Diffusion Magnetic Resonance Imaging Detects Progression in Parkinson's Disease: A Placebo-Controlled Trial of Rasagiline.

BACKGROUND: Rasagiline has received attention as a potential disease-modifying therapy for Parkinson's disease (PD). Whether rasagiline is disease modifying remains in question. OBJECTIVE: The main objective of this study was to determine whether rasagiline has disease-modifying effects in PD over 1 year. Secondarily we evaluated two diffusion magnetic resonance imaging pulse sequences to determine the best sequence to measure disease progression. METHODS: This prospective, randomized, double-blind, placebo-controlled trial assessed the effects of rasagiline administered at 1 mg/day over 12 months in early-stage PD. The primary outcome was 1-year change in free-water accumulation in posterior substantia nigra (pSN) measured using two diffusion magnetic resonance imaging pulse sequences, one with a repetition time (TR) of 2500 ms (short TR; n = 90) and one with a TR of 6400 ms (long TR; n = 75). Secondary clinical outcomes also were assessed. RESULTS: Absolute change in pSN free-water accumulation was not significantly different between groups (short TR: P = 0.346; long TR: P = 0.228). No significant differences were found in any secondary clinical outcomes between groups. Long TR, but not short TR, data show pSN free-water increased significantly over 1 year (P = 0.025). Movement Disorder Society Unified Parkinson's Disease Rating Scale testing of motor function, Part III increased significantly over 1 year (P = 0.009), and baseline free-water in the pSN correlated with the 1-year change in Movement Disorder Society Unified Parkinson's Disease Rating Scale testing of motor function, Part III (P = 0.004) and 1-year change in bradykinesia score (P = 0.044). CONCLUSIONS: We found no evidence that 1 mg/day rasagiline has a disease-modifying effect in PD over 1 year. We found pSN free-water increased over 1 year, and baseline free-water relates to clinical motor progression, demonstrating the importance of diffusion imaging parameters for detecting and predicting PD progression. © 2021 International Parkinson and Movement Disorder Society.

Functional imaging of the brainstem during visually-guided motor control reveals visuomotor regions in the pons and midbrain.

Integrating visual information for motor output is an essential process of visually-guided motor control. The brainstem is known to be a major center involved in the integration of sensory information for motor output, however, limitations of functional imaging in humans have impaired our knowledge about the individual roles of sub-nuclei within the brainstem. Thus, the bulk of our knowledge surrounding the function of the brainstem is based on anatomical and behavioral studies in non-human primates, cats, and rodents, despite studies demonstrating differences in the organization of visuomotor processing between mammals. fMRI studies in humans have examined activity related to visually-guided motor tasks, however, few have done so while controlling for both force without visual feedback activity and visual stimuli without force activity. Of the studies that have controlled for both conditions, none have reported brainstem activity. Here, we employed a novel fMRI paradigm focused on the brainstem and cerebellum to systematically investigate the hypothesis that the pons and midbrain are critical for the integration of visual information for motor control. Visuomotor activity during visually-guided pinch-grip force was measured while controlling for force without visual feedback activity and visual stimuli without force activity in healthy adults. Using physiological noise correction and multiple task repetitions, we demonstrated that visuomotor activity occurs in the inferior portion of the basilar pons and the midbrain. These findings provide direct evidence in humans that the pons and midbrain support the integration of visual information for motor control. We also determined the effect of physiological noise and task repetitions on the visuomotor signal that will be useful in future studies of neurodegenerative diseases affecting the brainstem.

Magnetic Resonance Imaging and Neurofilament Light in the Differentiation of Parkinsonism.

OBJECTIVE: Accurate diagnosis is particularly challenging in Parkinson's disease (PD), multiple system atrophy (MSAp), and progressive supranuclear palsy (PSP). We compare the utility of 3 promising biomarkers to differentiate disease state and explain disease severity in parkinsonism: the Automated Imaging Differentiation in Parkinsonism (AID-P), the Magnetic Resonance Parkinsonism Index (MRPI), and plasma-based neurofilament light chain protein (NfL). METHODS: For each biomarker, the area under the curve (AUC) of receiver operating characteristic curves were quantified for PD versus MSAp/PSP and MSAp versus PSP and statistically compared. Unique combinations of variables were also assessed. Furthermore, each measures association with disease severity was determined using stepwise multiple regression. RESULTS: For PD versus MSAp/PSP, AID-P (AUC, 0.900) measures had higher AUC compared with NfL (AUC, 0.747) and MRPI (AUC, 0.669), P < 0.05. For MSAp versus PSP, AID-P (AUC, 0.889), and MRPI (AUC, 0.824) measures were greater than NfL (AUC, 0.537), P < 0.05. We then combined measures to determine if any unique combination provided enhanced accuracy and found that no combination performed better than the AID-P alone in differentiating parkinsonisms. Furthermore, we found that the AID-P demonstrated the highest association with the MDS-UPDRS (Radj2 -AID-P, 26.58%; NfL,15.12%; MRPI, 12.90%). CONCLUSIONS: Compared with MRPI and NfL, AID-P provides the best overall differentiation of PD versus MSAp/PSP. Both AID-P and MRPI are effective in differentiating MSAp versus PSP. Furthermore, combining biomarkers did not improve classification of disease state compared with using AID-P alone. The findings demonstrate in the current sample that the AID-P and MRPI are robust biomarkers for PD, MSAp, and PSP. © 2020 International Parkinson and Movement Disorder Society.

