Progress Report
Towards overcoming disorders linked to dementia based on a comprehensive understanding of multiorgan network[1-4] Brain and multi-organ network in Alzheimer’s disease, vascular dementia and Parkinson’s disease dementia (2)
Progress until FY2024
1. Outline of the project
Our research targets three major causes of dementia—AD, VD, and DLB/PD-related dementia—using advanced model mice and human cohorts (e.g., J-PPMI, Nagahama), with a focus on inter-organ connections in the preclinical phase. Through mathematical analysis, we aim to predict disease risk and develop preventive strategies.
For PD-related dementia, we use prodromal model mice that accumulate disease proteins without motor symptoms, and track REM sleep behavior disorder patients in human cohorts. Collaborating with technology and data analysis teams, we work to identify early biomarkers and therapeutic targets to prevent disease onset.
- AD Group Lead: Koji Yamanaka (Nagoya Univ)
- VD Group Lead: Naoki Mochizuki (National Cerebral and Cardiovascular Center)
- PD Group Lead: Nobutaka Hattori (Juntendo Univ)
- Basic Technology Group Lead: Toshihisa Otsuka (Yamanashi Univ)
2. Outcome so far
Prodromal Parkinson’s Disease Cohort
REM sleep behavior disorder (RBD) is recognized as a prodromal symptom of Parkinson’s disease (PD). Individuals with RBD show progressive dopaminergic neuron loss and reduced DAT-SPECT uptake, with about 30% developing PD or dementia with Lewy bodies within 5 years, and 60% within 10 years. Longitudinal follow-up may help identify biomarkers and therapeutic targets for disease prediction and prevention. Dr. Yuji Takahashi’s group at the National Center of Neurology and Psychiatry runs a prospective cohort of over 100 RBD patients, uncovering features such as early autonomic dysfunction (J-PPMI cohort). Combining these human findings with animal model data aims to clarify prodromal PD-related disorders and identify markers and targets for prevention before disease onset.
Attempts to Diagnose PD Using Blood Samples
Pathologically aggregated α-synuclein (αSyn), which accumulates in the brain, has been detected leaking into bodily fluids such as cerebrospinal fluid (CSF) in patients with PD. However, CSF collection is invasive, making it unsuitable as a simple biomarker.
A research group led by Professor Nobutaka Hattori, Associate Professors Ayami Okuzumi and Taku Hatano at Juntendo Univ successfully detected pathological aggregates known as “αSyn seeds” in the serum of patients with PD and related disorders. Furthermore, they demonstrated that the structure and properties of αSyn seeds in serum differ depending on the disease, making them useful for differential diagnosis. This discovery provides a new avenue for understanding PD pathology and developing novel therapies (Nat Med, 2023).
Analysis of Immune Responses to the PD-Associated Protein α-syn
In PD, pathologicalαSyn aggregates are marked by phosphorylation at serine 129. A team led by Professor Yukiko Miyake at Juntendo Univ showed that Th17 cells—IL-17–producing CD4+ T cells—respond more strongly to a synthetic peptide containing phosphorylated serine 129 in PD patients, with this response correlating to disease severity. Their study also implicated the TLR4-XBP1s pathway in antigen-presenting cells exposed to αSyn aggregates. These findings suggest that αSyn-specific Th17 responses may drive PD pathology and represent a potential therapeutic target (J Neuroinflamm, 2025).
3. Future plans
Various types of data will be collected from original disease models and preclinical cohorts for dementia. Furthermore, we will identify candidate biomarkers that contribute to early diagnosis through data-driven analysis of multi-organ networks and try to predict and prevent the development of dementia.