To the best of our knowledge, this longitudinal study is the first to provide a comprehensive picture of BD patients with cognitive decline through long-term follow-up, and the results suggested the existence of subgroups with different cognitive trajectories. We classified our patients into two groups according to presence or absence of cognitive decline and correlated cognitive decline to their daily dysfunctions. We revealed that old age, baseline BMI > 25, and more number of manic episodes are risk factors for cognitive decline. Furthermore, we demonstrated a hinge at the age of 40 years with steeper decline of cognition in the cognitive decline group.
In our study, the picture of BD patients with longitudinal cognitive decline shows substantial degree of impairment, rather than on only some specific cognitive domains, which is consistent with most previous cross-sectional studies (Van Rheenen et al. 2020). Moreover, the magnitude of cognitive dysfunction reported in previous cross-sectional studies, which used BAC-A to assess cognitive function in BD, is similar to that obtained by combining the two subgroups in the present study (Bauer et al. 2015, Terachi et al. 2017). Our findings, showing longitudinal changes of BD are robust as suggested by those of previous cross-sectional literature. On the other hand, our findings of longitudinal cognitive heterogeneity in a subset of patients with BD are important and can partially explain the diverse and inconsistent findings for clinical characteristics and risk factor identification in the literature. In our study, the longitudinal cognitive decline group comprised nearly one-third of our sample, and this group may be established as a specific subtype of BD. Such longitudinal cognitive profiles can potentially facilitate further genetic and biological studies and help clinicians develop more effective intervention strategies (Solé et al. 2017). As we had suggested, the heterogeneity of the cognitive trajectory conformed to the progress of illness in clinical manifestation staging models including cognitive deterioration (de la Fuente-Tomas et al. 2020). Our findings revealed that cognitive decline varies from one patient to another, with decline in certain patients while others remain stable. Conversely, we may say that some patients maintained relatively stable cognitive function might be cognitive reserve, which reflects the partial capacity of the brain to endure neuropathology and minimize clinical cognitive deficits (Kohler et al. 2019). For the statement about the paradigms of cognitive impairment in BD as persistently stable or progressive are not exclusive or may partially overlap (Allott et al. 2020). The verification of heterogeneity of longitudinal cognitive change in our BD samples further comprehend the different faces of cognition in BD.
The risk factors identified for cognitive decline in BD suggest the converging evidence that patients with BD show cognitive impairment related to the clinical course and inflammation theory. For example, a cohort study that assessed longitudinal cognitive changes in BD showed that a higher number of manic episodes is associated with a decrease in global cognition as well as working memory and visual memory (Sanchez-Morla et al. 2019). However, most previous studies have not considered potential heterogeneity and have thus compared all BD together with healthy controls, leading to masking subgroup findings of cognitive change over time in BD (Santos et al. 2014, Ryan et al. 2016, Schouws et al. 2016, Sanchez-Morla et al. 2019). Previous studies have also implied the association of cognitive impairment with other adverse clinical characteristics, such as psychotic features or duration of illness; however, this link was not confirmed in other reports and neither in our study (Suwalska et al. 2001, Bora et al. 2007, Volkert et al. 2016). Moreover, current evidence associates cognitive deficits observed in individuals diagnosed with BD with an increased inflammatory state and decreased neurotrophic factors (Bauer et al. 2014). Recently, obesity has been proven to be associated with chronic systemic inflammation and the release of proinflammatory cytokines (Rodriguez-Hernandez et al. 2013). Peterman et al. also suggested the combined negative effects of obesity and diagnosis of BD on cognition (Peterman et al. 2020). Although our finding implied the pathway from being overweight or obese to cognitive decline in patients with BD, very little is known about why some patients with BD develop significant cognitive decline while others remain cognitively intact. We recommend that interventions targeting the risk factors of manic episode and high BMI would be effective in preventing cognitive decline in patients with BD and for detecting the underlying mechanism. Moreover, the subgroup of BD patients with cognitive decline showed steeper changes after the age of 40 years compared with those without cognitive decline, which is consistent with decline associated with accelerated aging in executive functions in BD (Seelye et al. 2019). We suggested that clinicians should pay attention to patients’ cognitive function before they reach middle age. Future research should focus on early intervention to determine whether it can delay the decline of cognition in BD.
Psychosocial function is a person’s ability to perform activities of daily living and to be involved in meaningful interpersonal relationships. As per our results, patients with BD have difficulties in several areas of function during their remitted status. These results are consistent with those of other studies demonstrating that most patients with BD have functional difficulties (Rosa et al. 2009, Samalin et al. 2016, Comes et al. 2017). However, there was no difference of functional outcome in patients with and without cognitive decline assessed by WHODAS 2.0. There may be possible floor effect of this subjective assessment for this population. We used the WHODAS 2.0 for evaluating our patients, rather than disease-specific questionnaires, such as Functioning Assessment Short Test (FAST), because the former disability assessment is more informative by comparing with general norm or other diseases. Results from the partial correlation analysis between cognitive and functional domains, controlling for age, indicated that the cognitive profile was correlated with some functional domains mainly in the subgroup of BD patients with cognitive decline. These results are in line with those of cross-sectional studies showing that the cognition-function relationship may be weaker among patients without cognitive deficits than among those with cognitive impairment (Moore et al. 2015). The distinct correlation results among patients with BD also responded to those of a previous study conducted by Sole et al. They suggested the more robust correlation between the poor function group of BD to their cognitive function and smaller correlations in less functional impair BD (Sole et al. 2018). In addition, the cluster of poor functional BD classified by Sole et al. revealed that the occupational domain was associated with executive function and verbal learning tests, which is consistent with our findings even with different cognitive measurements in the current study (Sole et al. 2018).
Several limitations should be considered of this study. First, our study sample was recruited from a tertiary psychiatry hospital where patients have more severe degree of illnesses. This is a potentially biased sample and may limit the generalizability of our findings to the whole BD population, especially the proportion with cognitive decline. Second, without a healthy control group, cognitive decline in patients should be viewed as evidence of relative cognitive decline. Furthermore, the restricted sample size limited the power to examine interaction effects among potential variables, such as interaction of disease course and medications. Third, WHODAS 2.0 is an interviewer-administered tool assessing subjective disability; a combination of objective measures may provide a more comprehensive outcome picture for BD patients with and without cognitive decline. Four, underlying mechanism between risk factors, cognitive decline, and functioning stilled need further investigation. Finally, the dichotomous categorized definition about cognitive decline in our study is arbitrary. However, the potential of misclassification is non-differential and bias the odds ratio toward the null, which suggested the robustness of our findings.