Impact and Risk Factors of Limbic Predominant Age-Related TDP-43 Encephalopathy Neuropathologic Change in an Oldest-Old Cohort.

Background and objectivesLimbic predominant age-related TAR DNA binding protein 43 (TDP-43) encephalopathy neuropathologic change (LATE-NC) is a prevalent degenerative pathology in the oldest-old who are the fastest-growing segment of our population with the highest rates of dementia. We aimed to determine the relationship between LATE-NC and cognitive impairment and to identify its potential risk factors by studying its relationship with common past medical histories in an oldest-old cohort.MethodsParticipants from The 90+ Study with longitudinal evaluations and autopsy data were included. Dementia status and impairment in 5 main cognitive domains were determined at postmortem conferences leveraging all clinical and neuropsychological data blind to neuropathologic diagnosis. Medical history information was obtained from patients and their informants. LATE-NC and Alzheimer disease neuropathologic change (ADNC) were considered present in those with TDP-43 pathology in the hippocampus and/or neocortex and those with high likelihood of ADNC according to NIA-AA guidelines, respectively. We examined the association of degenerative pathologies with cognitive outcomes and multiple comparisons-adjusted relationship of medical history variables with LATE-NC and ADNC using logistic regressions adjusted for age at death, sex, and education.ResultsThree hundred twenty-eight participants were included in this study. LATE-NC was present in 32% of the participants. It had a significant association with the presence of dementia (OR 2.8, 95% CI 1.7-4.6) and impairment in memory (OR 3.0, 95% CI 1.8-5.1), language (OR 2.6, 95% CI 1.6-4.3), and orientation (OR 3.5, 95% CI 2.1-5.9). The association with impaired orientation was unique to LATE-NC, and the strength and significance of the other associations were comparable to ADNC. Furthermore, we found that history of osteoarthritis (OR 0.37, adjusted 95% CI 0.21-0.66) and hypertension (OR 0.52, adjusted 95% CI 0.28-0.98) were associated with a reduced likelihood of LATE-NC, but not ADNC.DiscussionOur results suggest that LATE-NC is a prevalent degenerative pathology in the oldest-old and has significant associations with dementia and impairment in cognitive domains with magnitudes that are comparable to ADNC. We also found that past medical histories of hypertension and osteoarthritis were associated with a lower likelihood of LATE-NC. This might help identify upstream mechanisms leading to this important pathology

Markers for selection of the rice Xa21 disease resistance gene.

Six molecular markers were mapped to a 7.4-cM region of rice chromosome 11 containing the Xa21 gene, which confers resistance to the pathogen Xanthomonas oryzae pv oryzae. Three markers, RG103, 248 and 818, co-segregated with Xa21 in a population of 1141 plants. Multiple copies of all marker loci were present within the region that was introgressed from Oryza longistaminata into O. sativa. The marker loci were cloned and primers were designed that defined sequence-tagged sites. Physical mapping of the three tightly linked central markers revealed that RG103, the marker that hybridizes to the Xa21 gene, resides on a separate DNA fragment from the other two markers

Markers for selection of the rice Xa21 disease resistance gene.

Six molecular markers were mapped to a 7.4-cM region of rice chromosome 11 containing the Xa21 gene, which confers resistance to the pathogen Xanthomonas oryzae pv oryzae. Three markers, RG103, 248 and 818, co-segregated with Xa21 in a population of 1141 plants. Multiple copies of all marker loci were present within the region that was introgressed from Oryza longistaminata into O. sativa. The marker loci were cloned and primers were designed that defined sequence-tagged sites. Physical mapping of the three tightly linked central markers revealed that RG103, the marker that hybridizes to the Xa21 gene, resides on a separate DNA fragment from the other two markers

Markers for selection of the rice Xa21 disease resistance gene.

Six molecular markers were mapped to a 7.4-cM region of rice chromosome 11 containing the Xa21 gene, which confers resistance to the pathogen Xanthomonas oryzae pv oryzae. Three markers, RG103, 248 and 818, co-segregated with Xa21 in a population of 1141 plants. Multiple copies of all marker loci were present within the region that was introgressed from Oryza longistaminata into O. sativa. The marker loci were cloned and primers were designed that defined sequence-tagged sites. Physical mapping of the three tightly linked central markers revealed that RG103, the marker that hybridizes to the Xa21 gene, resides on a separate DNA fragment from the other two markers

Dementia is strongly associated with severity of hippocampal atrophy at autopsy even after accounting for degenerative neuropathologies.

Recent work from our research group has shown that dementia is strongly associated with hippocampal atrophy from in-vivo MRI even after accounting for degenerative neuropathologies. We sought to confirm this finding using ratings of hippocampal atrophy at autopsy and examining their relationship with dementia while also accounting for relevant degenerative neuropathologies. We used data from the National Alzheimer's Coordinating Center (NACC) neuropathology dataset (09/2005-05/2020). Our outcome measure was hippocampal atrophy severity assessed as part of gross findings at autopsy (NPGRHA variable, graded none/mild/moderate/severe). Inclusion criteria were availability of hippocampal atrophy rating, clinical assessment within a year before death, and death at age 65 years or older. For our independent variables we used dementia status and the following dichotomized neuropathologies: Alzheimer's disease neuropathological change (ADNC, high), hippocampal sclerosis (HS), limbic-transitional or neocortical Lewy Bodies (LB), cerebral amyloid angiopathy (CAA, moderate/severe), atherosclerosis (moderate/severe), gross infarcts, microinfarcts, and micro/macro-hemorrhages. We also examined a subset of the participants that had TAR DNA-binding protein 43 (TDP-43) assessed in the hippocampus, and due to the high correlation with HS, we excluded HS from these analyses. Ordinal logistic regressions were used for individual models of the variables of interest as well as for joint models which included dementia and all neuropathologies. All models were adjusted for age at death, sex, years of education, and months from last clinical assessment to death. We report odds ratios (OR). Table-1 summarizes participant characteristics across hippocampal atrophy ratings (N=1148). In the ordinal logistic regressions dementia was the strongest predictor of hippocampal atrophy (OR=6.6 in individual, 3.8 in joint model), followed by HS (OR=4.3 in individual, 3.2 in joint model), then ADNC (OR=3.9 in individual, 2.4 in joint model, Figure-1A,B). Results remained consistent for the TDP-43 subset analysis (N=717, 27% TDP-43 positive in the hippocampus, TDP-43 OR=1.9 for joint model, Figure-1C). In both individual and joint ordinal logistic regressions, dementia was the variable most strongly associated with hippocampal atrophy at autopsy, followed by hippocampal sclerosis, and then ADNC and TDP-43. Therefore, dementia is a significant and strong predictor of hippocampal atrophy, above and beyond common degenerative neuropathologies

Dementia is associated with medial temporal atrophy even after accounting for neuropathologies.

Brain atrophy is associated with degenerative neuropathologies and the clinical status of dementia. Whether dementia is associated with atrophy independent of neuropathologies is not known. In this study, we examined the pattern of atrophy associated with dementia while accounting for the most common dementia-related neuropathologies. We used data from National Alzheimer's Coordinating Center (n = 129) and Alzheimer's Disease Neuroimaging Initiative (n = 47) participants with suitable in vivo 3D-T1w MRI and autopsy data. We determined dementia status at the visit closest to MRI. We examined the following dichotomized neuropathological variables: Alzheimer's disease neuropathology, hippocampal sclerosis, Lewy bodies, cerebral amyloid angiopathy and atherosclerosis. Voxel-based morphometry identified areas associated with dementia after accounting for neuropathologies. Identified regions of interest were further analysed. We used multiple linear regression models adjusted for neuropathologies and demographic variables. We also examined models with dementia and Clinical Dementia Rating sum of the boxes as the outcome and explored the potential mediating effect of medial temporal lobe structure volumes on the relationship between pathology and cognition. We found strong associations for dementia with volumes of the hippocampus, amygdala and parahippocampus (semi-partial correlations ≥ 0.28, P < 0.0001 for all regions in National Alzheimer's Coordinating Center; semi-partial correlations ≥ 0.35, P ≤ 0.01 for hippocampus and parahippocampus in Alzheimer's Disease Neuroimaging Initiative). Dementia status accounted for more unique variance in atrophy in these structures (∼8%) compared with neuropathological variables; the only exception was hippocampal sclerosis which accounted for more variance in hippocampal atrophy (10%). We also found that the volumes of the medial temporal lobe structures contributed towards explaining the variance in Clinical Dementia Rating sum of the boxes (ranging from 5% to 9%) independent of neuropathologies and partially mediated the association between Alzheimer's disease neuropathology and cognition. Even after accounting for the most common neuropathologies, dementia still had among the strongest associations with atrophy of medial temporal lobe structures. This suggests that atrophy of the medial temporal lobe is most related to the clinical status of dementia rather than Alzheimer's disease or other neuropathologies, with the potential exception of hippocampal sclerosis