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 semi-quantitatively 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 < 0.0001). Digital measures of LC neurodegeneration in FTLD-tau were comparable to AD (z = − 1.84, p > 0.05) but greater than FTLD-TDP (z = − 3.85, p < 0.0001) and HC (z = − 4.12, p < 0.0001). Both tau burden and neurodegeneration were consistently elevated in the LC across pathologic and clinical subgroups of FTLD-tau compared to FTLD-TDP subgroups. Moreover, LC tau burden positively correlated with neurodegeneration in the total FTLD group (rho = 0.24, p = 0.001), while TDP-43 burden did not correlate with LC neurodegeneration in FTLD-TDP (rho = − 0.01, p = 0.90). These findings suggest that patterns of disease propagation across all tauopathies include prominent LC tau and neurodegeneration that are relatively distinct from the minimal degenerative changes to the LC in FTLD-TDP and HC. Antemortem detection of LC neurodegeneration and/or function could potentially improve antemortem differentiation of underlying FTLD tauopathies from clinically similar FTLD-TDP proteinopathies.
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The datasets collected and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
We greatly appreciate the technical assistance provided by John Robinson, Theresa Schuck, and Alejandra Bahena. We thank Dr. Peter Davies for his generous gift of the PHF-1 antibody and Drs. M. Neumann and E. Kremmer for their generous gift of the 1D3-p409-410 antibody. We also thank the patients and families who participated in the brain donation program, for without their deeply meaningful contribution to research, this study would not be possible.
Funding
This work was supported by grants from NIH grants R01-NS109260, P30-AG10124, P01-AG017586-01, R01-AG054519-02, R01-AG038490, U01-AG052943, and U19-AG062418, Penn Institute on Aging, the Wyncote Foundation, and former P50-NS053488 and P01-AG032953.
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All authors contributed to the interpretation of the work and approved the submitted manuscript. DTO and DJI contributed to the design, data acquisition, analyses, interpretation, drafting, and revising of the work. CP, RL, KAQC, and GSG contributed to data acquisition and analyses. DAW, VVD, LE, MS, AD, and AS contributed to data acquisition. CTM, JQT, EBL, and MG contributed to the design, data acquisition, analyses, drafting, and revising of the work.
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Ohm, D.T., Peterson, C., Lobrovich, R. et al. Degeneration of the locus coeruleus is a common feature of tauopathies and distinct from TDP-43 proteinopathies in the frontotemporal lobar degeneration spectrum. Acta Neuropathol 140, 675–693 (2020). https://doi.org/10.1007/s00401-020-02210-1
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DOI: https://doi.org/10.1007/s00401-020-02210-1