A mounting body of research points to cerebrovascular dysfunction as a fundamental element in the pathophysiology of Parkinson\'s disease (PD). In the current feasibility study, blood-oxygen-level-dependent (BOLD) MRI was used to measure cerebrovascular reactivity (CVR) in response to hypercapnia in 26 PD patients and 16 healthy controls (HC), and aimed to find a multivariate pattern specific to PD. Whole-brain maps of CVR amplitude (i.e., magnitude of response to CO2) and latency (i.e., time to reach maximum amplitude) were computed, which were further analyzed using scaled sub-profile model principal component analysis (SSM-PCA) with leave-one-out cross-validation. A meaningful pattern based on CVR latency was identified, which was named the PD CVR pattern (PD-CVRP). This pattern was characterized by relatively increased latency in basal ganglia, sensorimotor cortex, supplementary motor area, thalamus and visual cortex, as well as decreased latency in the cerebral white matter, relative to HC. There were no significant associations with clinical measures, though sample size may have limited our ability to detect significant associations. In summary, the PD-CVRP highlights the importance of cerebrovascular dysfunction in PD, and may be a potential biomarker for future clinical research and practice.

The underlying causes of Parkinson\'s disease are complex, and besides recent advances in elucidating relevant disease mechanisms, no disease-modifying treatments are currently available. One proposed pathophysiological hallmark is mitochondrial dysfunction, and a plethora of evidence points toward the interconnected nature of mitochondria in neuronal homeostasis. This also extends to iron and neuromelanin metabolism, two biochemical processes highly relevant to individual disease manifestation and progression. Modern neuroimaging methods help to gain in vivo insights into these intertwined pathways and may pave the road to individualized medicine in this debilitating disorder. In this narrative review, we will highlight the biological rationale for studying these pathways, how distinct neuroimaging methods can be applied in patients, their respective limitations, and which challenges need to be overcome for successful implementation in clinical studies.

The locus coeruleus (LC) is the major source of noradrenaline, which plays a key role in cognition. We aimed to detect the extent of the LC signal attenuation in Alzheimer\'s disease (AD) patients using a neuromelanin (NM)-sensitive MRI and how it may correlate with inflammatory and autonomic measures. An individually matched case-control study design was employed. 24 patients with AD and 24 age and gender matched controls with no cognitive impairment were recruited. The primary outcome measure was the LC signal intensity indicated by the LC contrast ratio (CR) and measured by the NM-sensitive MRI. Secondary outcome measures included neuropsychometric tests of cognitive state, peripheral inflammatory and autonomic measures. Conditional logistic regression analysis revealed a significant 22% LC-CR reduction in the AD group compared with the control group. However, there was no statistical significance from inflammatory or autonomic measures. This is the largest individually-matched case-control study to visualise the LC degeneration in AD patients. The study revealed significant LC degeneration which holds promise to stratify patients who may benefit from treatment targeting noradrenergic dysfunction.

BACKGROUND: Quantitative evaluation of degeneration of the substantia nigra (SN) is important for early, pre-symptomatic diagnosis of Parkinson\'s disease (PD). Accordingly, a clinically feasible imaging and quantification technique are needed.
OBJECTIVE: To investigate the T1 value of the SN in healthy individuals from phase-sensitive inversion recovery (PSIR) images and to clarify its correlation with the SN characteristics on neuromelanin (NM) images to identify an imaging biomarker for early diagnosis of PD.
METHODS: T1-weighted and NM images of the SN from 32 healthy volunteers were obtained using PSIR and turbo spin-echo sequences. The contrast between the SN and cerebral peduncle (CP) and area of the SN were measured; the T1 values of the SN from PSIR images and relationships between the T1 value and age/SN area were evaluated.
RESULTS: There was a significant negative correlation between age and the SN area obtained using PSIR imaging. The SN area on PSIR images (104.9 ± 20.9 mm2) was significantly larger than that on NM images (72.1 ± 14.9 mm2). There was a significant negative correlation between the SN area and the T1 value of the SN obtained from PSIR images.
CONCLUSIONS: In healthy adults, the area and T1 value of the SN measured on PSIR images were different from those obtained from NM images. This suggests that PSIR imaging may help in the assessment of SN degeneration.

