Evaluation of subcortical pathology and clinical correlations in FTLD-U subtypes

Abstract

Frontotemporal lobar degeneration (FTLD) can be classified as tau-positive (FTLD-tau) and tau-negative FTLD. The most common form of tau-negative FTLD is associated with neuronal inclusions that are composed of TAR DNA-binding protein 43 (TDP-43) (FTLD-TDP). Recent evidence suggests that FTLD-TDP can be further subdivided into at least three major histologic variants based on patterns of TDP-43 immunoreactive neuronal cytoplasmic inclusions (NCI) and dystrophic neurites (DN) in neocortex and hippocampus. The aim of this study was to extend the histologic analysis to other brain regions and to determine if there were distinct clinical and pathologic characteristics of the FTLD-TDP subtypes. Thirty-nine FTLD-TDP cases were analyzed (Mackenzie type 1 n = 24, Mackenzie type 2 n = 9, Mackenzie type 3 n = 6). There was a highly significant association between clinical syndrome and FTLD-TDP subtype, with progressive non-fluent aphasia associated with type 1, semantic dementia with type 2, and behavioral variant frontotemporal dementia with types 1, 2 and 3. Semi-quantitative analysis of NCI and DN demonstrated different patterns of involvement in cortical, subcortical and brainstem areas that were characteristic for each of the three types of FTLD-TDP. Type 1 had a mixture of NCI and DN, as well as intranuclear inclusions in most cases and TDP-43 pathology at all levels of the neuraxis, but less in brainstem than supratentorial structures. Type 2 cases were characterized by predominance of long, thick DN in the cortex, as well as numerous NCI in hippocampus, amygdala and basal ganglia, but virtually no NCI and only sparse DN in diencephalon and brainstem. Type 3 had a paucity of DN at all levels of the neuraxis and significantly more NCI in the hypoglossal nucleus than the other types. These findings extend previously described clinicopathological associations of FTLD-TDP subtypes and support the notion that FTLD-TDP subtypes may be distinct clinicopathologic disorders.

Figure 1

Distribution and density of NCI in cortical regions. * = p<0.05 compared to type 1. (MF = midfrontal; ST = superior temporal; IP = inferior parietal; ERC = entorhinal cortex)

Figure 2

Distribution and density of NCI in subcortical regions. * p<0.05 compared to type 1 (Hp = hippocampus, dentate fascia; Amg = amygdala; BG = basal ganglia, putamen; Thal = thalamus)

Figure 3

Distribution and density of NCI in brainstem regions * p<0.05 compared to type 2; ^# p<0.05 compared to types 1 and 2. (MB = midbrain, tectum; SN = substantia nigra; XII = hypoglossal nucleus’ IO = inferior olivary nucleus)

Figure 4

Distribution and density of DN in cortical regions. * p<0.05 compared to type 1. (MF = midfrontal; ST = superior temporal; IP = inferior parietal; ERC = entorhinal cortex)

Figure 5

Distribution and density of DN in subcortical regions. * p<0.05 compared to type 1; ^# p<0.05 compared to types 1 and 3. (Hp = hippocampus, dentate fascia; Amg = amygdala; BG = basal ganglia, putamen; Thal = thalamus)

Figure 6

Distribution and density of DN in brainstem regions. * p<0.05 compared to type 2; ^# p<0.05 compared to type 3. (MB = midbrain, tectum; SN = substantia nigra; XII = hypoglossal nucleus’ IO = inferior olivary nucleus)

Figure 7

Morphology of NCI in FTLD-TDP subtypes. Hippocampal dentate fascia in type 1 (a), type 2 (b) and type 3 (c). Note striking difference of inclusions in type 2, with a dense round, Pick body-like appearance. Pleomorphic cortical NCI in type 1 (d); Skein-like NCI in motor neuron in type 3 (e) and pre-inclusions in entorhinal cortical neurons in type 3 (f). (all x400)

Figure 8

Morphology of DN in FTLD-TDP subtypes. Cortical DN in type 1 (a) and type 2 (b). Note much thicker and longer neurites in type 2. NII (arrow) in cortex in type 1 (c). Delicate, thin neurites in hippocampal CA1 sector in type 1 (inset higher magnification) (d). (all x400, except inset, x800)