Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neurodegenerative diseases that are characterized by intracytoplasmic aggregates of hyperphosphorylated tau with four microtubule-binding repeats. Although PSP and CBD have distinctive pathological features, no biochemical difference in aggregated tau has been identified. In this study, we examined the brains of eight patients with PSP, six patients with CBD, and one atypical case with pathological features of both CBD and PSP. On immunoblots of sarkosyl-insoluble brain extracts, a 33kDa band predominated in the low molecular weight tau fragments in PSP, whereas two closely related bands of approximately 37kDa predominated in CBD. Immunoblots of the atypical case showed both the 33kDa band and the 37kDa doublet. Protein sequencing and immunochemical analyses showed that the 33kDa band and the 37kDa doublet consisted of the carboxyl half of tau with different amino termini. These results suggest that, despite the identical composition of tau isoforms, different proteolytic processing of abnormal tau takes place in these two diseases. Such a biochemical divergence may be related to the neuropathological features of these diseases.

Although frontotemporal lobar degeneration with ubiquitin/TDP-43-positive inclusions (FTLD-TDP) and Pick's disease are common pathological substrates in sporadic FTLD, clinical differentiation of these diseases is difficult. We performed a retrospective review of medical records and semiquantitative examination of neuronal loss of 20 sporadic FTLD-TDP and 19 Pick's disease cases. Semantic dementia as the first syndrome developed only in FTLD-TDP patients. Impaired speech output in the early stage was five times more frequent in Pick's disease than in FTLD-TDP. The total frequency of asymmetric motor disturbances (e.g., parkinsonism, pyramidal signs, and contracture) during the course was significantly more frequent in FTLD-TDP (78%) than in Pick's disease cases (14%). Asymmetric pyramidal signs were found in 7 of 13 FTLD-TDP cases with corticospinal tract degeneration similar to primary lateral sclerosis. Frontotemporal dementia as the first syndrome was noted in both FTLD-TDP (28%) and Pick's disease cases (64%); however, only FTLD-TDP cases subsequently developed asymmetric motor disturbances, and some of the cases further exhibited hemineglect. Concordant with these clinical findings, degeneration in the temporal cortex, caudate nucleus, putamen, globus pallidus, substantia nigra, and corticospinal tract was significantly more severe in FTLD-TDP, and degeneration in the frontal cortex tended to be more severe in Pick's disease. Given these findings, the initial impairment of semantic memory or comprehension and subsequent asymmetric motor disturbances in sporadic FTLD patients predict sporadic FTLD-TDP rather than Pick's disease, while initial behavioral symptoms or non-fluent aphasia without subsequent asymmetric motor disturbances predict Pick's disease rather than sporadic FTLD-TDP.

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We report a case displaying upper motor sign, parkinsonism, and behavioral abnormality, with marked degeneration of the precentral cortex, neostriatum and frontotemporal lobes, as well as ubiquitinated neuronal inclusions. The patient was a 66-year-old male at the time of death. At age 57, he noticed progressive difficulties in speaking and swallowing. At age 60, he was severely anarthric and displayed emotional lability and incontinence. Neurologically, very poor movement of tongue was observed, but without atrophy or fasciculation. Deep tendon reflexes were hyperactive. Grasp reflex and snout reflex were also positive. Needle electromyography revealed no abnormalities. A diagnosis of primary lateral sclerosis and character change was made. At age 62, he developed bradykinesia and rigidity of the neck and all extremities. Treatment with carbidopa-levodopa was initiated, but resulted in minimal improvement. At age 65, he was bed-ridden, and had repeated occurrences of aspiration pneumonia; he died of pneumonia. Neuropathological examination revealed marked atrophy of the frontal and temporal lobes with Betz cells completely absent and moderate atrophy of the neostriatum. The spinal cord and nerve roots appeared normal. Immunohistochemically, ubiquitin-positive but tau-negative intraneuronal inclusions were found in the frontal and temporal cortices, including the precentral cortex and the hippocampal dentate gyrus, and the neostriatum. This case could be included with inclusion-associated disorders such as frontotemporal dementia or amyotrophic lateral sclerosis with dementia, and furthermore, predominant upper motor sign and parkinsonism could represent phenotypes of clinical manifestations with such inclusions.

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