Degeneration of the locus coeruleus is a common feature of tauopathies and distinct from TDP-43 proteinopathies in the f
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ORIGINAL PAPER
Degeneration of the locus coeruleus is a common feature of tauopathies and distinct from TDP‑43 proteinopathies in the frontotemporal lobar degeneration spectrum Daniel T. Ohm1,2 · Claire Peterson1,2 · Rebecca Lobrovich1,2 · Katheryn A. Q. Cousins2 · Garrett S. Gibbons3 · Corey T. McMillan2 · David A. Wolk4,5 · Vivianna Van Deerlin3,4 · Lauren Elman6 · Meredith Spindler7 · Andres Deik7 · Andrew Siderowf7 · John Q. Trojanowski3,4 · Edward B. Lee3,4,8 · Murray Grossman2 · David J. Irwin1,2 Received: 8 June 2020 / Revised: 4 August 2020 / Accepted: 5 August 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Neurodegeneration of the locus coeruleus (LC) in age-related neurodegenerative diseases such as Alzheimer’s disease (AD) is well documented. However, detailed studies of LC neurodegeneration in the full spectrum of frontotemporal lobar degeneration (FTLD) proteinopathies comparing tauopathies (FTLD-tau) to TDP-43 proteinopathies (FTLD-TDP) are lacking. Here, we tested the hypothesis that there is greater LC neuropathology and neurodegeneration in FTLD-tau compared to FTLD-TDP. We examined 280 patients including FTLD-tau (n = 94), FTLD-TDP (n = 135), and two reference groups: clinical/pathological AD (n = 32) and healthy controls (HC, n = 19). Adjacent sections of pons tissue containing the LC were immunostained for phosphorylated TDP-43 (1D3-p409/410), hyperphosphorylated tau (PHF-1), and tyrosine hydroxylase (TH) to examine neuromelanin-containing noradrenergic neurons. Blinded to clinical and pathologic diagnoses, we semiquantitatively scored inclusions of tau and TDP-43 both inside LC neuronal somas and in surrounding neuropil. We also digitally measured the percent area occupied of neuromelanin inside of TH-positive LC neurons and in surrounding neuropil to calculate a ratio of extracellular-to-intracellular neuromelanin as an objective composite measure of neurodegeneration. We found that LC tau burden in FTLD-tau was greater than LC TDP-43 burden in FTLD-TDP (z = − 11.38, p 0.05) but greater than FTLD-TDP (z = − 3.85, p G, p.L266V, c.915 + 16C > T, p.?), AGD = argyrophilic grain disease, CVD cerebrovascular disease, HS hippocampal sclerosis, LBD Lewy body disease (LBD subtypes include: A amygdala-only, B brainstem, L limbic, N neocortical). Clinical diagnoses: AD Alzheimer’s disease, ALS amyotrophic lateral sclerosis, bvFTD behavioral variant frontotemporal dementia, CBS corticobasal syndrome, DLB dementia with Lewy Bodies, MCI mild cognitive impairment, PD Parkinson’s disease, PPA primary progressive aphasia, PSPS progressive supranuclear palsy syndrome, Low Low level, Int. Intermediate level, High High level. Data presented are patient frequency (italicized) or median and interquartile ranges. Significant differences between FTLD-tau and FTLD-TDP (*p
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