• ageing
• bipolar disorder
• cognitive impairment
• neurodegeneration

Background: patients with bipolar disorder (BD) display an increased risk of developing cognitive impairment (CI) of any type, but our knowledge of the specific factors driving this association is limited. When inquiring about the relationship between BD and CI, focusing the attention on older age BD (OABD) is paramount, as this disorder covers approximately ¼ of the whole BD population and represents a subgroup with high risk for dementia. In 2015 the International Society for Bipolar Disorders (ISBD) Task Force recommended defining OABD as occurring in individuals aged 50 years or older, in order to promote the evaluation of these patients across a longer life-span. Neurocognitive disorders represent highly heterogeneous conditions which are generally subtended by a multitude of concomitant factors (i.e. protein misfolding, vascular dysregulation, neuroinflammation). In this scenario, being able to pinpoint the clinical features forecasting the development of CI of any type in OABD may help promoting a deeper characterization of these patients, based both on clinical and biological criteria, and contribute to unveil the prominent pathophysiological process driving neurodegeneration at the individual level (i.e. proteinopathy, vascular brain pathology, BD-related neuroprogression).
Aim of the study: in this naturalistic observational study, we investigated potential clinical features (including BD subtypes) associated with the development of CI [i.e. mild cognitive impairment (MCI) and dementia] in patients with a disorder belonging to the bipolar spectrum aged 50 or over.
Methods: participants were recruited from June 2020 to September 2023, among a pool of patients attending the psychogeriatric outpatient clinic at Psychiatry Unit 2, University Hospital of Pisa, Italy. This research included subjects who met the following inclusion criteria: (1) aged 50 years or older, (2) diagnosed with BD [type 1, type 2, Other Specified BD (OS-BD)] or Cyclothymic Disorder based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-V-TR) criteria. Exclusion criteria comprised a diagnosis of Parkinson's disease or other parkinsonisms, Huntington’s disease and stroke. A number of 152 patients were finally included in the study based on the entrance criteria. All patients characteristics (i.e. demographic information, educational background, marital status, family psychiatric and neurodegenerative history, medical conditions - including a diagnosis of MCI based on Peterson criteria and of dementia based on DSM-V-TR criteria -, imaging findings, and current as well as lifetime psychiatric diagnoses per DSM-V-TR criteria) were collected at baseline. The Clinical Global Impression Severity Scale (CGI-S) was used at baseline and follow-up visits to evaluate the severity of psychiatric illness. Psychiatric symptoms severity was assessed using the Brief Psychiatric Rating Scale (BPRS) 4.0 with the four-factor structure suggested by Velligan and colleagues, while overall functioning was measured using the Global Assessment of Functioning (GAF). Additionally, the Mini-Mental State Examination (MMSE) was administered as part of our routine clinical practice both at baseline and follow-up visits. All data were recorded into a digital database. Descriptive statistical analyses were used to summarize both recorded demographic and clinical characteristics of the sample. At first, patients were divided into two subgroups based on the presence/absence of CI (i.e. MCI or dementia). Wilcoxon rank sum test was used for continuous variables after excluding normality using Shapiro-Wilk test while Pearson’s chi-squared tests or, when appropriate, Fisher’s exact test was used for categorical variables. Pairwise Fisher’s exact test with false discovery rate correction was used for post-hoc comparisons in case of multinomial variables. Moreover, logistic regression models were built to estimate the probability of CI based on the predictor variables having shown significant differences in the previous analysis. Finally, patients were divided into three subgroups, namely patients without CI, patients with MCI and patients with dementia. Kruskal-Wallis test was used to assess the between-group differences relative to continuous variables.
Results: CI patients had a higher prevalence of OS-BD (including cyclothymic disorder with major depressive episodes, major depressive episodes superimposed on a lifelong hyperthymic temperament, short-duration hypomanic episodes and major depressive episodes) and cyclothymic disorder, while BD type 2 was more common in the cognitively unimpaired group. Additionally, the CI group had a delayed onset of major mood episodes and a higher prevalence of vascular leukoencephalopathy (p=0.022), and dyslipidemia (p=0.043). At study entry patients with CI showed a significantly lower GAF score (p<0.001) and a higher BPRS score (p<0.001) as compared to the cognitively unimpaired group.
Conclusions: our investigation points out that less “canonical” OS-BD forms may be more closely related to CI as compared to the more penetrant BD types 1 and 2. Our results seem to suggest that atypical BD presentations occurring in older age may be considered as prodromal stages of dementia. Moreover, a delayed onset of major mood episodes is associated with the development of CI, substantiating the theory of a more roughly “neurodegenerative” burden in these patients as compared to the ones presenting an earlier onset. As expected, we observed an increasing severity of general psychopathology at the time of assessment along the whole neurocognitive continuum. Finally, it is likely that the multifaceted relationship between OABD and neurocognitive disorders encompasses common pathophysiological mechanisms related to the presence of vascular risk factors and cerebrovascular pathologic burden. In this framework, the identification of specific clinical features in OABD individuals forecasting the onset of CI could screen those patients that will benefit from second-level investigations in view of a precision-medicine approach to neuropsychiatric syndromes.