Roxana G. Burciu

Longitudinal changes in free-water within the substantia nigra of Parkinson’s disease

There is a clear need to develop non-invasive markers of substantia nigra progression in Parkinsons disease. We previously found elevated free-water levels in the substantia nigra for patients with Parkinsons disease compared with controls in single-site and multi-site cohorts. Here, we test the hypotheses that free-water levels in the substantia nigra of Parkinsons disease increase following 1 year of progression, and that baseline free-water levels in the substantia nigra predict the change in bradykinesia following 1 year. We conducted a longitudinal study in controls (n = 19) and patients with Parkinsons disease (n = 25). Diffusion imaging and clinical data were collected at baseline and after 1 year. Free-water analyses were performed on diffusion imaging data using blinded, hand-drawn regions of interest in the posterior substantia nigra. A group effect indicated free-water values were increased in the posterior substantia nigra of patients with Parkinsons disease compared with controls (P = 0.003) and we observed a significant group × time interaction (P < 0.05). Free-water values increased for the Parkinsons disease group after 1 year (P = 0.006), whereas control free-water values did not change. Baseline free-water values predicted the 1 year change in bradykinesia scores (r = 0.74, P < 0.001) and 1 year change in Montreal Cognitive Assessment scores (r = -0.44, P = 0.03). Free-water in the posterior substantia nigra is elevated in Parkinsons disease, increases with progression of Parkinsons disease, and predicts subsequent changes in bradykinesia and cognitive status over 1 year. These findings demonstrate that free-water provides a potential non-invasive progression marker of the substantia nigra.

Free-water imaging in Parkinson’s disease and atypical parkinsonism

Conventional single tensor diffusion analysis models have provided mixed findings in the substantia nigra of Parkinsons disease, but recent work using a bi-tensor analysis model has shown more promising results. Using a bi-tensor model, free-water values were found to be increased in the posterior substantia nigra of Parkinsons disease compared with controls at a single site and in a multi-site cohort. Further, free-water increased longitudinally over 1 year in the posterior substantia nigra of Parkinsons disease. Here, we test the hypothesis that other parkinsonian disorders such as multiple system atrophy and progressive supranuclear palsy have elevated free-water in the substantia nigra. Equally important, however, is whether the bi-tensor diffusion model is able to detect alterations in other brain regions beyond the substantia nigra in Parkinsons disease, multiple system atrophy, and progressive supranuclear palsy and to accurately distinguish between these diseases. Free-water and free-water-corrected fractional anisotropy maps were compared across 72 individuals in the basal ganglia, midbrain, thalamus, dentate nucleus, cerebellar peduncles, cerebellar vermis and lobules V and VI, and corpus callosum. Compared with controls, free-water was increased in the anterior and posterior substantia nigra of Parkinsons disease, multiple system atrophy, and progressive supranuclear palsy. Despite no other changes in Parkinsons disease, we observed elevated free-water in all regions except the dentate nucleus, subthalamic nucleus, and corpus callosum of multiple system atrophy, and in all regions examined for progressive supranuclear palsy. Compared with controls, free-water-corrected fractional anisotropy values were increased for multiple system atrophy in the putamen and caudate, and increased for progressive supranuclear palsy in the putamen, caudate, thalamus, and vermis, and decreased in the superior cerebellar peduncle and corpus callosum. For all disease group comparisons, the support vector machine 10-fold cross-validation area under the curve was between 0.93-1.00 and there was high sensitivity and specificity. The regions and diffusion measures selected by the model varied across comparisons and are consistent with pathological studies. In conclusion, the current study used a novel bi-tensor diffusion analysis model to indicate that all forms of parkinsonism had elevated free-water in the substantia nigra. Beyond the substantia nigra, both multiple system atrophy and progressive supranuclear palsy, but not Parkinsons disease, showed a broad network of elevated free-water and altered free-water corrected fractional anisotropy that included the basal ganglia, thalamus, and cerebellum. These findings may be helpful in the differential diagnosis of parkinsonian disorders, and thereby facilitate the development and assessment of targeted therapies.

