Clinicopathological study of diffuse neurofibrillary tangles with calcification. With special reference to TDP-43 proteinopathy and alpha-synucleinopathy.

Diffuse neurofibrillary tangles with calcification (DNTC) is a relatively rare presenile dementia that clinically shows overlapping symptoms of Alzheimer's disease and frontotemporal lobar degeneration (FTLD). DNTC is pathologically characterized by localized temporal or frontotemporal atrophy with massive neurofibrillary tangles, neuropil threads and Fahr's-type calcification without senile plaques. We tried to clarify the molecular basis of DNTC by immunohistochemically examining the appearance and distribution of accumulated alpha-synuclein (aSyn) and TAR DNA-binding protein of 43kDa (TDP-43) in the brains of 10 Japanese autopsy cases. We also investigated the clinically characteristic symptoms from the clinical charts and previous reports, and the correlations with neuropathological findings. The characteristic symptoms were evaluated using the Neuropsychiatric Inventory Questionnaire (NPI-Q). As a result, we confirmed the high frequency of neuronal cytoplasmic accumulation of aSyn (80%) and phosphorylated TDP-43 (90%) in DNTC cases. There was a significant correlation between some selected items of NPI-Q scores and the severity of the limbic TDP-43 pathology. The pathology of DNTC included TDP-43 and aSyn pathology with high frequency. These abnormal accumulations of TDP-43 might be involved in the pathological process of DNTC, having a close relationship to the FTLD-like psychiatric symptoms during the clinical course.