Neuropathological examination of 12 cases of familial Parkinson's disease with LRRK2 I2020T mutation including tau and TDP-43 pathology.

We previously reported a clinicopathological examination in the Sagamihara family, familial PD with LRRK I2020T mutation, highlighting the most common neuropathological finding as pure nigral degeneration without Lewy bodies (LBs). We applied immunohistochemical analysis to seven previously reported cases and evaluated five additional cases for a full neuropathological examination (altogether 12 cases). All cases exhibited nigral degeneration with a relatively preserved locus coeruleus (LC). Synuclein pathology was found in four cases, one of which showed multiple system atrophy pathology, and three showed LB pathology. Tau pathology in the brainstem mostly comprised a few neurofibrillary tangles and fell within the range of age-related changes. We found phosphorylated transactivation response element DNA-binding protein 43 kDa (pTDP-43) positive structures in five cases. Four of the five cases were observed in the substantia nigra (SN) but not limbic regions. The distribution pattern of pTDP-43 clearly differed from that in LB disease and older adults, suggesting that nigral degeneration is the primary lesion in the Sagamihara family. TDP-43 pathology in the Sagamihara family was different from those observed in TDP-43 proteinopathy that causes parkinsonism, which could be a secondary change; however, it may influence the course of the disease. Degeneration of the SN with relative preservation of the LC is a consistent finding in Sagamihara families, with or without LBs. These findings suggest that members of the Sagamihara family harbor a synuclein-independent neurodegenerative pathway and exhibit differential vulnerabilities depending on the brain region.