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Pathological, imaging and genetic characteristics support the existence of distinct TDP-43 types in non-FTLD brains

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TDP-43 is present in a high proportion of aged brains that do not meet criteria for frontotemporal lobar degeneration (FTLD). We determined whether there are distinct TDP-43 types in non-FTLD brains. From a cohort of 553 brains (Braak neurofibrillary tangle (NFT) stage 0-VI), excluding cases meeting criteria for FTLD, we identified those that had screened positive for TDP-43. We reviewed 14 different brain regions in these TDP-43 positive cases and classified them into those with typical TDP-43 immunoreactive inclusions (TDP type-), and those in which TDP-43 immunoreactivity was adjacent to/associated with NFTs in the same neuron (TDP type-). We compared pathological, genetic (APOE4, TMEM106B and GRN variants), neuroimaging and clinical data between types, as well as compared neuroimaging between types and a group of TDP-43 negative cases (n=309). Two-hundred forty-one cases were classified as TDP type- (n=131, 54%) or TDP type- (n=110, 46%). Type- cases were older than type- at death (median 89years vs. 87years; p=0.02). Hippocampal sclerosis was present in 78(60%) type- cases and 16 (15%) type- cases (p<0.001). Type- cases showed a pattern of widespread TDP-43 deposition commonly extending into temporal, frontal and brainstem regions (84% TDP-43 stage 4-6) while in type- cases deposition was predominantly limbic, located in amygdala, entorhinal cortex and subiculum of the hippocampus (84% TDP-43 stages 1-3) (p<0.001). There was a difference in the frequency of TMEM106B protective (GG) and risk (CC) haplotypes (SNP rs3173615 encoding p.T185S) in type- cases compared to type- cases (GG/CG/CC: 8%/42%/50% vs. 24%/49%/27%; p=0.01). Type- cases had smaller amygdala (-10.6% [-17.6%, -3.5%]; p=0.003) and hippocampal (-14.4% [-21.6%, -7.3%]; p<0.001) volumes on MRI at death compared to type- cases, although both types had smaller amygdala and hippocampal volumes compared to TDP-43 negative cases (-7.77%, -21.6%; p<0.001). These findings demonstrate that there is distinct heterogeneity of TDP-43 deposition in non-FTLD brains.
Tijdschrift: Acta Neuropathologica
ISSN: 0001-6322
Volume: 137
Pagina's: 227 - 238
Jaar van publicatie:2019