Urinary Incontinence in a Community-Based Autopsy Cohort Is Associated with Limbic Predominant Age-Related TDP-43 Encephalopathy Neuropathologic Changes

Di, Jing; Nelson, Ruth S.; Jicha, Gregory A.; Moga, Daniela C.; Barber, Justin M.; Cykowski, Matthew D.; Fardo, David W.; Abner, Erin L.; Nelson, Peter T.

doi:10.3233/jad-230425

Cited by 6 publications

(2 citation statements)

References 55 publications

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“…The pTDP-43 antibody used was the 1D3 clone (Sigma-Aldrich, USA) [ 36 ]. Stage-based diagnoses of LATE-NC, ADNC, and other pathologies used consensus-based criteria [ 3 , 11 , 28 , 34 ]. None of the included cases had FTLD-TDP or any other non-LATE-NC pathology.…”

Section: Methodsmentioning

confidence: 99%

Cryptic exon inclusion is a molecular signature of LATE-NC in aging brains

Chung,

Carter,

Veire

et al. 2024

Acta Neuropathol

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The aggregation, mislocalization, and phosphorylation of TDP-43 are pathologic hallmarks of several neurodegenerative diseases and provide a defining criterion for the neuropathologic diagnosis of Limbic-predominant Age-related TDP-43 Encephalopathy (LATE). LATE neuropathologic changes (LATE-NC) are often comorbid with other neurodegenerative pathologies including Alzheimer’s disease neuropathologic changes (ADNC). We examined whether TDP-43 regulated cryptic exons accumulate in the hippocampus of neuropathologically confirmed LATE-NC cases. We found that several cryptic RNAs are robustly expressed in LATE-NC cases with or without comorbid ADNC and correlate with pTDP-43 abundance; however, the accumulation of cryptic RNAs is more robust in LATE-NC with comorbid ADNC. Additionally, cryptic RNAs can robustly distinguish LATE-NC from healthy controls and AD cases. These findings expand our current understanding and provide novel potential biomarkers for LATE pathogenesis.

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Section: Methodsmentioning

confidence: 99%

Cryptic exon inclusion is a molecular signature of LATE-NC in aging brains

Chung,

Carter,

Veire

et al. 2024

Acta Neuropathol

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“…Participants were recruited from an existing longitudinal cohort of older adults spanning the cognitive continuum at UK’s Sanders-Brown Center on Aging (SBCoA). Information about recruitment, exclusion/inclusion criteria, and other aspects of the cohort are conveyed in prior studies ( 17 – 19 ). Briefly: Exclusionary criteria for enrollment into the SBCoA cohort include a past history of major head injury; major stroke, major psychiatric illness, or current substance abuse; and or encephalitis; meningitis; or epilepsy.…”

Section: Methodsmentioning

confidence: 99%

Exploratory mass spectrometry of cerebrospinal fluid from persons with autopsy-confirmed LATE-NC

Gal,

Vary,

Gartner

et al. 2023

Preprint

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Background: Common neuropathologies associated with dementia include Alzheimer’s disease neuropathologic change (ADNC) and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). Biofluid proteomics provides a window into the pathobiology of dementia and the information from biofluid tests may help guide clinical management. Methods: Participants were recruited from a longitudinal cohort of older adults at the University of Kentucky AD Research Center. A convenience sample of clinically obtained lumbar puncture cerebrospinal fluid (CSF) samples was analyzed from 29 older adults that had autopsy confirmation of the presence or absence of LATE-NC. Nine of the participants had autopsy-confirmed LATE-NC. Antemortem CSF specimens were analyzed in two separate processes: From one group, aliquots were depleted of highly abundant proteins using affinity spin columns. Tryptic digests of sample proteins were subjected to liquid chromatographic separation and mass spectrometry using an Eksigent Ekspert nanoLC 400 system in line with a Sciex 6600+ mass spectrometer. Protein identification was performed using Protein Pilot (Sciex, ver. 5) software, and relative quantification was performed using the SWATH processing microApp in PeakView and MarkerView software (Sciex), respectively. Following data analyses, additional studies were performed using western blots. Results: A total of 830 proteins were identified in the samples depleted of abundant proteins, and 730 proteins were identified in the non-depleted samples. Whereas some dementia-related proteins were detected (Aβ peptide and α-synuclein protein), others were not (TDP-43, TMEM106B, and tau proteins). When the Bonferroni correction was applied to correct for multiple comparisons, only 4 proteins showed differential expression (LATE-NC vs non-LATE-NC) in the nondepleted samples (RBP4, MIF, IGHG3 and ITM2B), whereas none showed statistically different changes in the depleted samples. Post-hoc western blots confirmed that RBP4 expression was higher in the LATE-NC cases at the group level, but there was overlap between the levels of RBP4 in LATE-NC and non-LATE-NC cases. Conclusions: An exploratory assessment of CSF proteomes of autopsy-confirmed LATE-NC and non-LATE-NC cases from a community-based cohort failed to demonstrate a clear-cut proteomic fingerprint that distinguished the two groups. There was intriguing increase in RBP4 protein levels in CSF from LATE-NC cases. This may provide clues about pathogenetic mechanisms in LATE-NC.

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