Stroh, Alex

Objective: To determine if subcortical, brainstem and cerebellar lesion pattern characteristics of the different types of tau‐negative frontotemporal lobar degeneration (FTLD) would be similar to neocortical and hippocampal patterns [Type 1 has neuronal cytoplasmic inclusions (NCI) and dystrophic neurites (DN), type 2 mainly DN, and type 3 mainly NCI (Mackenzie et al., 2006)]. Design/Methods: We analyzed 40 cases of tau‐negative FTLD from Mayo Clinic, Florida. For each case, 12 standardized sections covering 16 different brain regions or nuclei were sampled including neocortex, hippocampus, subcortical grey, brainstem and cerebellum. TDP‐43 immunohistochemistry was performed and abnormal immunoreactivity semiquantitated. Results: Thirty‐six cases were classified into one of the three types. For subcortical grey and brainstem regions, we did not see predominance of DN in type 2, and the density of NCI and DN were similar in type 3. Type 2 cases had significantly more NCI in basal ganglia compared to the other types (p<0.05). We found a trend that fine DN in hippocampal CA1 region was more frequent in type 1 compared to type 2 and 3 (p=0.07). A novel finding was that NCI were Pick body‐like in type 2 but granular‐like in type 3. Conclusion: This study extends the patterns of pathology previously described in the three variants of tau‐negative FTLD and shows how subcortical areas are affected by TDP‐43.

Objective: To determine whether all cases of tau‐negative frontotemporal lobar degeneration (FTLD) show abnormal TDP‐43 immunoreactivity. Design/methods: The neuropathological database at Mayo Clinic, Florida, was queried to identify all cases of tau‐negative FTLD. Forty cases were identified that underwent analysis with TDP‐43 immunohistochemistry. Cases without abnormal TDP‐43 immunoreactivity were further analyzed with H&E, PAS and silver stains, and with immunohistochemistry for phosphorylated tau, alpha‐synuclein, ubiquitin, neurofilament, alpha‐internexin and p62. Results: Of the 40 cases, 3 did not show abnormal TDP‐43 immunoreactivity. Cases 1 and 3 had clinical features of behavioral variant FTD while case 2 had features of the corticobasal syndrome. Case 3 had a positive family history. Case 1 had a pathological diagnosis of dementia lacking distinctive histology (DLDH) and case 2 basophilic inclusion body disease. Case 3 had ubiquitin‐positive but TDP‐43 negative neuronal inclusions and dystrophic neurites. Conclusion: Not all cases of tau‐negative FTLD have abnormal TDP‐43 immunoreactivity; basophilic inclusion body disease and DLDH are rare examples that do not. Given the positive family history and histological findings in case 3, there likely exists a yet to be identified gene and protein associated with tau negative FTLD.