Substantia Nigra Free Water Increases Longitudinally in Parkinson Disease

Guttuso, Thomas; Bergsland, Niels; Hagemeier, Jesper; Lichter, David; Pasternak, Ofer; Zivadinov, Robert

doi:10.3174/ajnr.a5545

Cited by 51 publications

(57 citation statements)

References 40 publications

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“…This study is the first to show elevated Viso in the posterior substantia nigra in PD, and both the anterior and posterior substantia nigra in MSAp and PSP compared to healthy controls. FW ss imaging results derived from the single‐shell scan confirm previous work that FW in the posterior substantia nigra is elevated in PD, MSAp, and PSP compared to controls (Burciu et al, ; Guttuso Jr. et al, ; Ofori et al, ; Ofori et al, ; Planetta et al, ). Increased FW and Viso are likely indicative of neurodegeneration wherein the ratio of intracellular to extracellular space is reduced leading to an increase in the measured fractional volume of extracellular fluid (Pasternak et al, ).…”

Section: Discussionsupporting

confidence: 82%

“…In the present study, Viso and FW in the posterior substantia nigra are the only diffusion measures that differed in PD relative to healthy control subjects, indicating that substantia nigra differences are consistent and highly replicable across studies implementing multicompartmental models Guttuso Jr. et al, 2018;Ofori et al, 2017;Ofori et al, 2015;Planetta et al, 2016;Yang et al, 2019). Studies implementing the NODDI model in PD have shown reduced Vic in the substantia nigra (Kamagata et al, 2016), and reduced Vic along the pathway in which seeds are placed in the substantia nigra and globus pallidus (Andica et al, 2018).…”

Section: Discussionsupporting

confidence: 68%

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Neurite orientation dispersion and density imaging (NODDI) and free‐water imaging in Parkinsonism

Mitchell

Archer

Chu

et al. 2019

Human Brain Mapping

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Neurite orientation dispersion and density imaging (NODDI) uses a three‐compartment model to probe brain tissue microstructure, whereas free‐water (FW) imaging models two‐compartments. It is unknown if NODDI detects more disease‐specific effects related to neurodegeneration in Parkinson's disease (PD) and atypical Parkinsonism. We acquired multi‐ and single‐shell diffusion imaging at 3 Tesla across two sites. NODDI (using multi‐shell; isotropic volume [Viso]; intracellular volume [Vic]; orientation dispersion [ODI]) and FW imaging (using single‐shell; FW; free‐water corrected fractional anisotropy [FAt]) were compared with 44 PD, 21 multiple system atrophy Parkinsonian variant (MSAp), 26 progressive supranuclear palsy (PSP), and 24 healthy control subjects in the basal ganglia, midbrain/thalamus, cerebellum, and corpus callosum. There was elevated Viso in posterior substantia nigra across Parkinsonisms, and Viso, Vic, and ODI were altered in MSAp and PSP in the striatum, globus pallidus, midbrain, thalamus, cerebellum, and corpus callosum relative to controls. The mean effect size across regions for Viso was 0.163, ODI 0.131, Vic 0.122, FW 0.359, and FAt 0.125, with extracellular compartments having the greatest effect size. A key question addressed was if these techniques discriminate PD and atypical Parkinsonism. Both NODDI (AUC: 0.945) and FW imaging (AUC: 0.969) had high accuracy, with no significant difference between models. This study provides new evidence that NODDI and FW imaging offer similar discriminability between PD and atypical Parkinsonism, and FW had higher effect sizes for detecting Parkinsonism within regions across the basal ganglia and cerebellum.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionsupporting

confidence: 68%

Neurite orientation dispersion and density imaging (NODDI) and free‐water imaging in Parkinsonism

Mitchell

Archer

Chu

et al. 2019

Human Brain Mapping

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“…As previously reported, of the 57 study participants enrolled at baseline, 18 were not available for assessment at the 3‐year time point and 1 was excluded because of a frontal lobe astrocytoma. Of the remaining 38 participants, 3 were excluded because of excessive movement during the MRI acquisition (1 PD patient and 2 HCs) and an additional HC was excluded because of corrupted MRI data that prevented QSM reconstruction.…”

Section: Methodsmentioning

confidence: 99%

“…This ventral–dorsal gradient in SN degeneration has not been previously assessed longitudinally in terms of iron accumulation in vivo in PD. However, previous studies using diffusion tensor imaging (DTI) assessments have shown the ventral posterior SN to be the most sensitive to both cross‐sectional and longitudinal changes in PD . In addition, a recent study found elevated iron levels in PD within the more ventral SN, although longitudinal changes were not assessed …”

mentioning

confidence: 95%

“…However, previous studies using diffusion tensor imaging (DTI) assessments have shown the ventral posterior SN to be the most sensitive to both cross-sectional and longitudinal changes in PD. [14][15][16][17][18] In addition, a recent study found elevated iron levels in PD within the more ventral SN, although longitudinal changes were not assessed. 12 Against this background, we investigated SN iron levels in PD in a longitudinal setting using quantitative susceptibility mapping (QSM).…”

