Association of Locus Coeruleus and Substantia Nigra Pathology With Cognitive and Motor Functions in Patients With Parkinson Disease

Abstract

Objective.To investigate the contribution of substantia nigra (SN) and locus coeruleus (LC) pathology to clinical signs and symptoms in Parkinson’s disease (PD) by applying neuromelanin-weighted imaging.Methods.Forty-seven patients with PD and 53 matched controls underwent motor assessment, a neuropsychological test battery and neuromelanin-weighted MRI. Patients with PD have been enrolled after fulfilling the criteria for ‘clinically established PD’ as defined by the Movement Disorders Society Clinical Diagnostic Criteria. Two independent raters identified SN and LC and calculated the contrast-to-noise ratio (CNR).Results.The intra-rater reliability demonstrated a good reliability between raters with an intraclass correlation coefficient of .88 (p<.001) and an inter-rater reliability of .80 (p<.001). Both, SN and LC CNRs were lower in patients with PD (p≤.001) compared to controls. The CNR of SN but not of LC was strongly correlated with disease duration (p≤.001). Neuromelanin pathology of the pars compacta-containing dorso-lateral SN correlated with MDS-UPDRS I, II and III but not cognitive functions. In contrast, neuromelanin pathology of LC was associated with cognitive functions in all tested domains but not with motor impairment or activities of daily living. No such associations were present in controls.Conclusions.Neuromelanin imaging of the SN and LC is well-suited to map neurodegeneration in PD. Neuromelanin pathology of the SN correlates with motor dysfunction whereas LC pathology is related to cognitive impairment. Neuromelanin-weighted imaging of the LC could thus serve as an imaging marker of executive and other cognitive dysfunctions in PD.Classification of Evidence:This study provides Class I evidence that neuromelanin-weighted imaging was associated with the severity of various signs and symptoms in patients with PD.

Locus coeruleus degeneration is associated with disorganized functional topology in Parkinson’s disease

“…This study investigated the relationships among LC degeneration, network disruption, and cognitive impairment in a large sample of PD patients. We confirmed the relationship between LC degeneration and cognitive impairment in PD patients, which had been reported by a recent study with moderate sample size ( Prasuhn et al, 2021 ). We further highlight the role of network disorganization in LC degeneration-related cognitive impairment.…”

“…This finding further suggested that the linking among LC integrity, STG disorganization, and cognitive impairment might be independent of the dopaminergic system. This finding was also supported by one of the latest studies, which suggested that SN degeneration correlates with motor dysfunction, whereas LC degeneration is related to cognitive impairment in PD patients ( Prasuhn et al, 2021 ). However, it is worth noting that confidence in the negative result (levodopa challenge test) might be less because of the small sample size of that study.…”

Magnetic Resonance Imaging Markers for Cognitive Impairment in Parkinson’s Disease: Current View

“…The substantia nigra (SN) of the midbrain and the locus coeruleus (LC) within the pons contain large clusters of neuromelanin-producing cells, and the loss of these neuromelanin-containing cells within the two regions is a primary pathological diagnostic criterion for PD. The NM signal intensity of the LC in PD-MCI patients is significantly lower than that of the control subjects, and may serve as an imaging marker for assessing cognitive dysfunction in PD ( Li et al, 2019 ; Prasuhn et al, 2021 ).…”

Increased Expression of Alpha-, Beta-, and Gamma-Synucleins in Brainstem Regions of a Non-Human Primate Model of Parkinson’s Disease

“…Finally, the PD pathological process also affects noradrenergic neurons from the locus coeruleus (LC) [ 7 , 16 , 17 , 18 ]. Noradrenergic deficits have been linked to cognitive dysfunction, REM sleep behavioral disorder, and freezing of gait [ 19 , 20 ].…”