Subcortical TDP-43 pathology patterns validate cortical FTLD-TDP subtypes and demonstrate unique aspects of C9orf72 mutation cases.

Frontotemporal lobar degeneration with TDP-43 immunoreactive (TDP-ir) inclusions (FTLD-TDP) is sub-classified based on the pattern of neocortical pathology, with each subtype showing clinical and genetic correlations. Recent studies indicate that accurate subtyping of cases may be important to help identify genetic risk factors and develop biomarkers. Although most FTLD-TDP cases are easily classified, some do not match well to one of the existing subtypes. In particular, cases with the C9orf72 repeat expansion (C9+) have been reported to show FTLD-TDP type A, type B or a combination of A and B pathology (A + B). In our series of FTLD-TDP cases, we found that those lacking the C9orf72 mutation (non-C9) were all readily classified as type A (n = 29), B (n = 16) or C (n = 18), using current criteria and standard observational methods. This classification was validated using non-biased hierarchical cluster analysis (HCA) of neocortical pathology data. In contrast, only 14/28 (50%) of the C9+ cases were classified as either pure type A or pure type B, with the remainder showing A + B features. HCA confirmed separation of the C9+ cases into three groups. We then investigated whether patterns of subcortical TDP-ir pathology helped to classify the difficult cases. For the non-C9 cases, each subtype showed a consistent pattern of subcortical involvement with significant differences among the groups. The most distinguishing features included white matter threads, neuronal intranuclear inclusions in hippocampus and striatum, and delicate threads in CA1 in type A; glial cytoplasmic inclusions in white matter and neuronal cytoplasmic inclusions (NCI) in lower motor neurons in type B; compact NCI in striatum in type C. HCA of the C9+ cases based on subcortical features increased the number that clustered with the non-C9 type A (46%) or non-C9 type B (36%); however, there remained a C9+ group with A + B features (18%). These findings suggest that most FTLD-TDP cases can be classified using existing criteria and that each group also shows characteristic subcortical TDP-ir pathology. However, C9+ cases may be unique in the degree to which their pathology overlaps between FTLD-TDP types A and B.