Accumulation of neurodegenerative proteins could be key to understanding bipolar disorder pathology

Bipolar disorder (BD) is a chronic psychiatric condition marked by recurring episodes of depression and mania, posing a significant burden on global health. Despite its prevalence, the underlying neuropathology remains poorly understood. While mitochondrial dysfunction has long been implicated in BD, the specific brain regions involved have remained unclear—until now.

A team of Japanese researchers has shed new light on the biological underpinnings of BD by examining key brain areas involved in mood regulation and cognitive function. Their study, published in Psychiatry and Clinical Neurosciences on September 2, 2025, highlights the role of the paraventricular thalamus and medial temporal regions, uncovering previously unreported neurodegenerative markers.

Investigating the brain in bipolar disorder

Led by Professor Tadafumi Kato of Juntendo University Graduate School of Medicine and Dr. Akito Nagakura of Tokyo Metropolitan Matsuzawa Hospital, the team analysed postmortem brain tissue from patients with BD. Their aim: to understand whether proteins commonly associated with neurodegeneration might contribute to BD pathology.

“Although animal studies have suggested involvement of the paraventricular thalamic nucleus in BD, neuropathological evidence has been limited,” explains Prof. Kato. “We wanted to see whether markers of neurodegenerative disease could be identified in these critical mood-regulating regions.”

The researchers focused on the paraventricular thalamus and medial temporal regions. Using immunohistochemistry, they examined the tissues for phosphorylated tau, amyloid β, α-synuclein, and TDP-43, as well as granulovacuolar degeneration (GVD) markers CHMP2B and CK-1δ. This comprehensive approach allowed for detailed mapping of proteins linked to neurodegenerative processes.

Key Findings: Tau and Granulovacuolar Degeneration

The study revealed several noteworthy patterns:

• Tau Pathology: Patients with BD exhibited significantly higher neurofibrillary tangle (NFT) stages and argyrophilic grain pathology—both associated with tau accumulation in brain cells and commonly linked to aging. These results align with prior postmortem and neuroimaging studies, suggesting that tau pathology may correlate with age of onset in BD.

• Granulovacuolar Degeneration: Crucially, CHMP2B-positive GVD was identified in the paraventricular thalamus in approximately half of the BD cases—a novel observation that had not been previously reported.

These findings indicate that protein accumulation and cellular degeneration in mood-related brain regions may play a significant role in BD pathology.

Implications for understanding and treating BD

Taken together, these insights reinforce the concept that BD is a brain-based disorder with identifiable neuropathological changes. By highlighting specific protein pathologies in the paraventricular thalamus and medial temporal regions, the study moves beyond symptom observation to a more precise understanding of the underlying biology.

“Demonstrating the presence of CHMP2B-positive GVD and elevated NFT stages in BD may open new avenues for diagnostics and targeted therapies,” says Prof. Kato.

With improved knowledge of the molecular changes in BD, researchers and clinicians can explore early detection strategies, personalized treatment approaches, and therapies that address root biological mechanisms rather than merely managing symptoms.

A path forward

As the field progresses, studies like this offer a promising foundation for transforming BD care. By linking clinical symptoms to specific brain changes, these findings provide a roadmap for innovative treatments that could improve quality of life for millions living with bipolar disorder.

“Our work underscores the importance of looking at BD as a disorder of the brain,” concludes Prof. Kato. “By understanding its biological roots, we can better support patients with targeted interventions and precision medicine strategies.”