Collaborating Researcher Shin Kurose of the Department of Neuropsychiatry at Keio University School of Medicine, Principal Investigator Keisuke Takahata, and their colleagues at the Advanced Neuroimaging Center, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology (QST), in collaboration with the Department of Neuropsychiatry, Keio University School of Medicine, National Center of Neurology and Psychiatry (NCNP), and Institute of Science Tokyo (Department of Psychiatry and Behavioral Sciences), used PET to visualize tau pathology accumulating in the brains of patients with late-life mood disorders (depression, bipolar disorder), revealing that tau pathology may be related to the onset of mood disorders. Their findings were published in the Journal of the Alzheimer's Association: Alzheimer's & Dementia.
Patients with mental illness in middle-aged and elderly populations are rapidly increasing, with dementia cases increasing by approximately 7.3 times and mood disorders approximately 1.8 times over the past 15 years. Correspondingly, an increase in social costs is estimated: from approximately 14.5 trillion yen (2014) to approximately 24.3 trillion yen by 2060. Late-life mood disorders tend to be severe and directly lead to decreased independence in daily life. Recent epidemiological studies suggest that late-life mood disorders may appear as a precursor stage to dementia.
Most cases of dementia are thought to progress through the accumulation of abnormal proteins such as tau and amyloid β in the brain, causing neuronal cell death. However, how these abnormal proteins are involved in the onset of late-life mood disorders had not been sufficiently clarified.
Meanwhile, dementia treatment has changed significantly with the emergence of new drugs that remove causative proteins. These are the disease-modifying drugs lecanemab and donanemab. For example, lecanemab reduces amyloid β accumulation by approximately 70% and slows disease progression by approximately 30%. The earlier treatment is started, the more effective it is, but due to financial issues in healthcare, in addition to MCI diagnosis, confirmation of amyloid β accumulation through PET or cerebrospinal fluid examination has become essential.
To clarify what tau pathology is involved in the onset of late-life mood disorders, the research group investigated the frequency and distribution of tau pathology in the brains of patients with late-life mood disorders using the tau PET tracer 18F-PM-PBB3 (florzolotau(18F)) developed by QST. Furthermore, they analyzed the frequency of tau pathology in patients who first developed depressive or manic states in middle age using postmortem brain data.
The study compared 52 patients with depression and bipolar disorder who developed symptoms after age 40 (average age 66) with 47 age- and sex-matched healthy controls for amyloid PET and tau PET positivity rates. In the mood disorder group, 15 people (28.8%) were amyloid-positive and 26 people (50%) were tau-positive, compared with the healthy controls where 1 person (2.1%) was amyloid-positive and 7 people (14.9%) were tau-positive, showing tau PET positivity was 4.8 times higher. Increased tau accumulation in the frontal lobe and striatum was particularly found in patients with psychotic symptoms (hallucinations, delusions).
Kurose noted: "These regions are known to be related to hallucinations and delusions, so these results suggest that people with psychotic symptoms are particularly likely to have tau accumulation, which is a causative substance of dementia."
Furthermore, analysis of 208 autopsy brain cases stored at the NCNP brain bank compared neuropathological findings between cases that showed depressive or manic states after age 40 and those that did not. Results showed that among 208 cases, 57.1% of 21 cases with initial depression/mania had tau pathology, compared with 28.2% in other cases, showing a significant difference. These 21 cases included various tau pathologies such as Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration, and argyrophilic grain dementia. There was an average 7-year time lag from mood symptom appearance to dementia onset.
Currently, QST is conducting Phase 1 and Phase 2 clinical trials in collaboration with APRINOIA in the United States, Taiwan, Japan, and other countries to obtain approval for florzolotau (18F) as a diagnostic drug.
Kurose commented, "In this research, we clarified that in late-life mood disorders, tau pathology can appear at a stage when cognitive function is normal, and that there is a relationship with psychiatric symptoms. By adding analysis using postmortem brains, we were able to obtain more reliable data. In the future, we will advance research to realize early detection of and intervention in dementia based on these findings."
Takahata added, "When mood disorders appear, even if there are no symptoms of cognitive decline, the presence of tau and amyloid pathology means that these people may potentially progress to dementia later on. This offers the advantage of being able to consider early treatment with lecanemab and similar drugs. We want to clarify whether this leads to dementia by following their status after 2-3 years."
Journal Information
Publication: Alzheimer's & Dementia
Title: Diverse tau pathologies in late-life mood disorders revealed by PET and autopsy assays
DOI: 10.1002/alz.70195
This article has been translated by JST with permission from The Science News Ltd. (https://sci-news.co.jp/). Unauthorized reproduction of the article and photographs is prohibited.