Background and PurposeClinically, 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.MethodsOur 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.ResultsOur 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.ConclusionsWe 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.
ObjectiveDysarthric speech of persons with Huntington disease (HD) is typically described as hyperkinetic; however, studies suggest that dysarthria can vary and resemble patterns in other neurologic conditions. To test the hypothesis that distinct motor speech subgroups can be identified within a larger cohort of patients with HD, we performed a cluster analysis on speech perceptual characteristics of patient audio recordings.MethodsAudio recordings of 48 patients with mild to moderate dysarthria due to HD were presented to 6 trained raters. Raters provided scores for various speech features (e.g., voice, articulation, prosody) of audio recordings using the classic Mayo Clinic dysarthria rating scale. Scores were submitted to an unsupervised k-means cluster analysis to determine the most salient speech features of subgroups based on motor speech patterns.ResultsFour unique subgroups emerged from the cohort of patients with HD. Subgroup 1 was characterized by an abnormally fast speaking rate among other unique speech features, whereas subgroups 2 and 3 were defined by an abnormally slow speaking rate. Salient speech features for subgroup 2 overlapped with subgroup 3; however, the severity of dysarthria differed. Subgroup 4 was characterized by mild deviations of speech features with typical speech rate. Length of CAG repeats, Unified Huntington’s Disease Rating Scale total motor score, and percent intelligibility were significantly different for pairwise comparisons of subgroups.ConclusionThis study supports the existence of distinct presentations of dysarthria in patients with HD, which may be due to divergent pathologic processes. The findings are discussed in relation to previous literature and clinical implications.
BackgroundDopamine therapy in Parkinson disease (PD) can have differential effects on inhibitory action control, or the ability to inhibit reflexive or impulsive actions. Dopamine agonist (DAAg) medications, which preferentially target D2 and D3 receptors, can either improve or worsen control of impulsive actions in patients with PD. We have reported that the direction of this effect depends on baseline levels of performance on inhibitory control tasks. This observation suggests that there may exist certain biologic determinants that contribute to these patient‐specific differences. We hypothesized that one important factor might be functional polymorphisms in D2‐like receptor genes.AimThe goal of this study was to determine whether the direction of DAAg effects on inhibitory control depends on functional polymorphisms in the DRD2 and DRD3 genes.MethodsTwenty‐eight patients with PD were genotyped for known functional polymorphisms in DRD2 (rs6277 and rs1800497) and DRD3 (rs6280) receptors. These patients then completed the Simon conflict task both on and off DAAg therapy in a counterbalanced manner.ResultsWe found that patients with the rs1800497 Taq1A (A1) polymorphism (A1/A1 or A1/A2: 11 subjects) showed improved proficiency to suppress impulsive actions when on DAAg; conversely, patients with the A2/A2 allele (14 patients) became less proficient at suppressing incorrect response information on DAAg therapy (Group × Medication, F(1, 23) = 5.65, p < 0.05). Polymorphisms in rs6277 and rs6280 were not associated with a differential medication response.ConclusionThese results suggest that certain DRD polymorphisms may determine the direction of DAAg effects on critical cognitive control processes impaired in PD. Our findings have implications for understanding pharmacogenomics interactions on a larger scale and the role these may play in the wide variability of treatment effects seen in the PD population.
Introduction:Orthostatic hypotension (OH) is a common cause of hospitalization, particularly in the elderly. Hospitalized patients with OH are often severely ill, with complex medical comorbidities and high rates of disability. Droxidopa is a norepinephrine precursor approved for the treatment of neurogenic OH (nOH) associated with autonomic failure that is commonly used in the outpatient setting, but there is currently no data regarding the safety and efficacy of droxidopa initiation in medically complex patients. Methods:We performed a retrospective review of patients started on droxidopa for refractory nOH while hospitalized at Vanderbilt University Medical Center between October 2014 and May 2017. Primary outcome measures were safety, change in physician global impression of illness severity from admission to discharge, and persistence on medication after 180-day follow-up. Results:A total of 20 patients were identified through chart review. Patients were medically complex with high rates of cardiovascular comorbidities and a diverse array of underlying autonomic diagnoses. Rapid titration of droxidopa was safe and well-tolerated in this cohort, with no cardiovascular events or new onset arrhythmias. Supine hypertension requiring treatment occurred in four patients. One death occurred during hospital admission due to organ failure associated with end-stage amyloidosis. Treating physicians noted improvements in presyncopal symptoms in 80% of patients. After 6 months, 13 patients (65%) continued on droxidopa therapy. Conclusion:In a retrospective cohort of hospitalized, severely ill patients with refractory nOH, supervised rapid titration of droxidopa was safe and effective. Treatment persistence was high, suggesting that symptomatic benefit extended beyond acute intervention.
The autonomic nervous system appears to be uniquely susceptible to degeneration in disorders of α-synuclein pathology. Clinically, autonomic dysfunction in these disorders manifests as neurogenic orthostatic hypotension (nOH), a condition that results in substantial morbidity and mortality. nOH results from pathology affecting either the central autonomic pathways or peripheral autonomic nerve fibers. Determining the localization and pathophysiology of nOH is critical in effectively managing this disorder and selecting appropriate treatment options. In this review, we discuss the pathophysiology of nOH with respect to the various α-synuclein-related neurodegenerative conditions. We highlight the associated clinical features, including gait instability, rapid eye movement behavior disorder, and hyposmia. We also review the current pharmacologic treatment options for nOH. Overall, the goals of therapy are to improve symptoms and prevent syncope and falls. Non-pharmacologic interventions should be introduced first, followed by carefully selected pharmacologic therapies. Treatment decisions should be directed by an understanding of the underlying pathophysiology, as well as the comorbidities and potential contributing factors present in each individual patient.
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