Increased free water in the substantia nigra of Parkinson's disease: a single-site and multi-site study

Measures from diffusion magnetic resonance imaging reflect changes in the substantia nigra of Parkinsons disease. It is the case, however, that partial volume effects from free water can bias diffusion measurements. The bi-tensor diffusion model was introduced to quantify the contribution of free water and eliminates its bias on estimations of tissue microstructure. Here, we test the hypothesis that free water is elevated in the substantia nigra for Parkinsons disease compared with control subjects. This hypothesis was tested between large cohorts of Parkinsons disease and control participants in a single-site study and validated against a multisite study using multiple scanners. The fractional volume of free water was increased in the posterior region of the substantia nigra in Parkinsons disease compared with control subjects in both the single-site and multi-site studies. We did not observe changes in either cohort for free-water-corrected fractional anisotropy or free-water-corrected mean diffusivity. Our findings provide new evidence that the free-water index reflects alteration of the substantia nigra in Parkinsons disease, and this was evidenced across both single-site and multi-site cohorts.

Resting State Functional Magnetic Resonance Imaging in Parkinson’s Disease

Neuroimaging advances over the past several decades have provided increased understanding of the structural and functional brain changes that occur with Parkinson’s disease (PD). Examination of resting state functional magnetic resonance imaging (rs-fMRI) provides a noninvasive method that focuses on low-frequency spontaneous fluctuations in the blood-oxygenation-level-dependent signal that occurs when an individual is at rest. Several analysis methods have been developed and used to explore how PD affects resting state activity and functional connectivity, and the purpose of this review is to highlight the critical advances made thus far. Some discrepancies in the rs-fMRI and PD literature exist, and we make recommendations for consideration in future studies. The rs-fMRI technique holds promise for investigating brain changes associated with the motor and nonmotor symptoms of PD, and for revealing important variations across large-scale networks of the brain in PD.

Distinct patterns of brain activity in progressive supranuclear palsy and Parkinson's disease

The basal ganglia‐thalamo‐cortical and cerebello‐thalamo‐cortical circuits are important for motor control. Whether their functioning is affected in a similar or different way by progressive supranuclear palsy (PSP) and Parkinsons disease (PD) is not clear. A functional magnetic resonance imaging (fMRI) force production paradigm and voxel‐based morphometry were used to assess differences in brain activity and macrostructural volumes between PSP, PD, and healthy age‐matched controls. We found that PSP and PD share reduced functional activity of the basal ganglia and cortical motor areas, but this is more pronounced in PSP than in PD. In PSP the frontal regions are underactive, whereas the posterior parietal and occipital regions are overactive as compared with controls and PD. Furthermore, lobules I through IV, V, and VI of the cerebellum are hypoactive in PSP and PD, whereas Crus I and lobule IX are hyperactive in PSP only. Reductions in gray and white matter volume are specific to PSP. Finally, the functional status of the caudate as well as the volume of the superior frontal gyrus predict clinical gait and posture measures in PSP. PSP and PD share hypoactivity of the basal ganglia, motor cortex, and anterior cerebellum. These patients also display a unique pattern, such that anterior regions of the cortex are hypoactive and posterior regions of the cortex and cerebellum are hyperactive. Together, these findings suggest that specific structures within the basal ganglia, cortex, and cerebellum are affected differently in PSP relative to PD.

Subthalamic nucleus - sensorimotor cortex functional connectivity in de novo and moderate Parkinson’s disease

Previous research has indicated increased functional connectivity between subthalamic nucleus (STN) and sensorimotor cortex in off-medication Parkinsons disease (PD) compared with control subjects. It is not clear if the increase in functional connectivity between STN and sensorimotor cortex occurs in de novo PD, which is before patients begin dopamine therapy. Resting-state functional magnetic resonance imaging was carried out in 20 de novo (drug naïve) patients with PD (Hoehn and Yahr stage: I-II), 19 patients with moderate PD (Hoehn and Yahr stage: II-III), and 19 healthy controls. The functional connectivity analysis in de novo and moderate PD patients focused on the connectivity of the more affected STN and the sensorimotor cortex. Using resting-state functional connectivity analysis, we provide new evidence that people with de novo PD and off-medicated moderate PD have increased functional connectivity between the more affected STN and different regions within the sensorimotor cortex. The overlapping sensorimotor cortex found in both de novo and moderate PD had functional connectivity values that correlated positively with the Unified Parkinsons Disease Rating Scale part III. This key finding suggests that changes in functional connectivity between STN and sensorimotor cortex occur early in the disease following diagnosis and before dopamine therapy.

