Repository logo

Locus coeruleus pathology in progressive supranuclear palsy, and its relation to disease severity.

Accepted version

Change log


Kaalund, Sanne Simone  ORCID logo
Passamonti, Luca 
Allinson, Kieren SJ 
Murley, Alexander G 
Robbins, Trevor W 


The locus coeruleus is the major source of noradrenaline to the brain and contributes to a wide range of physiological and cognitive functions including arousal, attention, autonomic control, and adaptive behaviour. Neurodegeneration and pathological aggregation of tau protein in the locus coeruleus are early features of progressive supranuclear palsy (PSP). This pathology is proposed to contribute to the clinical expression of disease, including the PSP Richardson's syndrome. We test the hypothesis that tau pathology and neuronal loss are associated with clinical heterogeneity and severity in PSP.We used immunohistochemistry in post mortem tissues from 31 patients with a clinical diagnosis of PSP (22 with Richardson's syndrome) and 6 control cases. We quantified the presence of hyperphosphorylated tau, the number of pigmented cells indicative of noradrenergic neurons, and the percentage of pigmented neurons with tau-positive inclusions. Ante mortem assessment of clinical severity using the PSP rating scale was available within 1.8 (±0.9) years for 23 patients.We found an average 49% reduction of pigmented neurons in PSP patients relative to controls. The loss of pigmented neurons correlated with disease severity, even after adjusting for disease duration and the interval between clinical assessment and death. The degree of neuronal loss was negatively associated with tau-positive inclusions, with an average of 44% of pigmented neurons displaying tau-inclusions.Degeneration and tau pathology in the locus coeruleus are related to clinical heterogeneity of PSP. The noradrenergic deficit in the locus coeruleus is a candidate target for pharmacological treatment. Recent developments in ultra-high field magnetic resonance imaging to quantify in vivo structural integrity of the locus coeruleus may provide biomarkers for noradrenergic experimental medicines studies in PSP.



Frontotemporal dementia, Locus coeruleus, Neurodegeneration, Noradrenalin, Progressive supranuclear palsy, Tau, Adrenergic Neurons, Aged, Aged, 80 and over, Female, Humans, Locus Coeruleus, Male, Middle Aged, Phosphorylation, Severity of Illness Index, Supranuclear Palsy, Progressive, tau Proteins

Journal Title

Acta Neuropathol Commun

Conference Name

Journal ISSN


Volume Title



Springer Science and Business Media LLC


All rights reserved
MRC (unknown)
Medical Research Council (MC_U105597119)
Wellcome Trust (103838/Z/14/Z)
Medical Research Council (MR/P01271X/1)
Medical Research Council (G0301152)
Medical Research Council (MC_UU_00005/12)
This work was funded by Lundbeck Fonden R232-2016-2333, and R265-2017-3722; Wellcome Trust (103838); Medical Research Council (MC_U105597119 & MC_UU_00005/12 & SUAG004/051 RG91365), the Holt fellowship, NIHR Cambridge Biomedical Research Centre and Cambridge Brain Bank, and the Cambridge Centre for Parkinson plus. The Cambridge Brain Bank is supported by the NIHR Cambridge Biomedical Research Centre
Is derived from: