Relation of Motor Impairments to Neuropathologic Changes of Limbic-Predominant Age-Related TDP-43 Encephalopathy in Older Adults

Background: Limbic-predominant age-related transactive response DNA-binding protein 43 (TDP-43) encephalopathy-neuropathologic change (LATE-NC) is common and is a major contributor to cognitive decline and Alzheimer’s dementia in older adults. The objective of the current study was to examine whether LATE-NC was also associated with declining motor function in older adults.

Methods: Participants were from 2 longitudinal clinical pathological studies of aging who did not have dementia at the time of enrollment. Postmortem pathological exam included immunohistochemical staining for TDP-43 in 8 brain regions, which was summarized as a dichotomous variable indicating advanced LATE-NC stages at which TDP-43 pathology had accumulated in the hippocampus, entorhinal or neocortical regions. Annual motor testing included maximal inspiratory and expiratory pressures (summarized as respiratory muscle strength), grip and pinch strength (summarized as hand strength), finger tapping speed and the Purdue Pegboard test (summarized as hand dexterity), walking 8 feet and turning 360^o (summarized as gait function). The severity of parkinsonism was also assessed and summarized as global parkinsonism score. Global cognition was a summary of standardized scores of 19 neuropsychological tests. We used linear mixed effects models to examine the associations of LATE-NC with longitudinal changes of motor decline, and used multivariate random coefficients models to simultaneously examine the associations of LATE-NC with cognitive and motor decline.

Results: Among 1483 participants (mean age at death 90.1 (SD=6.4) years, 70% women, mean follow up 7.4 (SD=3.8) years), LATE-NC was present in 34.0% (n=504). In separate linear mixed effects models controlling for demographics and other brain pathologies, LATE-NC was associated with faster decline in respiratory muscle strength (Estimate=-0.021, SE=0.007, p=0.005) and hand strength (Estimate=-0.005, SE=0.002, p=0.005), but was not related to hand dexterity, gait function, or parkinsonism. In multivariate random coefficients models including respiratory muscle strength, hand strength, and global cognition as the outcomes, LATE-NC remained associated with faster respiratory muscle strength decline rate (Estimate=-0.021, SE=0.009, p=0.023), but the association with hand strength was no longer significant (Estimate=-0.002, SE=0.003, p=0.390).

Discussion: Motor impairment, specifically respiratory muscle weakness, may be an unrecognized co-morbidity of LATE-NC, that highlights the potential association of TDP-43 proteinopathy with non-cognitive phenotypes in aging adults.