Sequential distribution of pTDP-43 pathology in behavioral variant frontotemporal dementia (bvFTD)

Abstract

We examined regional distribution patterns of phosphorylated 43-kDa TAr DNA-binding protein (pTDP-43) intraneuronal inclusions in frontotemporal lobar degeneration (FTLD). Immunohistochemistry was performed on 70 μm sections from FTLD-TDP autopsy cases (n = 39) presenting with behavioral variant frontotemporal dementia. Two main types of cortical pTDP-43 pathology emerged, characterized by either predominantly perikaryal pTDP-43 inclusions (cytoplasmic type, cFTLD) or long aggregates in dendrites (neuritic type, nFTLD). Cortical involvement in nFTLD was extensive and frequently reached occipital areas, whereas cases with cFTLD often involved bulbar somatomotor neurons and the spinal cord. We observed four patterns indicative of potentially sequential dissemination of pTDP-43: cases with the lowest burden of pathology (pattern I) were characterized by widespread pTDP-43 lesions in the orbital gyri, gyrus rectus, and amygdala. With increasing burden of pathology (pattern II) pTDP-43 lesions emerged in the middle frontal and anterior cingulate gyrus as well as in anteromedial temporal lobe areas, the superior and medial temporal gyri, striatum, red nucleus, thalamus, and precerebellar nuclei. More advanced cases showed a third pattern (III) with involvement of the motor cortex, bulbar somatomotor neurons, and the spinal cord anterior horn, whereas cases with the highest burden of pathology (pattern IV) were characterized by pTDP-43 lesions in the visual cortex. We interpret the four neuropathological patterns in bvFTD to be consistent with the hypothesis that pTDP-43 pathology can spread sequentially and may propagate along axonal pathways.

TDP-43 in the hypoglossal nucleus identifies amyotrophic lateral sclerosis in behavioral variant frontotemporal dementia

“…Family history for ALS was more prevalent in pure bvFTD cases with TDP-43 in the hypoglossal nucleus, but this did not reach significance compared to other bvFTD cohorts (p = 0.06). The recent topographical staging of TDP-43 pathology in bvFTD and ALS [6,7] demonstrated that TDP-43 initiated in the motor system network in ALS is also seen in the majority of bvFTD cases, despite the absence of ALS in over 50% of these [6,21]. In a recent analysis [21], we identified the hypoglossal nucleus as a key brain region in discriminating between cases with and without ALS and the present study corroborates this finding in bvFTD cases.…”

“…The TAR DNA-binding protein 43 (TDP-43) in behavioral variant frontotemporal dementia (bvFTD) was recently proposed to have a regional distribution, initiated in the orbitofrontal cortex and amygdala before progressing to the frontal and temporal cortices, eventually involving the motor system, visual cortex and cerebellum [5]. Although the majority of bvFTD cases were found to have TDP-43 pathology in motor system regions, less than half of these demonstrated clinical features suggestive or diagnostic of amyotrophic lateral sclerosis (ALS) [5].…”

“…Although the majority of bvFTD cases were found to have TDP-43 pathology in motor system regions, less than half of these demonstrated clinical features suggestive or diagnostic of amyotrophic lateral sclerosis (ALS) [5].…”

Myelin oligodendrocyte basic protein and prognosis in behavioral-variant frontotemporal dementia

“…Indeed, PSP and other forms of FTLD-tau have significant WM oligodendritic pathology 28,29 that is more prominent than in FTLD-TDP. [30][31][32] While animal-and cell-model experiments are needed to clarify the normal function of MOBP and the association of the rs1768208 polymorphism with neurodegeneration in FTLD, our neuroimaging findings are consistent with the possibility that degeneration particularly involving WM myelin may be contributing to poorer prognosis in MOBP RA1 patients. Specifically, we found increased RD in the WM of the midbrain and SCR, and additional decrease in FA in the SLF and ILF ( figure 2, A and B) in MOBP RA1 patients.…”

Semi-Automated Digital Image Analysis of Pick’s Disease and TDP-43 Proteinopathy

“…In contrast, our data in FTLD-TDPC finds similar disease burden in STG and ACG compared with a lower amount of TDP-43 pathology in MFG. However, we previously found MFG, STG and ACG affected in the same early phase of pathology through examination of 70-µm-thick sections (Brettschneider et al 2014); that study included other FTLD-TDP subtypes (i.e., A, B) and ordinal ratings of both STG and MTG combined, in comparison to our present focused study of STG, which may explain this partial discrepancy. Further study is needed to determine the exact nature of associations between staging and quantitative measures of pathological burden in FTLD.…”