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confidence: 97%

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Ventral posterior substantia nigra iron increases over 3 years in Parkinson's disease

et al. 2019

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Background Parkinson's disease (PD) is characterized in part by the progressive accumulation of iron within the substantia nigra (SN); however, its spatial and temporal dynamics remain relatively poorly understood. Objectives The objective of this study was to investigate spatial patterns and temporal evolution of SN iron accumulation in PD. Methods A total of 18 PD patients (mean disease duration = 6.2 years) receiving dopaminergic therapy and 16 healthy controls were scanned with 3T MRI at baseline and 3 years later using quantitative susceptibility mapping, an indirect marker of iron content. Iron was assessed separately in the posterior SN and anterior SN at the ventral and dorsal levels of the SN. The results were corrected for the false discovery rate. Results A significant group effect was found for the ventral posterior SN (P < .001) and anterior SN (P = .042) quantitative susceptibility mapping as well as significant group x time interaction effects (P = .02 and P = .043, respectively). In addition, a significant intragroup change during 3 years of follow‐up was found only in the ventral posterior SN of PD (P = .012), but not healthy controls. No significant effects were detected for any dorsal SN measures. No associations were identified with clinical measures. Conclusions We found both cross‐sectional and longitudinal SN iron changes to be confined to its more ventral location in PD. Because pathology studies also show the ventral SN to degenerate early and to the greatest extent in PD, the assessment of iron levels by quantitative susceptibility mapping in this area may potentially represent a disease progression biomarker in PD. © 2019 International Parkinson and Movement Disorder Society

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Emerging Neuroimaging Biomarkers Across Disease Stage in Parkinson Disease

et al. 2021

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Imaging biomarkers in Parkinson disease (PD) are increasingly important for monitoring progression in clinical trials and also have the potential to improve clinical care and management. This Review addresses a critical need to make clear the temporal relevance for diagnostic and progression imaging biomarkers to be used by clinicians and researchers over the clinical course of PD. Magnetic resonance imaging (diffusion imaging, neuromelanin-sensitive imaging, iron-sensitive imaging, T1-weighted imaging), positron emission tomography/single-photon emission computed tomography dopaminergic, serotonergic, and cholinergic imaging as well as metabolic and cerebral blood flow network neuroimaging biomarkers in the preclinical, prodromal, early, and moderate to late stages are characterized.OBSERVATIONS If a clinical trial is being carried out in the preclinical and prodromal stages, potentially useful disease-state biomarkers include dopaminergic imaging of the striatum; metabolic imaging; free-water, neuromelanin-sensitive, and iron-sensitive imaging in the substantia nigra; and T1-weighted structural magnetic resonance imaging. Disease-state biomarkers that can distinguish atypical parkinsonisms are metabolic imaging, free-water imaging, and T1-weighted imaging; dopaminergic imaging and other molecular imaging track progression in prodromal patients, whereas other established progression biomarkers need to be evaluated in prodromal cohorts. Progression in early-stage PD can be monitored using dopaminergic imaging in the striatum, metabolic imaging, and free-water and neuromelanin-sensitive imaging in the posterior substantia nigra. Progression in patients with moderate to late-stage PD can be monitored using free-water imaging in the anterior substantia nigra, R2* of substantia nigra, and metabolic imaging. Cortical thickness and gyrification might also be useful markers or predictors of progression. Dopaminergic imaging and free-water imaging detect progression over 1 year, whereas other modalities detect progression over 18 months or longer. The reliability of progression biomarkers varies with disease stage, whereas disease-state biomarkers are relatively consistent in individuals with preclinical, prodromal, early, and moderate to late-stage PD.CONCLUSIONS AND RELEVANCE Imaging biomarkers for various stages of PD are readily available to be used as outcome measures in clinical trials and are potentially useful in multimodal combination with routine clinical assessment. This Review provides a critically important template for considering disease stage when implementing diagnostic and progression biomarkers in both clinical trials and clinical care settings.

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Substantia Nigra Free Water Increases Longitudinally in Parkinson Disease

Cited by 51 publications

References 40 publications

Neurite orientation dispersion and density imaging (NODDI) and free‐water imaging in Parkinsonism

Neurite orientation dispersion and density imaging (NODDI) and free‐water imaging in Parkinsonism

Ventral posterior substantia nigra iron increases over 3 years in Parkinson's disease

Emerging Neuroimaging Biomarkers Across Disease Stage in Parkinson Disease

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