Distribution and characteristics of transactive response DNA binding protein 43 kDa pathology in progressive supranuclear palsy

Abstract

Introduction This study aimed to determine the frequency of transactive response DNA binding protein 43 kDa (TDP-43) pathology in PSP, the clinical features of patients with this pathology, and genetic risk factors for it.. Methods Hippocampal sections were screened with immunohistochemistry for TDP-43 in 945 PSP cases. A subset of 261 cases that were negative in hippocampus was screened in the amygdala. The density and disruption of this pathology, as well as regional tau burden, and clinical and genetic characteristics were analyzed. Results We observed TDP-43pathology in 47 cases in the hippocampus and an additional 9 cases that only affected the amygdala. Hippocampal sclerosis was the strongest risk factor, followed by Alzheimer’s disease pathology, argyrophilic grain disease, and older age at death. Five stages of TDP-43 pathology were identified in PSP: Stage A had pathology only in the amygdala (16%); stage I had pathology confined to the hippocampus and entorhinal cortex (9%); stage II included both regions of stage A and I (38%); stage III spread further to medial occipitotemporal gyrus (20%); and stage IV had pathology in the dorsolateral frontal lobe (18%). Anatomical areas vulnerable to PSP pathology had varying degrees of this pathology in stage II and later. PSP with TDP-43pathology were older at disease onset and had lower median MMSE scores; however, the latter was driven by concurrent pathologies. Conclusions Distribution and clinical characteristics of TDP-43pathology in PSP were influenced by concurrent pathologies. This is the first study to observe that PSP-vulnerable regions are also susceptible to this non-tau pathology.

Corticobasal degeneration with TDP-43 pathology presenting with progressive supranuclear palsy syndrome: a distinct clinicopathologic subtype

“…The frequency of TDP-43 pathology in CBD (45%) was much higher than that of PSP from literature (0% to 26%) [29,63,60,52], although the screening method was different among the studies. To compare the frequency of TDP-43 pathology between CBD and PSP with the same method, we screened 40 consecutive PSP cases using sections of the midbrain, pons, basal forebrain including the amygdala, and subthalamic nucleus.…”

“…Several studies showed that TDP-43 pathology was frequent (55–60%) in the limbic structures in AGD [13,59]. AGD coexisted more frequently in TDP-43 positive PSP compared with TDP-43 negative PSP [29]. In addition, many cases of multiple system atrophy with extensive TDP-43 pathology had concurrent AGD [27].…”

“…For genotyping, genomic DNA was extracted from the cerebellum of frozen brain tissue using standard procedures. Genotyping for GRN (SNP rs5848 C/T SNPs, T minor allele), TMEM106B (rs3173615 C/G SNPs, G minor allele), MAPT H1/H2 (SNP rs1052553 A/G, A = H1, G = H2), and APOE alleles (SNP rs429358 C/T and rs7412 C/T) was assessed with TaqMan SNP genotyping assays (Applied Biosystems, Foster City, CA) as previously reported [29,28,50,27]. Genotype calls were obtained with QuantStudio™ Real-Time PCR Software (Applied Biosystems).…”

TDP‐43 pathology in multiple system atrophy: colocalization of TDP‐43 and α‐synuclein in glial cytoplasmic inclusions

“…Arnold et al demonstrated argyrophilic grains, but not age or Alzheimer's-type pathology was correlated with frequency of TDP-43 pathology in cognitively normal elderly individuals [30]. Similarly, the previous study showed that concurrent AGD was a risk factor for TDP-43 pathology in PSP [27]. Taken together, AGD may be associated with TDP-43 pathology in MSA; however, it is still unknown whether AGD can cause widespread TDP-43 pathology beyond limbic structures affected by AGD.…”

“…who agreed on the presence of TDP-43 immunoreactivity, defined as NCI, GCI, DNs, fine neurites, neuronal intranuclear inclusions, spheroids, or perivascular inclusions in any region. The severity of TDP-43 pathology was graded semi-quantitatively on a four-point scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe) [27]. …”