Microstructural changes associated with degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNc) in Parkinson\'s disease (PD) have been studied using Diffusion Tensor Imaging (DTI). However, these studies show inconsistent results, mainly due to methodological variations in delineation of SNc. To mitigate this, our work aims to construct a probabilistic atlas of SNc based on a 3D Neuromelanin Sensitive MRI (NMS-MRI) sequence and demonstrate its applicability to investigate microstructural changes on a large dataset of PD. Using manual segmentation and deformable registration we created a novel SNc atlas in the MNI space using NMS-MRI sequences of 27 healthy controls (HC). We first quantitatively evaluated this atlas and then employed it to investigate the micro-structural abnormalities in SNc using diffusion MRI from 133 patients with PD and 99 HCs. Our results demonstrated significant increase in diffusivity with no changes in anisotropy. In addition, we also observed an asymmetry of the diffusion metrics with a higher diffusivity and lower anisotropy in the left SNc than the right. Finally, a multivariate classifier based on SNc diffusion features could delineate patients with PD with an average accuracy of 71.7%. Overall, from this work we establish a normative baseline for the SNc region of interest using NMS-MRI while the application on PD data emphasizes on the contribution of diffusivity measures rather than anisotropy of white matter in PD.

We aimed to investigate neuromelanin-sensitive magnetic resonance imaging (NM-MRI) features in the locus coeruleus of de novo Parkinson\'s disease patients with different cognitive states and to determine whether these features are associated with cognitive impairment.
Three groups of subjects were recruited in this study, including patients with de novo PD with mild cognitive impairment (n = 23), patients with de novo PD without cognitive impairment (n = 48), and control subjects (n = 32). All subjects underwent clinical evaluations, as well as MRI scanning. The contrast-to-noise ratio of the locus coeruleus in the neuromelanin-sensitive MRI images and cortical thickness were measured.
The contrast-to-noise ratio of the locus coeruleus in PD patients with mild cognitive impairment was significantly lower than that of controls (P = 0.016). The contrast-to-noise ratio of the locus coeruleus for PD patients without cognitive impairment was intermediate between that of controls and PD patients with mild cognitive impairment. Furthermore, multiple linear regression analysis showed that the contrast-to-noise ratio of the locus coeruleus was negatively associated with performance on the Trail Making Test B in all PD patients, controlling for age, sex, years of education, the Unified Parkinson\'s Disease Rating Scale motor scores from right upper limb, Geriatric Depression Rating Scales scores, Rapid Eye Movement Sleep Behavior Disorder Screening Questionnaire scores, and cortical thickness.
Dysfunction of the locus coeruleus neurons may partly contribute to the decline in executive function in early de novo PD. In the future, the locus coeruleus-norepinephrine system might be targeted for early-intervention strategies in PD patients. © 2019 International Parkinson and Movement Disorder Society.

UNASSIGNED: Studies using neuromelanin-sensitive-MRI have established the locus coeruleus (LC)-to-pons intensity ratio as a biomarker for diagnosis of Parkinson\'s and Alzheimer\'s diseases. More detailed analysis is needed for exploiting the highest clinical potential of this technique.
UNASSIGNED: The aim is to determine the location of the highest LC-to-pons ratio within the LC and develop an easy-to-use tool for clinical application.
UNASSIGNED: Ten patients diagnosed with various stages of Alzheimer\'s disease (74.1±3.9 years, range 68-80, 7 females) and ten healthy elderly subjects (72.4±3.1 years, range 68-77, 5 females) participated in the study. Five subsequent slices with a thickness of 2.5 millimeters were analyzed using the image analysis tool FSL, starting with the first slice below inferior colliculus. The outcome variable was the intensity ratio between maximum values of LC and adjacent pontine region.
UNASSIGNED: The section located 10 millimeters below the inferior colliculus has the highest potential in differentiating between healthy controls and patients, with the intensity-ratio difference between groups of 12.3% and effect size of 1.577. For the cut-off value of 1.09, the sensitivity and specificity values were 100% and 80%, respectively.
UNASSIGNED: We consider the method a promising clinical tool to aid AD diagnosis workup.