In a cross-sectional study of United States women sampled from the 2010–2011 and 2013–2014 NHANES, serum sodium levels were positively associated with cognitive test scores in the elderly. Serum sodium levels were positively associated with CERAD WLT scores, which assess the memory sub-domain. Compared to individuals with normal sodium levels, individuals with serum sodium levels below 135 mmol/L showed lower CERAD WLT (memory sub-domain) and AFT (executive function) scores. The relationship between hyponatremia status and the DSST, which assesses processing speed, sustained attention, and working memory scores, was no longer significant after adjustment. In short, serum sodium levels were significantly associated with the memory sub-domain assessed by the CERAD WLT and executive function assessed by the AFT, but not with processing speed, sustained attention, and working memory evaluated by the DSST.
In line with the results of our study, previous studies have reported an association between low sodium levels and cognitive function; however, these studies have only examined single domains of cognitive function (i.e. attention), or have assessed multiple domains grouped as a single variable. A case-control study performed in a general hospital in Brussels reported that individuals with low serum sodium levels (n = 122, range: 115–132 mmol/L, mean ± standard deviation [SD] = 126 ± 5 mmol/L) were associated with a higher odds of falling (odds ratio [OR] = 67.43, 95% confidence interval [CI] = 7.48–607.42) and significantly slower mean response times in the attention tests (difference: 58 milliseconds, P < .001) compared to individuals with normal sodium levels (n = 244, mean ± SD = 139 ± 2 mmol/L) (7). Eight different visual and auditory attention tests were included in the battery of attentional tests (7). A cross-sectional study from the Hunter Community Study, a population-based prospective cohort study in Australia revealed that subjects with serum sodium levels equal to 130 mmol/L showed lower ARCS tool scores compared to individuals with serum sodium levels equal to 135 mmol/L (8). The ARCS scores is a vague tool which reflects a wide range of cognitive domains (22). A recent study from the Osteoporotic Fractures in Men study, revealed that men with sodium levels of 126–140 mmol/L were associated with a 1.30 odds (95% CI = 1.06–1.61) of cognitive impairment, compared to individuals with sodium levels of 141–142 mmol/L. In this study, cognitive impairment was defined as a modified Mini-Mental Status score less than 84 or a Trail Making Test Part B time greater than 233 seconds (9). In addition, a study conducted in 150 patients aged 70 years and older from the University Hospital Cologne, showed that resolution of hyponatremia (< 130 mmol/L) by > 5 mmol/L was significantly associated with an increase in MMSE scores (ΔMMSE: 1.8 ± 3.0 vs. 0.7 ± 1.9; p = 0.002) (23). Reversibility has also been reported in previous animal studies mentioned below (24, 25).
The mechanisms behind this association is unclear; however, abnormalities in brain osmolyte levels such as glutamate may play a role (6, 24, 25). In chronic hyponatremia, brain cells export osmolytes such as glutamate, which may influence memory (26, 27). An animal study showed that sustained low levels of serum sodium concentrations caused reversible cognitive impairment measured by a novel object recognition test and contextual fear conditioning tests (25). In vivo analysis of brain samples from chronic hyponatremic rats in this study revealed elevated extracellular glutamate concentrations in the hippocampus and decreased glutamate uptake by astrocyte cultures (25, 28). In addition, another study in rats proposed brain cell swelling as another explanation. In this study, rats with chronic hyponatremia, which showed reversible memory impairments assessed using the passive avoidance test, also showed brain swelling (24). However, the reason why lower serum sodium levels are associated with memory sub-domain and executive function, in contrast to sustained attention, working memory, and processing speed, is unknown, and further studies are recommended to clarify the mechanism behind such association.
Our study has examined the relationship between serum sodium levels and various cognitive domains in a nation-wide population of US adults. Nevertheless, our study has several limitations. Firstly, due to the cross-sectional nature of the study, any casual or temporal relationships cannot be assessed. Moreover, due to the cross-sectional nature of the NHANES data, we were unable to differentiate between acute and chronic hyponatremia. Despite this fact, it is more likely that the sodium status of most participants reflect chronic levels as acute changes in sodium levels are known to cause neurologic symptoms (i.e. seizures and altered mental status) as a result of cerebral edema (3). Thirdly, the relationship between cognitive test scores and serum sodium levels may not necessarily be linear. Resultantly, our results may not be generalized to populations with different sodium levels. Fourthly, although we have considered basic sociodemographic variables, GFR, and serum glucose levels as covariates, previous studies have also included disease history and quality-of-life measures (7, 9). Therefore, we cannot completely eliminate the possibility of residual confounding. Fifthly, the range of cognitive test scores performed by the NHANES remains limited, and further studies evaluating the relationship between other domains of cognitive function and serum sodium levels are recommended.