-Frequency Body Composition Analyzer; Tanita, Tokyo, Japan), which is a scale that uses bioelectrical impedance analysis to determine body composition. We calculated BMI (body weight [kg]/height squared [m2]) and SMM index (SMI; i.e., SMM [kg]/height squared [m2]). Low SMM was defined as SMI < 7.0 kg/m2 in men and < 5.7 kg/m2 in women.(11)
Physical function was assessed by measuring GS, WS, and OLS time. Muscle strength was from upper extremity strength measured with a digital force gauge (ZP 500N; Imada, Toyohashi, Japan).(12) The best GS (kg) was determined, with low muscle strength defined as < 28 kg in men and < 18 kg in women, in accordance with the Asian Working Group for Sarcopenia (AWGS) criteria.(11) Velocity was determined by measuring normal WS, with poor physical performance defined as WS < 1.0 m/s.(11) Postural function was assessed using the OLS test, which measures the time in seconds (up to a maximum of 60 s) that participants can stand unassisted on one leg for as long as possible with their eyes open. The best score was used for the analysis.(9) Impaired postural function was defined as OLS time < 15 s according to the locomotive syndrome criteria.(13) Sarcopenia was defined as low SMM, low muscle strength, and/or low physical function.(11)
Assessment of cognitive function
Cognitive function was assessed with the Mini-Mental State Examination (MMSE),(14) executive function with the Frontal Assessment Battery (FAB),(15) working memory with the Digit Span subtest (forward and backward) of the Wechsler Adult Intelligence Scale,(16) attention with the category fluency subtest of the Hasegawa Dementia Rating Scale-Revised,(17) and memory with the Logical Memory II subtest of the Wechsler Memory Scale-Revised (WMS-R).(18)
Cognitive impairment was indicated by MMSE score ≤ 23, FAB score £ 11,(19) Digit Span forward score £ 5, Digit Span backward score £ 3, category fluency test score £ 5, and WMS-R Logical Memory II subtest raw score £ 8 for > 16 years of education, £ 4 for 8-15 years of education, and £ 2 for 0-7 years of education.(20) Depressive mood was assessed using the Geriatric Depression Scale 15 (GDS-15),(21) with a score ³ 10 indicating severe depressive mood.(22) All of the cognitive test results were reviewed by neuropsychologists.
Statistical analysis
The Chi-squared test and Mann–Whitney’s U test were used to investigate differences in characteristics between mild hyponatremia and normonatremia. One-way analysis of covariance (ANCOVA) was used to identify significant differences between the 2 groups in SMI, the 3 physical function test scores, and all the neuropsychological test scores after controlling for covariates. Then, multiple logistic regression analysis was conducted to examine the correlation between mild hyponatremia and sarcopenia, SMI, physical function test scores, and all the neuropsychological test scores. Cutoff scores for these dependent variables were based on the studies mentioned above. All the variables whose p-value was < 0.2 in Table 1 were selected as covariates for both ANCOVA and multiple regression analysis as shown under Table3 and 4. All analyses were performed using SPSS Statistics for Windows ver. 26.0 (IBM Corp., Armonk, NY). A p-value < 0.05 was considered significant.