Abstract
TAR-DNA binding protein 43 (TDP-43) proteinopathy is a common brain pathology in elderly persons, but much remains to be learned about this high-morbidity condition. Published stage-based systems for operationalizing disease severity rely on the involvement (presence/absence) of pathology in specific anatomic regions. To examine the comorbidities associated with TDP-43 pathology in aged individuals, we studied data from the National Alzheimer’s Coordinating Center (NACC) Neuropathology Data Set. Data were analyzed from 929 included subjects with available TDP-43 pathology information, sourced from 27 different American Alzheimer’s Disease Centers (ADCs). Cases with relatively unusual diseases including autopsy-proven frontotemporal lobar degeneration (FTLD-TDP or FTLD-tau) were excluded from the study. Our data provide new information about pathologic features that are and are not associated with TDP-43 pathologies in different brain areas—spinal cord, amygdala, hippocampus, entorhinal cortex/inferior temporal cortex, and frontal neocortex. Different research centers used cite-specific methods including different TDP-43 antibodies. TDP-43 pathology in at least one brain region was common (31.4%) but the pathology was rarely observed in spinal cord (1.8%) and also unusual in frontal cortex (5.3%). As expected, TDP-43 pathology was positively associated with comorbid hippocampal sclerosis pathology and with severe AD pathology. TDP-43 pathology was also associated with comorbid moderate-to-severe brain arteriolosclerosis. The association between TDP-43 pathology and brain arteriolosclerosis appears relatively specific since there was no detected association between TDP-43 pathology and microinfarcts, lacunar infarcts, large infarcts, cerebral amyloid angiopathy (CAA), or circle of Willis atherosclerosis. Together, these observations provide support for the hypothesis that many aged brains are affected by a TDP-43 proteinopathy that is more likely to be seen in brains with AD pathology, arteriolosclerosis pathology, or both.
Highlights
There is an evolving appreciation of a common brain disease with TAR-DNA binding protein 43 (TDP-43) proteinopathy that mimics Alzheimer’s disease (AD) clinically [5, 25, 26, 34, 39, 50] and affects 10–25% of persons aged 85 or older [5, 19, 21, 33, 50]
In prior published papers that have studied the spectrum of TDP-43 pathologies in aged brains, the severity of TDP-43 proteinopathy has been mostly graded according to stage-based classification systems where the presence of any TDP-43 pathology in a given region defines a particular stage [15, 17, 27, 29, 44]
We excluded 476 subjects who had at least one rare neurological disease listed in Additional file 1: Table S1, and we excluded 562 subjects who had no TDP-43 pathology data reported in all five brain regions and 1 subject with “other” reported as the TDP-43 antibody used (Fig. 3)
Summary
There is an evolving appreciation of a common brain disease with TAR-DNA binding protein 43 (TDP-43) proteinopathy that mimics Alzheimer’s disease (AD) clinically [5, 25, 26, 34, 39, 50] and affects 10–25% of persons aged 85 or older [5, 19, 21, 33, 50]. In prior published papers that have studied the spectrum of TDP-43 pathologies in aged brains (often with comorbid AD pathology), the severity of TDP-43 proteinopathy has been mostly graded according to stage-based classification systems where the presence of any TDP-43 pathology in a given region defines a particular stage [15, 17, 27, 29, 44]. In cases with extensive pathology, the frontal neocortex may be affected and if this region has any detectable TDP-43 pathology, that is indicative of a late disease stage. The stage-based classification systems for common age-related disease differ from TDP-43 pathologic staging systems that were developed for amyotrophic lateral sclerosis (ALS) and/or frontotemporal lobar degeneration (FTLD)-TDP [6, 10, 45]
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