Chidinma Anyaike

Introduction: Abnormal noradrenergic signaling from the locus coeruleus-norepinephrine (LC/NE) system has been increasingly recognized as a potential major contributor to cognitive manifestations in early Parkinson disease (PD).¹ Mechanistic studies show that two inflammatory components, α-synuclein (asyn) and CD11b, stimulate chronic inflammation and neuronal loss in PD patients.² The LC’s compounding effects on drug action also predict PD progression. Methods: Wild type and CD11b KO mice were used to determine whether integrin CD11b is involved in LC/NE neurodegeneration in PD.² Effects of increases in asyn, the primary component of Lewy body aggregates, on noradrenergic neurons in the LC were investigated in aging transgenic mice expressing human asyn with a noradrenergic-specific promoter.³  Neurocognitive tests and neuromelanin-MRI (NM-MRI) quantified the contribution of substantia nigra pars compacta (SNPC) and LC pathology to the clinical signs and symptoms of 47 PD patients and  53 control patients.⁶ Neuromelanin-MRI (NM-MRI) of 57 PD patients examined the relationship between LC degeneration and levodopa responsiveness.⁵  Psychopharmacological challenge and MRI examined effects of atomoxetine, a norepinephrine reuptake inhibitor improving non-motor symptoms of PD patients, on integrity of the LC and response inhibition⁴. Results: CD11b deficiency markedly suppressed microglial activation and dopaminergic neurodegeneration in PD-induced mice.² Inhibition of NLRP3 inflammasome by glibenclamide, a sulfonylurea inhibitor of NLRP3 inflammasome, suppressed microglial proinflammatory activation.² Overexpression of asyn and formation of oligomers was linked to LC dysfunction, fiber degeneration, and behavioral deficits associated with PD.³ The contrast-to-noise ratio of LC correlated with motor improvement of PD patients after levodopa administration (R = 0.421, p = 0.004) and improvement in somatomotor network synchronization (R = -0.323, p = 0.029).⁵ The variations of cognitive improvement in response to atomoxetine were linked to the severity of LC damage before treatment.⁵ Conclusions: The proposed mechanistic factors of neurodegeneration are intertwined through their roles in immune response.² CD11b’s effects on the LC are congruent with asyn’s effects.³ Studies of humans confirm the link between the LC and the cognitive symptoms associated with PD. Studies of drug therapies targeting the SN and LC suggest LC neuroimaging can be used to stratify patients into clinical trials aimed at improving the efficacy of existing therapies and developing new therapies. Atomoxetine therapy has promising implications, particularly for patients having severely compromised LC integrity due to lack of early treatment. More investigation into the mechanism behind this interaction can be applied in developing drug therapies that will better target LC neurodegeneration at earlier stages.⁴

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2. Hou L, Qu X, Qiu X, Huang R, Zhao X, Wang Q. Integrin CD11b mediates locus coeruleus noradrenergic neurodegeneration in a mouse Parkinson’s disease model. J Neuroinflammation. 2020;17(1):148. Published 2020 May 6. doi:10.1186/s12974-020-01823-3
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