Neuropathological heterogeneity in frontotemporal lobar degeneration with TDP-43 proteinopathy: a quantitative study of 94 cases using principal components analysis

Abstract

Studies suggest that frontotemporal lobar degeneration with transactive response DNA-binding protein of 43 kDa (TDP-43) proteinopathy (FTLD-TDP) is heterogeneous with division into four or five subtypes. To determine the degree of heterogeneity and the validity of the subtypes, we studied neuropathological variation within the frontal and temporal lobes of 94 cases of FTLD-TDP using quantitative estimates of density and principal components analysis (PCA). A PCA based on the density of TDP-43 immunoreactive neuronal cytoplasmic inclusions, oligodendroglial inclusions, neuronal intranuclear inclusions, and dystrophic neurites, surviving neurons, enlarged neurons, and vacuolation suggested that cases were not segregated into distinct subtypes. Variation in the density of the vacuoles was the greatest source of variation between cases. A PCA based on TDP-43 pathology alone suggested that cases of FTLD-TDP with progranulin (GRN) mutation segregated to some degree. The pathological phenotype of all four subtypes overlapped but subtypes 1 and 4 were the most distinctive. Cases with coexisting motor neuron disease (MND) or hippocampal sclerosis (HS) also appeared to segregate to some extent. We suggest: (1) pathological variation in FTLD-TDP is best described as a 'continuum' without clearly distinct subtypes, (2) vacuolation was the single greatest source of variation and reflects the 'stage' of the disease, and (3) within the FTLD-TDP 'continuum' cases with GRN mutation and with coexisting MND or HS may have a more distinctive pathology.

Fig. 1

a Neuronal loss, microvacuolation, and gliosis in lamina II of the superior temporal gyrus and b abnormally enlarged neuron (arrow) in lamina III of the superior temporal gyrus in a case of frontotemporal lobar degeneration with TDP proteinopathy (FTLD-TDP) (H/E, bars a, b = 20 μm)

Fig. 2

TDP-43 immunoreactive lesions in the frontal cortex (a) and granule cells of the dentate fascia (b) showing neuronal cytoplasmic inclusion (NCI) (arrow), dystrophic neurite (DN) (double arrow), and glial inclusion (GI) (arrow head) (TDP-43 immunohistochemistry, bars a, b = 50 μm)

Fig. 3

a Neuronal intranuclear inclusion (NII) (arrow) in lamina III of the superior temporal gyrus and b glial inclusion (GI) (arrow) in underlying white matter (TDP-43 immunohistochemistry, bars a, b = 50 μm)

Fig. 4

Principal components analysis of 94 cases of frontotemporal lobar degeneration with TDP proteinopathy (FTLD-TDP) based on all histological variables (PCA-1). Identified on the plot are the subtypes of disease based on the system of Cairns et al. (2007b). Cases labelled ND could not be ascribed readily to disease subtype

Fig. 5

Principal components analysis of 94 cases of frontotemporal lobar degeneration with TDP proteinopathy (FTLD-TDP) based on TDP-43 pathology only (PCA-2). Identified on the plot are familial and sporadic cases, those with progranulin (GRN), valosin containing protein (VCP), and chromosome 9p21 (CH9) mutation. The familial/sporadic status of cases labelled ND has not been determined to date

Fig. 6

Principal components analysis of 94 cases of frontotemporal lobar degeneration with TDP proteinopathy (FTLD-TDP) based on TDP-43 pathology only (PCA-2). Identified on the plot are cases with coexisting motor neuron disease (MND), hippocampal sclerosis (HS), and Alzheimer's disease (AD)

Fig. 7

Principal components analysis of 94 cases of frontotemporal lobar degeneration with TDP proteinopathy (FTLD-TDP) based on TDP-43 pathology only (PCA-2). Identified on the plot are the subtypes of disease based on the system of Cairns et al. (2007b). Cases labelled ND could not be ascribed readily to disease subtype