研究開発論文
Path integration deficits predict phosphorylated tau accumulation in the entorhinal cortex
嗅内野の神経原繊維変化の進行が空間ナビ脳機能（経路統合能）の低下で測定可能（AMEDプロジェクト）
Brain Communications - Oxford Academic
DOI: 10.1093/braincomms/fcad359
URL: https://academic.oup.com/braincomms/article/6/1/fcad359/7606401
Abstract
Alzheimer’s disease is a devastating disease that is accompanied by dementia, and its incidence increases with age. However, no interventions have exhibited clear therapeutic effects. We aimed to develop and characterize behavioural tasks that allow the earlier identification of signs preceding dementia that would facilitate the development of preventative and therapeutic interventions for Alzheimer’s disease. To this end, we developed a 3D virtual reality task sensitive to the activity of grid cells in the entorhinal cortex, which is the region that first exhibits neurofibrillary tangles in Alzheimer’s disease. We investigated path integration (assessed by error distance) in a spatial navigation task sensitive to grid cells in the entorhinal cortex in 177 volunteers, aged 20–89 years, who did not have self-reported dementia. While place memory was intact even in old age, path integration deteriorated with increasing age. To investigate the relationship between neurofibrillary tangles in the entorhinal cortex and path integration deficit, we examined a mouse model of tauopathy (P301S mutant tau-overexpressing mice; PS19 mice). At 6 months of age, PS19 mice showed a significant accumulation of phosphorylated tau only in the entorhinal cortex, associated with impaired path integration without impairments in spatial cognition. These data are consistent with the idea that path integration deficit is caused by the accumulation of phosphorylated tau in the entorhinal cortex. This method may allow the early identification of individuals likely to develop Alzheimer’s disease.
最初期アルツハイマー病を検出する脳ナビゲーションタスクの開発とその神経回路基盤解明に関する研究開発
VR測定エラー距離と血液バイオマーカー(p-tau, NF-L, GFAP)の高い相関性確認（AMEDプロジェクト）
研究開発期間（予定）：令和3年度～令和6年度（2021年度～2024年度）
藤田医大渡辺宏久教授、国立量研機構徳田隆彦医長、名古屋大学医学部、滋賀大学医学部、学習院大学理学部など
アルツハイマー病の前期を検出し、認知機能低下を予測する経路統合能力に関する研究開発
MCI期患者に対するVR測定(エラー距離＋AI航路解析角度誤差)により、既存の神経心理学検査では判定出来ないMCI期前期患者を正確に識別、また既存の脳画像検査(VSRADやSPECT)よりも高い精度で進行度判定が出来ることが報告（共同臨床研究プロジェクト）
Journal of Alzheimer‘s Disease
DOI: 10.3233/JAD-240347
URL: https://content.iospress.com/articles/journal-of-alzheimers-disease/jad240347
Abstract
Background:
The entorhinal cortex is the very earliest involvement of Alzheimer’s disease (AD). Grid cells in the medial entorhinal cortex form part of the spatial navigation system.Objective:
We aimed to determine whether path integration performance can be used to detect patients with mild cognitive impairment (MCI) at high risk of developing AD, and whether it can predict cognitive decline.Methods:
Path integration performance was assessed in 71 patients with early MCI (EMCI) and late MCI (LMCI) using a recently developed 3D virtual reality navigation task. Patients with LMCI were further divided into those displaying characteristic brain imaging features of AD, including medial temporal lobe atrophy on magnetic resonance imaging and posterior hypoperfusion on single-photon emission tomography (LMCI+), and those not displaying such features (LMCI–).Results:
Path integration performance was significantly lower in patients with LMCI+than in those with EMCI and LMCI–. A significantly lower performance was observed in patients who showed progression of MCI during 12 months, than in those with stable MCI. Path integration performance distinguished patients with progressive MCI from those with stable MCI, with a high classification accuracy (a sensitivity of 0.88 and a specificity of 0.70).Conclusions:
Our results suggest that the 3D virtual reality navigation task detects prodromal AD patients and predicts cognitive decline after 12 months. Our navigation task, which is simple, short (12–15 minutes), noninvasive, and inexpensive, may be a screening tool for therapeutic choice of disease-modifiers in individuals with prodromal AD.”