Transactivation response DNA-binding protein 43 microvasculopathy in frontotemporal degeneration and familial lewy body disease

We describe novel transactivation response DNA-binding protein of43 kd (TDP-43)-positive structures in the brains of patients withfrontotemporal lobar degeneration with ubiquitin-positive inclusions and familial Lewy body disease. The TDP-43 immunohistochemistry revealed small round structures closely associated with small blood vessels. By immunoelectron microscopy, these TDP-43-positive structures were unmyelinated cell processes located adjacent to and sometimes enclosed by the capillary basal lamina. Some processes protruded from outside of the vascular basal lamina toa position beneath the basal lamina. The processes contained 10-to 17-nm-diameter straight filaments or filaments coated with granular material similar to those described in neurites in frontotemporal lobar degeneration with ubiquitin-positive inclusions and other disorders. Insome of the abnormal structures, electron-dense material formed paracrystalline arrays composed of TDP-43. The inclusions were variably positive by immunostaining for the small heat shock protein αB-crystallin and less often glial fibrillary acidic protein. Bundles of astrocytic glial fibrils characteristic of reactive astrocytes were often found in proximity, but glial fibrils were negative for TDP-43. These data suggest that these processes are astrocytic end-feet with abnormal TDP-43 fibrillary inclusions. The significance of this novel TDP-43 microvasculopathy on blood-brain barrier integrity warrants further investigation.