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

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.

Advanced diffusion imaging to track progression in Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy.

Advanced diffusion imaging which accounts for complex tissue properties, such as crossing fibers and extracellular fluid, may detect longitudinal changes in widespread pathology in atypical Parkinsonian syndromes. We implemented fixel-based analysis, Neurite Orientation and Density Imaging (NODDI), and free-water imaging in Parkinson's disease (PD), multiple system atrophy (MSAp), progressive supranuclear palsy (PSP), and controls longitudinally over one year. Further, we used these three advanced diffusion imaging techniques to investigate longitudinal progression-related effects in key white matter tracts and gray matter regions in PD and two common atypical Parkinsonian disorders. Fixel-based analysis and free-water imaging revealed longitudinal declines in a greater number of descending sensorimotor tracts in MSAp and PSP compared to PD. In contrast, only the primary motor descending sensorimotor tract had progressive decline over one year, measured by fiber density (FD), in PD compared to that in controls. PSP was characterized by longitudinal impairment in multiple transcallosal tracts (primary motor, dorsal and ventral premotor, pre-supplementary motor, and supplementary motor area) as measured by FD, whereas there were no transcallosal tracts with longitudinal FD impairment in MSAp and PD. In addition, free-water (FW) and FW-corrected fractional anisotropy (FAt) in gray matter regions showed longitudinal changes over one year in regions that have previously shown cross-sectional impairment in MSAp (putamen) and PSP (substantia nigra, putamen, subthalamic nucleus, red nucleus, and pedunculopontine nucleus). NODDI did not detect any longitudinal white matter tract progression effects and there were few effects in gray matter regions across Parkinsonian disorders. All three imaging methods were associated with change in clinical disease severity across all three Parkinsonian syndromes. These results identify novel extra-nigral and extra-striatal longitudinal progression effects in atypical Parkinsonian disorders through the application of multiple diffusion methods that are related to clinical disease progression. Moreover, the findings suggest that fixel-based analysis and free-water imaging are both particularly sensitive to these longitudinal changes in atypical Parkinsonian disorders.

Emerging Neuroimaging Biomarkers Across Disease Stage in Parkinson Disease: A Review.

Importance: 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.

Gait and trunk kinematics during prolonged turning in Parkinson's disease with freezing of gait.

INTRODUCTION: Although turning during walking is known to trigger freezing of gait (FOG) in Parkinson's disease (PD), little is known about kinematic strategies used by individuals with PD and FOG while performing prolonged turning. OBJECTIVE: Our aim was to compare gait and trunk kinematics during straight walking and continuous turning over 20-min in PD with and without FOG. METHODS: 18 individuals with idiopathic PD (n = 9 with FOG, n = 9 without FOG), performed two 20-min walking tasks: straight ahead, and turning, in a laboratory setting in their OFF medication state. Accelerometer-based spatial and temporal gait parameters and trunk kinematics (range of motion, peak velocity, variability of range of motion and peak velocity) were analyzed. RESULTS: During turning, PD with FOG reduced cadence more compared to PD without FOG (P <0.045), despite similar decline in stride velocity (28-32%) and stride length (24-27%). Participants with FOG had decreased variability of gait speed (P <0.011), stride length (P <0.035), frontal trunk range of motion (P <0.040) and peak trunk velocity (P <0.017) compared to PD without FOG during turning, whereas there was no difference between groups during straight walking. Gait speed variability and cadence between these two tasks differentiated the PD groups (sensitivity 89% and specificity 78%). CONCLUSIONS: We demonstrate that PD with FOG decreased cadence and reduced variability of walking speed, stride length, and lateral flexion of the trunk compared to PD without FOG during prolonged turning. These real-life gait markers are observable during lab-based gait that is similar to daily-life.

Changes in Resting-State Functional Connectivity Related to Freezing of Gait in Parkinson's Disease.

