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

• Published in: Acta neuropathologica 2019-02, Vol.137 (2), p.227-238
• Main Authors: Josephs, Keith A., Murray, Melissa E., Tosakulwong, Nirubol, Weigand, Stephen D., Serie, Amanda M., Perkerson, Ralph B., Matchett, Billie J., Jack, Clifford R., Knopman, David S., Petersen, Ronald C., Parisi, Joseph E., Petrucelli, Leonard, Baker, Matthew, Rademakers, Rosa, Whitwell, Jennifer L., Dickson, Dennis W.
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Amygdala; Apolipoprotein E4; Brain; Brain - metabolism; Brain - pathology; Brain stem; Comparative analysis; Cortex (entorhinal); Diagnostic imaging; DNA-Binding Proteins - genetics; Female; Frontotemporal dementia; Frontotemporal Dementia - genetics; Frontotemporal Dementia - pathology; Frontotemporal Lobar Degeneration - genetics; Haplotypes; Hippocampus; Humans; Immunoreactivity; Intercellular Signaling Peptides and Proteins - genetics; Magnetic resonance imaging; Male; Medical imaging; Medicine; Medicine & Public Health; Middle Aged; Mutation - genetics; Neurodegeneration; Neurofibrillary Tangles - genetics; Neurofibrillary Tangles - pathology; Neuroimaging; Neurons; Neurosciences; Original Paper; Pathology; Sclerosis; Single-nucleotide polymorphism; Subiculum; Temporal cortex
• ISSN: 0001-6322; 1432-0533
• DOI: 10.1007/s00401-018-1951-7

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-α), and those in which TDP-43 immunoreactivity was adjacent to/associated with NFTs in the same neuron (TDP type-β). 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-α ( n  = 131, 54%) or TDP type-β ( n  = 110, 46%). Type-α cases were older than type-β at death (median 89 years vs. 87 years; p  = 0.02). Hippocampal sclerosis was present in 78 (60%) type-α cases and 16 (15%) type-β cases ( p