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.

An autopsy case of diffuse neurofibrillary tangles with calcification: early stage pathologic findings.

A 66-year-old man with no medically remarkable past or family history gradually showed personality changes, memory disturbance, sleeplessness and abnormal behavior. Neurologic examination showed no focal signs and neither parkinsonism nor cerebellar ataxia was recognized. He died 4 years after the onset of dementia due to chronic renal failure. Neuropathologic examination revealed neuronal loss and gliosis in the temporal cortex, particularly in the subiculum, parahippocampal gyrus and entorhinal cortex, and insular cortex. NFTs were observed to be widespread in the cerebral cortex, especially the temporal cortex and brainstem, while senile plaques were not observed. Gallyas-Braak silver staining revealed the presence of numerous NFTs, glial inclusions and neuropil threads throughout the cerebral neocortex, limbic system, hippocampus and brainstem. The subiculum showed the most severe involvement; severe atrophy, severe neuron loss, and numerous ghost tangles (extracellular NFTs) were apparent. Although NFTs contained both monoclonal anti-3repeat-tau antibody (RD3) and RD4 immunoreactivity, this differed between the intracellular NFTs and ghost tangles. RD3 immunoreactivity was mainly observed in ghost tangles and neuropil threads, whereas RD4 immunoreactivity was mainly observed in intracellular NFTs and glial inclusions. Calcification was also found to be widespread in the cerebral cortex and white matter, basal ganglia, thalamus, cerebellar cortex, white matter and dentate nucleus. These characteristic neuropathologic findings lead to the pathologic diagnosis of diffuse neurofibrillary tangles with calcification (DNTC). It is argued that this patient showed early stage pathologic signs of DNTC due to a short disease duration, which may provide clues regarding the progression of this rare disease.