These accumulate with proteins and lipids into autophagic organelles, which fuse with lysosomes to form neuromelanin organelles. Neuromelanin is synthesised through complex pathways involving iron- and copper-mediated oxidation of cytosolic catecholamines into quinones. In humans, the noradrenergic neurons of the locus coeruleus contain a pigment called neuromelanin. However, there is evidence, from studies in Parkinson’s disease, that cognitive and behavioural deficits associated with locus coeruleus’ degeneration can be partially restored by noradrenergic therapies, raising the possibility of noradrenergic treatments in PSP.Īt the neuropathological level, the degeneration of the locus coeruleus in PSP includes neuronal loss and the presence of neuronal and glial inclusions of hyperphosphorylated 4-repeat isoforms of microtubule-associated protein tau. The motor and cognitive symptoms of PSP are not relieved by standard anti-parkinsonian medications including dopaminergic therapies. Many of these functions are affected by PSP, over and above the PSP’s classical movement disorder. Its connectivity enables a concerted release of noradrenaline in multiple target areas with modulatory effects on several physiological and cognitive functions including arousal, vigilance, sleep, attention, working-memory, and adaptive behaviour (reviewed by ). Despite its small size, with only tens of thousands of neurons in adult humans, the locus coeruleus sends widespread projections to the neocortex, thalamus, and sub-cortical areas, sparing the majority of the striatum. The locus coeruleus is located in the posterior margin of the rostral pons, near the lateral floor of the fourth ventricle. We test the hypotheses that, in patients with clinical and pathologically confirmed diagnosis of PSP, there is severe degeneration and tau-pathology in the locus coeruleus, and that the degree of noradrenergic cell loss relates to clinical severity. Here, we focus on the neuropathology of the locus coeruleus in PSP, a complex parkinsonian syndrome characterised by postural instability, falls, oculomotor impairment, cognitive, and behavioural changes. The locus coeruleus is vulnerable to neurodegeneration in several diseases including Alzheimer’s disease, Parkinson’s disease, and progressive supranuclear palsy (PSP). The locus coeruleus is the principal source of noradrenaline, with diverse influences on arousal, behaviour, movement, and cognition. 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. The noradrenergic deficit in the locus coeruleus is a candidate target for pharmacological treatment. The degree of neuronal loss was negatively associated with tau-positive inclusions, with an average of 44% of pigmented neurons displaying tau-inclusions.ĭegeneration and tau pathology in the locus coeruleus are related to clinical heterogeneity of PSP. The loss of pigmented neurons correlated with disease severity, even after adjusting for disease duration and the interval between clinical assessment and death. We found an average 49% reduction of pigmented neurons in PSP patients relative to controls. Ante mortem assessment of clinical severity using the PSP rating scale was available within 1.8 (☐.9) years for 23 patients. 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. 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 test the hypothesis that tau pathology and neuronal loss are associated with clinical heterogeneity and severity in PSP. This pathology is proposed to contribute to the clinical expression of disease, including the PSP Richardson’s syndrome. Neurodegeneration and pathological aggregation of tau protein in the locus coeruleus are early features of progressive supranuclear palsy (PSP). 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.
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