Distinct characteristics of limbic-predominant age-related TDP-43 encephalopathy in Lewy body disease

• Published in: Acta neuropathologica Vol. 143; no. 1; pp. 15 - 31
• Main Authors: Uemura, Maiko T., Robinson, John L., Cousins, Katheryn A. Q., Tropea, Thomas F., Kargilis, Daniel C., McBride, Jennifer D., Suh, EunRan, Xie, Sharon X., Xu, Yan, Porta, Sílvia, Uemura, Norihito, Van Deerlin, Vivianna M., Wolk, David A., Irwin, David J., Brunden, Kurt R., Lee, Virginia M.-Y., Lee, Edward B., Trojanowski, John Q.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-01-2022; Springer; Springer Nature B.V
• Subjects: Advertising executives; Aged; Aged, 80 and over; Aging; Aging - pathology; Alzheimer Disease - complications; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Alzheimer's disease; Analysis; Autopsy; Axons; Brain - pathology; Brain stem; Cognitive ability; Dentate gyrus; DNA-binding protein; Encephalopathy; Female; Genetic analysis; Hippocampus; Humans; Inclusion bodies; Lewy bodies; Lewy body disease; Lewy Body Disease - complications; Lewy Body Disease - genetics; Lewy Body Disease - pathology; Male; Medical research; Medicine; Medicine & Public Health; Medicine, Experimental; Middle Aged; Neurodegenerative diseases; Neuropathology; Neurosciences; Original Paper; Pathology; Protein binding; Risk factors; Subiculum; Synuclein; TDP-43 Proteinopathies - complications; TDP-43 Proteinopathies - genetics; TDP-43 Proteinopathies - pathology; TMEM106B; Limbic-predominant age-related TDP-43 encephalopathy; GRN; Lewy body disease; TDP-43 proteinopathy
• ISSN: 0001-6322; 1432-0533
• DOI: 10.1007/s00401-021-02383-3

Limbic-predominant age-related TDP-43 encephalopathy (LATE) is characterized by the accumulation of TAR-DNA-binding protein 43 (TDP-43) aggregates in older adults. LATE coexists with Lewy body disease (LBD) as well as other neuropathological changes including Alzheimer’s disease (AD). We aimed to identify the pathological, clinical, and genetic characteristics of LATE in LBD (LATE-LBD) by comparing it with LATE in AD (LATE-AD), LATE with mixed pathology of LBD and AD (LATE-LBD + AD), and LATE alone (Pure LATE). We analyzed four cohorts of autopsy-confirmed LBD (
n
 = 313), AD (
n
 = 282), LBD + AD (
n
 = 355), and aging (
n
 = 111). We assessed the association of LATE with patient profiles including LBD subtype and AD neuropathologic change (ADNC). We studied the morphological and distributional differences between LATE-LBD and LATE-AD. By frequency analysis, we staged LATE-LBD and examined the association with cognitive impairment and genetic risk factors. Demographic analysis showed LATE associated with age in all four cohorts and the frequency of LATE was the highest in LBD + AD followed by AD, LBD, and Aging. LBD subtype and ADNC associated with LATE in LBD or AD but not in LBD + AD. Pathological analysis revealed that the hippocampal distribution of LATE was different between LATE-LBD and LATE-AD: neuronal cytoplasmic inclusions were more frequent in cornu ammonis 3 (CA3) in LATE-LBD compared to LATE-AD and abundant fine neurites composed of C-terminal truncated TDP-43 were found mainly in CA2 to subiculum in LATE-LBD, which were not as numerous in LATE-AD. Some of these fine neurites colocalized with phosphorylated α-synuclein. LATE-LBD staging showed LATE neuropathological changes spread in the dentate gyrus and brainstem earlier than in LATE-AD. The presence and prevalence of LATE in LBD associated with cognitive impairment independent of either LBD subtype or ADNC; LATE-LBD stage also associated with the genetic risk variants of
TMEM106B
rs1990622 and
GRN
rs5848. These data highlight clinicopathological and genetic features of LATE-LBD.