Brainstem neuromelanin and iron MRI reveals a precise signature for idiopathic and LRRK2 Parkinson’s disease

Abstract

Neuromelanin (NM) loss in substantia nigra pars compacta (SNc) and locus coeruleus (LC) reflects neuronal death in Parkinson’s disease (PD). Since genetically-determined PD shows varied clinical expressivity, we wanted to accurately quantify and locate brainstem NM and iron, to discover whether specific MRI patterns are linked to Leucine-rich repeat kinase 2 G2019S PD (LRRK2-PD) or idiopathic Parkinson’s disease (iPD). A 3D automated MRI atlas-based segmentation pipeline (3D-ABSP) for NM/iron-sensitive MRI images topographically characterized the SNc, LC, and red nucleus (RN) neuronal loss and calculated NM/iron contrast ratio (CR) and normalized volume (nVol). Left-side NM nVol was larger in all groups. PD had lower NM CR and nVol in ventral-caudal SNc, whereas iron increased in lateral, medial-rostral, and caudal SNc. The SNc NM CR reduction was associated with psychiatric symptoms. LC CR and nVol discriminated better among subgroups: LRRK2-PD had similar LC NM CR and nVol as that of controls, and larger LC NM nVol and RN iron CR than iPD. PD showed higher iron SNc nVol than controls, especially among LRRK2-PD. ROC analyses showed an AUC > 0.92 for most pairwise subgroup comparisons, with SNc NM being the best discriminator between HC and PD. NM measures maintained their discriminator power considering the subgroup of PD patients with less than 5 years of disease duration. The SNc iron CR and nVol increase was associated with longer disease duration in PD patients. The 3D-ABSP sensitively identified NM and iron MRI patterns strongly correlated with phenotypic PD features.

Diagnostic utility of 7T neuromelanin imaging of the substantia nigra in Parkinson’s disease

“…Additionally, a meta-analysis reported a sensitivity of 82% and specificity of 82% in diagnosing PD at 3T 17 . Few 3T studies have compared PD and ET cohorts with NM imaging, but many with relatively low AUC 36 – 39 . The best outcomes reported were by Jin et al 40 with an AUC of 0.89, sensitivity of 88%, and specificity of 80% in differentiating PD from ET.…”

Regional nigral neuromelanin degeneration in asymptomatic leucine-rich repeat kinase 2 gene carrier using MRI

“…However, experienced raters can achieve excellent reproducibility of manual measurements as our rater 1 achieved intra-rater ICC volume of 0.82 in line with several studies (ICC ranging 0.69-0.95 for manual measurements) [42][43][44][45][46] . Recent NM-MRI studies demonstrated nigral NM damage in LRRK2-associated PD patients 47,48 . Although similar studies validated in several cohorts will help better understand whether nigral neurodegeneration mechanism is similar in genetic and idiopathic PD.…”

Imaging Markers in Genetic Forms of Parkinson’s Disease

“…Furthermore, while the measured NM-SN was a good discriminator between PD patients and controls, the NM-LC was found to best discriminate among PD subgroups with LRRK2 -PD showing preserved NM-LC content compared to sPD. Based on these observations, the authors speculated that NM-based markers can serve as candidate markers for phenotypic PD features [ 42 ]. In a recent study, we investigated NM-SN differences among sPD, LRRK2 -PD, and GBA1 -PD patients.…”