Bipolar disorder (BD) is a chronic psychiatric illness characterized by recurrent episodes of depression and mania. While it is generally seen as a functional disease, research shows that it may be linked with neurological abnormalities found in neurodegenerative diseases. Patients who have BD have cognitive impairment and a high risk of dementia. Tau-related pathology, like amyloid-β (Aβ)  accumulation and neurofibrillary tangle (NFT), is associated with neurodegeneration in disorders like Alzheimer’s disease (AD) and primary age-related tauopathy (PART). The scope, distribution, and clinical relevance of these alterations in BD are not clear.
This study aims to evaluate neurodegenerative changes in postmortem brain samples from individuals with BD, in comparison with an age-matched control group. This study focused on Aβ deposition, tau pathology, and novel observation of granulovacuolar degeneration (GVD) in the thalamus, specifically in the paraventricular thalamic nucleus (PVT). It also investigates the differences between early- and late-onset BD patients to determine the role of age of onset in determining the neurodegenerative pathology.
Postmortem brain samples from 23 individuals with BD and 9 age-matched controls were examined. The mean age at death was 51.3 years, and in BD cases, 28.2 years, with no major change from the control group. Neuropathological assessment included hematoxylin-eosin (HE) staining and immunohistochemistry for tau, amyloid-β, α-synuclein, TDP-43, and GVD markers. Tau pathology was staged by using Braak and Saito criteria. Amyloid-β was evaluated for diffuse and neuritic plaques. GVD was assessed by using CHMP2B and CK-1δ immunostaining, with anatomical localization performed by using calretinin staining as a PVT marker. Analyses were stratified in early-onset (<40 years) and late-onset (≥40 years) BD subgroups. Statistical comparisons were made by using Fisher’s exact test and two-tailed t tests.
Tau pathology was significantly more prevalent in BD cases than in controls. NFT accumulation was observed in 39.1% of BD cases versus 11.1% of controls. Braak staging revealed significantly higher tau burden in BD cases (P = 0.015). Argyrophilic grain pathology (Saito stage ≥ I) was present in 43.5% of BD cases compared with 11.1% of controls, with severity significantly greater in the BD group (P = 0.029). All tau pathologies remained confined to the medial temporal lobe with no spread into neocortical regions.
Amyloid-β accumulation was present in 17.4% of BD cases and 11.1% of controls, with no overall significant difference. In subgroup analysis, late-onset BD cases showed significantly higher amyloid-β deposition than early-onset cases (P = 0.048). Lewy body and TDP-43 pathologies were absent in both groups.
GVD represented a novel and striking finding. By using CHMP2B immunostaining, GVD was identified in the thalamus of five of nine BD cases compared with none of the controls (P = 0.029). This pathology was specifically localized to the PVT and confirmed by calretinin staining. Stratification by age of onset showed that GVD was present in only one of five early-onset BD cases but in all four late-onset BD cases (P = 0.048). In the hippocampus, GVD was observed in four of nine BD cases, all of which also had thalamic GVD. In contrast, only one of nine controls showed hippocampal GVD without thalamic involvement. CHMP2B-positive GVD structures were CK-1δ negative, which suggests they may represent an early or immature stage of autophagic or lysosomal dysfunction.
This study found that BD is associated with increased vulnerability to neurodegenerative protein accumulation, specifically tau pathology and argyrophilic grains in late-onset cases. This result of CHMP2B-positive GVD in the thalamic PVT recommends the potential disease-specific pathology in BD. This suggests that BD may overlap with the age-related neurodegenerative process. However, this study does not establish the causal connection between neurodegeneration and BD.
References: Nagakura A, Kawakami I, Kimura A, et al. Increased granulovacuolar degeneration in the thalamus and higher neurofibrillary tangle Braak stages in bipolar disorder. Psychiatry Clin Neurosci. 2025. doi:10.1111/pcn.13891
