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.

Distribution of neurofibrillary tangles in diffuse neurofibrillary tangles with calcification.

AIMS: In this study, the appearance and distribution of neurofibrillary tangles (NFT) in diffuse neurofibrillary tangles with calcification (DNTC) were investigated neuropathologically in order to elucidate the detailed distribution pattern in this disease. METHODS: The distribution of NFT in six cases neuropathologically diagnosed as DNTC (two men and four women) was studied using Gallyas-Braak silver stain. The age at death ranged from 56 to 73, with an average of 63.5 +/- 7.5 years. RESULTS: NFT were seen throughout the cerebral cortex, and were especially marked in the temporal and limbic cortices. The distribution pattern of NFT in the limbic lobe was similar to that in Alzheimer's disease as reported in the previous studies. In the temporal lobe, more NFT were distributed in the anterior than in the posterior area, which was confirmed in all six cases. The temporal pole showed the highest density of NFT including ghost tangles. CONCLUSIONS: The diffuse appearance of NFT in the cerebral cortex with the highest severity in the temporal pole was found to be a neuropathological characteristic of DNTC.

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.