Freezing of gait (FOG) is a common motor symptom in Parkinson's disease (PD) thought to arise from the dysfunctional cortico-basal ganglia-thalamic circuity. The purpose of this study was to assess the changes in brain resting-state functional connectivity (rs-FC) of subcortical structures comprising the cortico-basal ganglia-thalamic circuity in individuals with PD with and without FOG. Resting-state functional magnetic resonance imaging was acquired in 27 individuals with idiopathic PD (14 with FOG and 13 without FOG). A seed-to-voxel analysis was performed with the seeds in the bilateral basal ganglia nuclei, thalamus, and pedunculopontine nucleus. Between-group differences in rs-FC revealed that the bilateral thalamus and globus pallidus external were significantly more connected with visual areas in PD with FOG compared to PD without FOG. In addition, PD with FOG had increased connectivity between the left putamen and retrosplenial cortex as well as with the cerebellum. Our findings suggest an increased connectivity at rest of subcortical and cortical regions involved in sensory and visuospatial processing that may be compensating for sensorimotor deficits in FOG. This increased connectivity may contribute to the hypothesized overload in the cortico-basal ganglia-thalamic circuity processing capacity, which may ultimately result in FOG occurrence.

Impaired Sensorimotor Processing During Complex Gait Precedes Behavioral Changes in Middle-aged Adults.

Gait impairment during complex walking in older adults is thought to result from a progressive failure to compensate for deteriorating peripheral inputs by central neural processes. It is the primary hypothesis of this article that failure of higher cerebral adaptations may already be present in middle-aged adults who do not present observable gait impairments. We, therefore, compared metabolic brain activity during steering of gait (ie, complex locomotion) and straight walking (ie, simple locomotion) in young and middle-aged individuals. Cerebral distribution of [18F]-fluorodeoxyglucose, a marker of brain synaptic activity, was assessed during over ground straight walking and steering of gait using positron emission tomography in seven young adults (aged 24 ± 3) and seven middle-aged adults (aged 59 ± 3). Brain regions involved in steering of gait (posterior parietal cortex, superior frontal gyrus, and cerebellum) are retained in middle age. However, despite similar walking performance, there are age-related differences in the distribution of [18F]-fluorodeoxyglucose during steering: middle-aged adults have (i) increased activation of precentral and fusiform gyri, (ii) reduced deactivation of multisensory cortices (inferior frontal, postcentral, and fusiform gyri), and (iii) reduced activation of the middle frontal gyrus and cuneus. Our results suggest that preclinical decline in central sensorimotor processing in middle age is observable during complex walking.

Cerebral Metabolic Changes Related to Freezing of Gait in Parkinson Disease.

Freezing of gait (FOG) in Parkinson disease (PD) often occurs during steering of gait (i.e., complex gait), which is thought to arise from executive dysfunction. Our aim was to test whether cognitive corticobasal ganglia-thalamocortical circuitry is impaired and whether alternate neural circuits are used for complex gait in PD with FOG. Methods: Eighteen individuals with idiopathic PD in the off-medication state, 9 with FOG (aged 68 ± 6 y) and 9 without FOG (aged 65 ± 5 y), were included. PET was used to measure cerebral glucose metabolism during 2 gait tasks, steering and straight walking, performed during the radiotracer uptake period. Results: During steering, there was a reduced change in cerebral glucose metabolism within the cognitive corticothalamic circuit. More specifically, those with FOG had less activation of the posterior parietal cortex, less deactivation of the dorsolateral prefrontal cortex and thalamus, and increased activation in the supplementary motor area. Interestingly, activity in the dorsolateral prefrontal cortex correlated with gait impairment (i.e., reduced stride length) in the FOG group. Conclusion: These results demonstrate decreased parietal control and an alternate control mechanism mediated by prefrontal and supplementary motor areas in PD with FOG.

Development and Validation of the Automated Imaging Differentiation in Parkinsonism (AID-P): A Multi-Site Machine Learning Study.