Functional MRI of disease progression in Parkinson disease and atypical parkinsonian syndromes

Objective: To explore longitudinal changes in brain activity in patients with Parkinson disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP) using task-based functional MRI (fMRI). Methods: A total of 112 individuals were scanned 1 year apart while performing a unimanual grip force task: 46 PD, 13 MSA, 19 PSP, and 34 healthy controls. The outcome measure was percent signal change in prespecified regions of interest: putamen, primary motor cortex (M1), supplementary motor area (SMA), and superior motor regions of the cerebellum (lobules V–VI). Results: Patients with PD showed a decline in functional activity over the course of 1 year in the putamen and M1 compared to controls. Changes after 1 year in MSA were exclusively extrastriatal, and included a reduction in functional activity in M1, SMA, and superior cerebellum. In PSP, all regions of interest were less active at 1 year compared to baseline. The functional activity of these regions did not change in the control group. Conclusions: We provide evidence using task-based fMRI for cortical and striatal functional deterioration in PD over a 1-year period of time. Results also describe more widespread and unique patterns of functional changes in MSA and PSP compared to PD, suggesting distinct rates of disease progression in parkinsonian disorders that may assist in future clinical studies testing the potential efficacy of disease-modifying therapies.

Progression marker of Parkinson's disease: a 4-year multi-site imaging study.

Progression markers of Parkinson’s disease are crucial for therapeutic development. Burciu et al. validate free-water in the substantia nigra as a progression marker at one- and four-year follow-up, in an international cohort of de novo Parkinson’s disease. One-year changes in free-water predict the progression of motor symptoms over four years.

Free‐water and BOLD imaging changes in Parkinson's disease patients chronically treated with a MAO‐B inhibitor

Rasagiline is a monoamine oxidase type B inhibitor that possesses no amphetamine‐like properties, and provides symptomatic relief in early and late stages of Parkinsons disease (PD). Data in animal models of PD suggest that chronic administration of rasagiline is associated with structural changes in the substantia nigra, and raise the question whether the structure and function of the basal ganglia could be different in PD patients treated chronically with rasagiline as compared with PD patients not treated with rasagiline. Here, we performed a retrospective cross‐sectional magnetic resonance imaging (MRI) study at 3 T that investigated nigrostriatal function and structure in PD patients who had taken rasagiline before testing (∼8 months), PD who had not taken rasagiline before testing, and age‐matched controls. The two PD groups were selected a priori to not differ significantly in age, sex, disease duration, severity of symptoms, cognitive status, and total levodopa equivalent daily dose of medication. We evaluated percent signal change in the posterior putamen during force production using functional MRI, free‐water in the posterior substantia nigra using diffusion MRI, and performance on a bimanual coordination task using a pegboard test. All patients were tested after overnight withdrawal from antiparkinsonian medication. The rasagiline group had greater percent signal change in the posterior putamen, less free‐water in the posterior substantia nigra, and better performance on the coordination task than the group not taking rasagiline. These findings point to a possible chronic effect of rasagiline on the structure and function of the basal ganglia in PD. Hum Brain Mapp 37:2894–2903, 2016.

Free water improves detection of changes in the substantia nigra in parkinsonism: A multisite study

Imaging markers that are sensitive to parkinsonism across multiple sites are critically needed for clinical trials. The objective of this study was to evaluate changes in the substantia nigra using single‐ and bi‐tensor models of diffusion magnetic resonance imaging in PD, MSA, and PSP.