Tokyo, Japan — September 2, 2025 — A new study led by Professor Tadafumi Kato (Juntendo University Graduate School of Medicine) and Dr. Akito Nagakura (Tokyo Metropolitan Matsuzawa Hospital) has uncovered evidence of neurodegeneration in a key brain region implicated in bipolar disorder (BD). The research, published in Psychiatry and Clinical Neurosciences, provides the strongest neuropathological evidence to date that BD is not just a psychiatric condition but also a brain-based disease with distinct biological underpinnings.

A Major Health Burden with Unresolved Biology

Bipolar disorder, marked by recurrent episodes of mania and depression, is a chronic mental illness affecting millions worldwide. Despite its prevalence and rising incidence, the neuropathological changes behind BD remain poorly understood. Previous studies have pointed to mitochondrial dysfunction, but the specific brain regions most affected have remained elusive.

Targeting the Paraventricular Thalamus

The Japanese research team investigated the paraventricular thalamus and medial temporal regions of postmortem brain tissue, areas strongly involved in mood regulation and cognitive function.

“Although animal models have pointed to the involvement of the paraventricular thalamic nucleus in the pathophysiology of BD, neuropathological knowledge is limited. In particular, we aimed to investigate whether the accumulation of certain neurodegenerative proteins, previously associated with neurological diseases, might play a role in the pathology of BD,” says Prof. Kato.

Using immunohistochemical analyses, the team examined key neurodegenerative markers—including phosphorylated tau, amyloid β, α-synuclein, and TDP-43—as well as granulovacuolar degeneration (GVD) markers CHMP2B and CK-1δ.

Tau Pathology and Novel Findings

The researchers discovered:

• Elevated neurofibrillary tangle (NFT) stages in BD patients, indicating a higher burden of tau-related pathology.
• Argyrophilic grain pathology, reinforcing evidence of abnormal tau protein accumulation.
• CHMP2B-positive GVD in the paraventricular thalamus in about half of BD cases — a previously unreported finding.
  

These results suggest that tau-related pathology and CHMP2B-associated degeneration in the paraventricular thalamus may contribute to BD’s underlying biology, linking it to processes commonly associated with neurodegenerative disorders.

From Clinical Symptoms to Biological Understanding

The findings strengthen the case that bipolar disorder has a biological disease basis, not merely a psychiatric presentation. Identifying specific protein abnormalities in the brain could pave the way for:

• Earlier detection of disease progression
• Personalized treatment strategies
• Novel therapies targeting root mechanisms

“Our study, by demonstrating the presence of CHMP2B-positive GVD in the paraventricular thalamus and increased NFT stages in patients with BD, may pave the way for the development of new diagnostic tools and targeted therapies,” concludes Prof. Kato.

Key Highlights

• Bipolar disorder shows neuropathological changes in the paraventricular thalamus and medial temporal regions.
• BD patients had higher tau-related pathology (NFTs and argyrophilic grains).
• CHMP2B-positive granulovacuolar degeneration was detected in about half of BD cases — a novel discovery.
• Findings confirm BD as a biological brain disease, opening doors to new diagnostic and therapeutic approaches.

Original Publication
Authors: Akito Nagakura, Ito Kawakami, Araki Kimura, Kenji Ikeda, Kenichi Oshima, Mie Kubota‐Sakashita and Tadafumi Kato.
Journal: Psychiatry and Clinical Neurosciences
DOI: 10.1111/pcn.13891
Method of Research: Experimental study
Subject of Research: Human tissue samples
Article Title: Increased Granulovacuolar Degeneration in Thalamus and Higher Neurofibrillary Tangle Braak Stages in Bipolar Disorder
Article Publication Date: 2-Sep-2025
COI Statement: T.K. is an Editor-in-Chief of the journal but was not involved in the handling of this manuscript. Other authors declare conflict of interest directly related to this work.

Original Source: https://en.juntendo.ac.jp/highlights/news/nid1015

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