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 < 0.001). Type-α 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-β 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-α cases compared to type-β cases (GG/CG/CC: 8%/42%/50% vs. 24%/49%/27%; p = 0.01). Type-α 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-β 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.
This is a preview of subscription content, log in to check access.
This study was funded by the following grants from the US National Institutes of Health (National Institute on Aging): R01 AG037491, P50 AG16574, U01 AG006786 and R35 NS097261 (National Institute of Neurological Disorders and Stroke). We thank the families of the patients who donated their brains to science and thus allowed completion of this study.
Braak H, Braak E (1991) Neuropathological staging of Alzheimer-related changes. Acta Neuropathol 82:239–259CrossRefGoogle Scholar
Brun A (1987) Frontal lobe degeneration of non-Alzheimer type. I. Neuropathology. Arch Gerontol Geriatr 6:193–208CrossRefGoogle Scholar
Cairns NJ, Bigio EH, Mackenzie IR, Neumann M, Lee VM, Hatanpaa KJ et al (2007) Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol 114:5–22. https://doi.org/10.1007/s00401-007-0237-2CrossRefGoogle Scholar
Davidson YS, Raby S, Foulds PG, Robinson A, Thompson JC, Sikkink S et al (2011) TDP-43 pathological changes in early onset familial and sporadic Alzheimer’s disease, late onset Alzheimer’s disease and Down’s syndrome: association with age, hippocampal sclerosis and clinical phenotype. Acta Neuropathol 122:703–713. https://doi.org/10.1007/s00401-011-0879-yCrossRefGoogle Scholar
Dickson DW, Davies P, Bevona C, Van Hoeven KH, Factor SM, Grober E et al (1994) Hippocampal sclerosis: a common pathological feature of dementia in very old (> or = 80 years of age) humans. Acta Neuropathol 88:212–221CrossRefGoogle Scholar
Folstein MF, Robins LN, Helzer JE (1983) The Mini-Mental State Examination. Arch Gen Psychiatry 40:812CrossRefGoogle Scholar
Group Working (1998) Consensus report of the Working Group on: “Molecular and Biochemical Markers of Alzheimer’s Disease”. The Ronald and Nancy Reagan Research Institute of the Alzheimer’s Association and the National Institute on Aging Working Group. Neurobiol Aging 19:109–116CrossRefGoogle Scholar
McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH et al (2011) The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:263–269. https://doi.org/10.1016/j.jalz.2011.03.005CrossRefGoogle Scholar
Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM et al (1991) The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41:479–486CrossRefGoogle Scholar
Van Deerlin VM, Sleiman PM, Martinez-Lage M, Chen-Plotkin A, Wang LS, Graff-Radford NR et al (2010) Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. Nat Genet 42:234–239. https://doi.org/10.1038/ng.536CrossRefGoogle Scholar
Watts GD, Wymer J, Kovach MJ, Mehta SG, Mumm S, Darvish D et al (2004) Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet 36:377–381. https://doi.org/10.1038/ng1332CrossRefGoogle Scholar
Wechsler D (1987) Wechsler Memory Scale-Revised (Manual). Psychological Corporation, San AntonioGoogle Scholar
Wennberg A, Tosalkulwong N, Lesnick T, Murray ME, Whitwell JL, Liesinger AM et al (2018) Association of apolipoprotein E epsilon 4 with transactive response DNA binding protein 43. JAMA Neurol 75:1347–1354CrossRefGoogle Scholar
Whitwell JL, Crum WR, Watt HC, Fox NC (2001) Normalization of cerebral volumes by use of intracranial volume: implications for longitudinal quantitative MR imaging. AJNR Am J Neuroradiol 22:1483–1489Google Scholar