Background: There is a critical need to develop valid, non-invasive biomarkers for Parkinsonian syndromes. The current 17-site, international study assesses whether non-invasive diffusion MRI (dMRI) can distinguish between Parkinsonian syndromes. Methods: We used dMRI from 1002 subjects, along with the Movement Disorders Society Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS III), to develop and validate disease-specific machine learning comparisons using 60 template regions and tracts of interest in Montreal Neurological Institute (MNI) space between Parkinson's disease (PD) and Atypical Parkinsonism (multiple system atrophy - MSA, progressive supranuclear palsy - PSP), as well as between MSA and PSP. For each comparison, models were developed on a training/validation cohort and evaluated in a test cohort by quantifying the area under the curve (AUC) of receiving operating characteristic (ROC) curves. Findings: In the test cohort for both disease-specific comparisons, AUCs were high in the dMRI + MDS-UPDRS (PD vs. Atypical Parkinsonism: 0·962; MSA vs. PSP: 0·897) and dMRI Only (PD vs. Atypical Parkinsonism: 0·955; MSA vs. PSP: 0·926) models, whereas the MDS-UPDRS III Only models had significantly lower AUCs (PD vs. Atypical Parkinsonism: 0·775; MSA vs. PSP: 0·582). Interpretations: This study provides an objective, validated, and generalizable imaging approach to distinguish different forms of Parkinsonian syndromes using multi-site dMRI cohorts. The dMRI method does not involve radioactive tracers, is completely automated, and can be collected in less than 12 minutes across 3T scanners worldwide. The use of this test could thus positively impact the clinical care of patients with Parkinson's disease and Parkinsonism as well as reduce the number of misdiagnosed cases in clinical trials.

Development and validation of the automated imaging differentiation in parkinsonism (AID-P): a multicentre machine learning study.

BACKGROUND: Development of valid, non-invasive biomarkers for parkinsonian syndromes is crucially needed. We aimed to assess whether non-invasive diffusion-weighted MRI can distinguish between parkinsonian syndromes using an automated imaging approach. METHODS: We did an international study at 17 MRI centres in Austria, Germany, and the USA. We used diffusion-weighted MRI from 1002 patients and the Movement Disorders Society Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS III) to develop and validate disease-specific machine learning comparisons using 60 template regions and tracts of interest in Montreal Neurological Institute space between Parkinson's disease and atypical parkinsonism (multiple system atrophy and progressive supranuclear palsy) and between multiple system atrophy and progressive supranuclear palsy. For each comparison, models were developed on a training and validation cohort and evaluated in an independent test cohort by quantifying the area under the curve (AUC) of receiving operating characteristic curves. The primary outcomes were free water and free-water-corrected fractional anisotropy across 60 different template regions. FINDINGS: In the test cohort for disease-specific comparisons, the diffusion-weighted MRI plus MDS-UPDRS III model (Parkinson's disease vs atypical parkinsonism had an AUC 0·962; multiple system atrophy vs progressive supranuclear palsy AUC 0·897) and diffusion-weighted MRI only model had high AUCs (Parkinson's disease vs atypical parkinsonism AUC 0·955; multiple system atrophy vs progressive supranuclear palsy AUC 0·926), whereas the MDS-UPDRS III only models had significantly lower AUCs (Parkinson's disease vs atypical parkinsonism 0·775; multiple system atrophy vs progressive supranuclear palsy 0·582). These results indicate that a non-invasive imaging approach is capable of differentiating forms of parkinsonism comparable to current gold standard methods. INTERPRETATIONS: This study provides an objective, validated, and generalisable imaging approach to distinguish different forms of parkinsonian syndromes using multisite diffusion-weighted MRI cohorts. The diffusion-weighted MRI method does not involve radioactive tracers, is completely automated, and can be collected in less than 12 min across 3T scanners worldwide. The use of this test could positively affect the clinical care of patients with Parkinson's disease and parkinsonism and reduce the number of misdiagnosed cases in clinical trials. FUNDING: National Institutes of Health and Parkinson's Foundation.

Response suppression delays the planning of subsequent stimulus-driven saccades.

The completion of an antisaccade selectively increases the reaction tiME (RT) of a subsequent prosaccade: a result that has been interpreted to reflect the residual inhibition of stimulus-driven saccade networks [1], [2]. In the present investigation we sought to determine whether the increase in prosaccade RT is contingent on the constituent antisaccade planning processes of response suppression and vector inversion or is limited to response suppression. To that end, in one block participants alternated between pro- and antisaccades after every second trial (task-switching block), and in another block participants completed a series of prosaccades that were randomly (and infrequently) interspersed with no-go catch-trials (go/no-go block). Notably, such a design provides a framework for disentangling whether response suppression and/or vector inversion delays the planning of subsequent prosaccades. As expected, results for the task-switching block showed that antisaccades selectively increased the RTs of subsequent prosaccades. In turn, results for the go/no-go block showed that prosaccade RTs were increased when preceded by a no-go catch-trial. Moreover, the magnitude of the RT 'cost' was equivalent across the task-switching and go/no-go blocks. That prosaccades preceded by an antisaccade or a no-go catch-trial produced equivalent RT costs indicates that the conjoint processes of response suppression and vector inversion do not drive the inhibition of saccade planning mechanisms. Rather, the present findings indicate that a general consequence of response suppression is a residual inhibition of stimulus-driven saccade networks.