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Preferential degeneration of the locus coeruleus in tauopathies relative to TDP‐43 proteinopathies
Author(s) -
Ohm Daniel T.,
Peterson Claire,
Lobrovich Rebecca,
Bahena Alejandra,
Gibbons Garrett S.,
Wolk David A.,
Grossman Murray,
Lee Eddie B.,
Trojanowski John Q.,
Irwin David J.
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.045904
Subject(s) - neuromelanin , neurodegeneration , locus coeruleus , frontotemporal lobar degeneration , pathology , autopsy , tauopathy , medicine , psychology , neuroscience , parkinson's disease , disease , dementia , central nervous system , frontotemporal dementia , substantia nigra
Abstract Background The locus coeruleus (LC) is the brain’s primary source of norepinephrine and is vulnerable to neurodegeneration in Parkinson’s disease and tauopathies including Alzheimer’s disease (AD). However, detailed comparative studies of LC neurodegeneration between clinically similar tauopathies (FTLD‐tau) and TDP‐43 proteinopathies (FTLD‐TDP) are lacking. Using a large autopsy cohort, we tested the hypothesis that the LC has greater neuropathologic change in FTLD‐tau compared to FTLD‐TDP. Method The LC was examined in 333 patients representing autopsy‐confirmed FTLD‐tau (n=126), FTLD‐TDP (n=152), and two reference cohorts: clinical/pathological AD (n=36) and age‐matched healthy controls (HC, n=19). Pons tissue containing the LC was cut into 6µm‐thick sections and stained for hematoxylin and near‐adjacent sections immunostained for phosphorylated TDP‐43 (p409/410), hyperphosphorylated tau (PHF‐1), and AD‐neurofibrillary tau (GT‐38) to detect comorbid AD tau pathology in a FTLD‐tau subgroup (n=69). Blinded to diagnoses, an ordinal rating scale (0‐3) was used to semi‐quantitatively score tau inclusions, TDP‐43 inclusions, and neurodegeneration based on an averaged composite score of neuromelanin depigmentation and extracellular neuromelanin in hematoxylin sections. Result Tau burden in FTLD‐tau (median=2.5, IQR[2,3]) was greater than TDP‐43 burden in FTLD‐TDP (median=0.5, IQR[0,1]; p <0.0001). Similarly, neurodegeneration was greater in FTLD‐tau (median=1.5, IQR[1,2]) compared to FTLD‐TDP (median=1, IQR[1,1]; p <0.0001). Subanalyses of clinical subgroups with either dementia (n=117) or motor syndromes (n=124) found similar results: tau burden in FTLD‐tau was greater than TDP‐43 burden in FTLD‐TDP (dementia syndromes, p <0.0001; motor syndromes, p <0.0001); neurodegeneration was greater in FTLD‐tau compared to FTLD‐TDP (dementia syndromes, p =0.004; motor syndromes, p< 0.0001). AD neurodegeneration (median=1.75, IQR[1,2]) was greater than neurodegeneration in FTLD‐tau ( p= 0.0004), FTLD‐TDP ( p <0.0001), and HC ( p <0.0001). HC neurodegeneration (median=1, IQR[0.5,1]) was significantly less than neurodegeneration in FTLD‐tau ( p =0.002), but similar to the minimal neurodegeneration in FTLD‐TDP ( p =0.38). Greater tau burden correlated with greater neurodegeneration (rho=0.35, p <0.0001). Only 39% of the FTLD‐tau subgroup had a mild burden of AD tau co‐pathology suggesting LC neurodegeneration was driven by FTLD‐tauopathies. Conclusion FTLD‐tau showed histological evidence of greater LC neurodegeneration compared to FTLD‐TDP, independent of clinical phenotypes or AD co‐pathology. These findings suggest FTLD‐tau‐mediated noradrenergic neurodegeneration may be a commonality of tauopathies that could help improve antemortem diagnoses and symptomatic treatments.