Citations

Abstract TAR DNA-binding protein 43 (TDP-43) pathology frequently co-occurs with Tau neurofibrillary tangles (NFTs) and amyloid β plaques in Alzheimer’s disease (AD), driving significant clinical heterogeneity. Whether TDP-43 engages autonomous molecular programs or instead amplifies Tau-driven neurodegeneration remains difficult to resolve, largely because these pathologies often co-occur. To separate these overlapping signatures, we generated regionally resolved transcriptomic profiles from cognitively normal controls (Controls), neuropathologically defined cohorts of AD, AD with limbic-predominant age-related TDP-43 encephalopathy (AD/LATE), and frontotemporal lobar degeneration (FTLD-TDP), categorizing them by their distinct TDP-43 subtypes (types α and β for AD/LATE; types A and B for FTLD-TDP). By integrating transcriptomic profiles with quantitative measures of phosphorylated TDP-43 (pTDP-43) and Tau (pTau), we separated pathology-associated signals within mixed disease contexts. We found that TDP-43 is linked to distinct transcriptomic programs in AD/LATE that are largely uncoupled from Tau burden and diverge from those observed in FTLD-TDP. These signatures showed regional specificity, with transcriptomic remodeling occurring in the amygdala across both diseases, whereas frontal cortex alterations were largely restricted to FTLD-TDP. Furthermore, by stratifying cases by TDP-43 morphological subtype, we unmasked specific biological trajectories, from immune activation to unique cellular vulnerabilities, that are not apparent in unstratified cohorts. Together, our findings provide a framework for decoupling mixed proteinopathies and demonstrate that TDP-43 shapes autonomous, subtype-dependent transcriptional landscapes in AD.

Abstract Background Perry syndrome (PS) is a rare and fatal hereditary autosomal dominant neurodegenerative disorder caused by mutations in dynactin ( DCTN1 ). PS brains accumulate inclusions positive for ubiquitin, transactive‐response DNA‐binding protein of 43 kDa (TDP‐43), and to a lesser extent dynactin. Objectives Little is known regarding the contributions of TDP‐43, an RNA binding protein that represses cryptic exon inclusion, in PS. Therefore, we sought to identify the degree of TDP‐43 dysfunction in two regions of PS brains. Methods We evaluated the levels of insoluble pTDP‐43 and TDP‐43‐regulated cryptic RNAs and protein in the caudate nucleus and substantia nigra of 7 PS cases, 12 cases of frontotemporal lobar degeneration (FTLD) with TDP‐43 pathology, and 11 cognitively healthy controls without TDP‐43 pathology. Results Insoluble pTDP‐43 protein levels were detected in PS brains to a similar extent in the caudate nucleus and substantia nigra but lower than those in FTLD brains. The caudate nucleus of PS showed accumulation of eight TDP‐43‐regulated cryptic RNAs ( ACTL6B , CAMK2B , STMN2 , UNC13A , KCNQ2 , ATG4B , GPSM2 , and HDGFL2 ) and cryptic protein (HDGFL2) characteristic of FTLD. Conversely, only one cryptic target, UNC13A , reached significance in the substantia nigra despite similar pTDP‐43 levels. Conclusion We detected TDP‐43 cryptic RNAs and protein in PS caudate nucleus. Given the importance of cryptic exon biology in the development of biomarkers, and the identification of novel targets for therapeutic intervention, it is imperative we understand the consequences of TDP‐43 dysfunction across different brain regions and determine the targets that are specific and common to TDP‐43 proteinopathies. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Objective To identify factors associated with delayed adherence to follow-up in lung cancer screening. Methods Utilizing a data warehouse and lung cancer screening registry, variables were collected from a referred sample of 3110 unique participants with follow-up CT during the study period (1 January 2016 to 17 October 2018). Adherence was defined as undergoing chest CT within 90 days and 30 days of the recommended time for follow-up and was determined using proportions and multiple variable logistic regression models across the American College of Radiology Lung Imaging Reporting and Data System (Lung-RADS®) categories. Results Of 1954 lung cancer screening participants (51.9% (1014/1954) males, 48.1% (940/1954) female; mean age 65.7 (range 45–87), smoking history median 40 pack-years, 60.2% and 44.5% did not follow-up within 30 and 90 days, respectively. Participants receiving Lung-RADS® category 1 or 2 presented later than those with Lung-RADS® category 3 at 90 days (coefficient −27.24, 95% CI −51.31, −3.16, p = 0.027). Participants with Lung-RADS® category 1 presented later than those with Lung-RADS® category 2 at both 90- and 30-days past due (OR 0.76 95% CI [0.59–0.97], p = 0.029 and OR 0.63 95% CI [0.48–0.83], p = 0.001, respectively). Conclusions Adherence to follow-up was higher among participants receiving more suspicious Lung-RADS® results at index screening CT and among those who had undergone more non-lung cancer screening imaging examinations prior to index lung cancer screening CT. These observations may inform strategies aimed at prospectively identifying participants at risk for delayed or nonadherence to prevent potential morbidity and mortality from incident lung cancers.

Abstract Introduction Transgender and gender diverse (TGD) persons disproportionately face many health disparities including a higher risk of lung cancer. Lung cancer screening (LCS) using low-dose chest computed tomography has reduced lung cancer mortality in eligible high-risk smokers across several large trials, yet utilization of LCS remains low. TGD persons may be less likely to receive recommended cancer screening compared with cisgender populations. We sought to compare eligibility for and utilization of LCS between TGD and cisgender persons in the United States. We also examined if the utilization of LCS varied by smoking status within each gender identity group. Methods We analyzed data from the 2017 and 2018 Behavioral Risk Factor Surveillance System (BRFSS) cross-sectional survey to determine eligibility and utilization of LCS among TGD participants compared with cisgender persons. Logistical regression analysis of potentially confounding variables included age category, race/ethnicity, income, employment status, health insurance, and having a personal doctor. Results Of 37 023 weighted respondents, 0.5% were TGD. Although eligibility for LCS was statistically similar (8.8% TGD vs. 12.2% cisgender) (adjusted odds ratio = 0.81, 95% confidence interval = 0.27–2.39, p = .703), only 2.3% of TGD participants reported obtaining a LCS chest computed tomography versus 17.2% of cisgender participants (adjusted odds ratio = 0.04, 95% confidence interval = 0.01–0.59, p = .019). Smoking status showed no association with LCS utilization among gender identity groups. Conclusions TGD persons may be less likely to receive LCS despite having similar smoking status and eligibility of cisgender persons, suggesting a disparity in utilization of this preventative health service. Implications Targeted efforts to increase LCS utilization and promote smoking cessation for at-risk TGD patients may be warranted.