Background and Purpose: Clinically, Parkinson's disease (PD) presents with asymmetric motor symptoms. The left nigrostriatal system appears more susceptible to early degeneration than the right, and a left‐lateralized pattern of early neuropathological changes is also described in several neurodegenerative conditions, including Alzheimer's disease, frontotemporal dementia, and Huntington's disease. In this study, we evaluated hemispheric differences in estimated rates of atrophy in a large, well‐characterized cohort of PD patients.Methods: Our cohort included 205 PD patients who underwent clinical assessments and T1‐weighted brain MRI's. Patients were classified into Early (n = 109) and Late stage (n = 96) based on disease duration, defined as greater than or less than 10 years of motor symptoms. Cortical thickness was determined using FreeSurfer, and a bootstrapped linear regression model was used to estimate differences in rates of atrophy between Early and Late patients.Results: Our results show that patients classified as Early stage exhibit a greater estimated rate of cortical atrophy in left frontal regions, especially the left insula and olfactory sulcus. This pattern was replicated in left‐handed patients, and was not influenced by the degree of motor symptom asymmetry (i.e., left‐sided predominant motor symptoms). Patients classified as Late stage exhibited greater atrophy in the bilateral occipital, and right hemisphere‐predominant cortical areas.Conclusions: We show that cortical degeneration in PD differs between cerebral hemispheres, and findings suggest a pattern of early left, and late right hemisphere with posterior cortical atrophy. Further investigation is warranted to elucidate the underlying mechanisms of this asymmetry and pathologic implications.

Vesicular monoamine transporter 2 (VMAT2) inhibitors can improve hyperkinetic movements, and are effective treatment options for chorea of Huntington disease (HD). Tetrabenazine was assessed for treating chorea in the TETRA-HD trial, and while efficacious, there are tolerability concerns possibly due to its pharmacokinetic properties. Deutetrabenazine is a novel VMAT2 inhibitor that contains deuterium, which extends active metabolite half-lives and minimizes drug concentration fluctuations. In the First-HD trial, deutetrabenazine was efficacious in treating chorea and was generally well tolerated. In the absence of a head-to-head trial, we performed an indirect treatment comparison (ITC) of the tolerability of deutetrabenazine and tetrabenazine for the treatment of HD-associated chorea, as observed in the First-HD and TETRA-HD trials, using well-established comparison methods. Data from the Phase III, 12-week, parallel-group, clinical trials First-HD (N = 90) and TETRA-HD (N = 84) were used to conduct an ITC of the tolerability of deutetrabenazine versus tetrabenazine using two anchor-based methods: Bucher comparison for unadjusted ITCs, and matching indirect comparison for adjusted ITCs. Overall adverse events (AEs; mild, moderate, and severe), serious AEs, specific AEs occurring in ≥10% of patients, and discontinuations (all-cause and AE-related) were included in the analysis. The risk differences of these outcomes for deutetrabenazine and tetrabenazine were estimated by subtracting the applicable placebo-adjusted risk in First-HD from that of TETRA-HD. Sensitivity analyses were performed to address differences between trials, and p-values were obtained from z-tests. Compared with tetrabenazine, deutetrabenazine was associated with a significantly lower risk of moderate to severe AEs and neuropsychiatric AEs including agitation, akathisia, depression, depression/agitated depression, drowsiness/somnolence, insomnia, and parkinsonism in both adjusted and unadjusted analyses (p < 0.05 for each). Deutetrabenazine had a significantly lower rate of dose reduction or dose reduction/suspension in the unadjusted and adjusted analyses (p < 0.001 for each). Deutetrabenazine resulted in numerically more mild AEs, such as diarrhea and coughing; however, these results were not statistically significant. This indirect treatment comparison demonstrates that for the treatment of HD chorea, deutetrabenazine has a favorable tolerability profile compared to tetrabenazine. ClinicalTrials.gov NCT01795859 and NCT00219804 .

The nigrostriatal and mesocorticolimbic dopamine networks regulate reward-driven behavior. Regional alterations to mesolimbic dopamine D_2/3receptor expression are described in drug-seeking and addiction disorders. Parkinson's disease (PD) patients are frequently prescribed D₂-like dopamine agonist (DAgonist) therapy for motor symptoms, yet a proportion develop clinically significant behavioral addictions characterized by impulsive and compulsive behaviors (ICBs). Until now, changes in D_2/3receptor binding in both striatal and extrastriatal regions have not been concurrently quantified in this population. We identified 35 human PD patients (both male and female) receiving DAgonist therapy, with (n= 17) and without (n= 18) ICBs, matched for age, disease duration, disease severity, and dose of dopamine therapy. In the off-dopamine state, all completed PET imaging with [¹⁸F]fallypride, a high affinity D₂-like receptor ligand that can measure striatal and extrastriatal D_2/3nondisplaceable binding potential (BP_ND). Striatal differences between ICB+/ICB− patients localized to the ventral striatum and putamen, where ICB+ subjects had reduced BP_ND. In this group, self-reported severity of ICB symptoms positively correlated with midbrain D_2/3receptor BP_ND. Group differences in regional D_2/3BP_NDrelationships were also notable: ICB+ (but not ICB−) patients expressed positive correlations between midbrain and caudate, putamen, globus pallidus, and amygdala BP_NDs. These findings support the hypothesis that compulsive behaviors in PD are associated with reduced ventral and dorsal striatal D_2/3expression, similar to changes in comparable behavioral disorders. The data also suggest that relatively preserved ventral midbrain dopaminergic projections throughout nigrostriatal and mesolimbic networks are characteristic of ICB+ patients, and may account for differential DAgonist therapeutic response.SIGNIFICANCE STATEMENTThe biologic determinants of compulsive reward-based behaviors have broad clinical relevance, from addiction to neurodegenerative disorders. Here, we address biomolecular distinctions in Parkinson's disease patients with impulsive compulsive behaviors (ICBs). This is the first study to image a large cohort of ICB+ patients using positron emission tomography with [18F]fallypride, allowing quantification of D_2/3receptors throughout the mesocorticolimbic network. We demonstrate widespread differences in dopaminergic networks, including (1) D2-like receptor distinctions in the ventral striatum and putamen, and (2) a preservation of widespread dopaminergic projections emerging from the midbrain, which is associated with the severity of compulsive behaviors. This clearly illustrates the roles of D_2/3receptors and medication effects in maladaptive behaviors, and localizes them specifically to nigrostriatal and extrastriatal regions.

A subgroup of Parkinson's disease (PD) patients treated with dopaminergic therapy develop compulsive reward‐driven behaviors, which can result in life‐altering morbidity. The mesocorticolimbic dopamine network guides reward‐motivated behavior; however, its role in this treatment‐related behavioral phenotype is incompletely understood. Here, mesocorticolimbic network function in PD patients who develop impulsive and compulsive behaviors (ICB) in response to dopamine agonists was assessed using BOLD fMRI. The tested hypothesis was that network connectivity between the ventral striatum and the limbic cortex is elevated in patients with ICB and that reward‐learning proficiency reflects the extent of mesocorticolimbic network connectivity. To evaluate this hypothesis, 3.0T BOLD‐fMRI was applied to measure baseline functional connectivity on and off dopamine agonist therapy in age and sex‐matched PD patients with (n = 19) or without (n = 18) ICB. An incentive‐based task was administered to a subset of patients (n = 20) to quantify positively or negatively reinforced learning. Whole‐brain voxelwise analyses and region‐of‐interest‐based mixed linear effects modeling were performed. Elevated ventral striatal connectivity to the anterior cingulate gyrus (P = 0.013), orbitofrontal cortex (P = 0.034), insula (P = 0.044), putamen (P = 0.014), globus pallidus (P < 0.01), and thalamus (P < 0.01) was observed in patients with ICB. A strong trend for elevated amygdala‐to‐midbrain connectivity was found in ICB patients on dopamine agonist. Ventral striatum‐to‐subgenual cingulate connectivity correlated with reward learning (P < 0.01), but not with punishment‐avoidance learning. These data indicate that PD‐ICB patients have elevated network connectivity in the mesocorticolimbic network. Behaviorally, proficient reward‐based learning is related to this enhanced limbic and ventral striatal connectivity.Hum Brain Mapp 39:509–521, 2018. ©2017 Wiley Periodicals, Inc.