Vocal Responses to Perturbations in Voice Auditory Feedback in Individuals with Parkinson's Disease

One of the most common symptoms of speech deficits in individuals with Parkinson's disease (PD) is significantly reduced vocal loudness and pitch range. The present study investigated whether abnormal vocalizations in individuals with PD are related to sensory processing of voice auditory feedback. Perturbations in loudness or pitch of voice auditory feedback are known to elicit short latency, compensatory responses in voice amplitude or fundamental frequency.Twelve individuals with Parkinson's disease and 13 age- and sex-matched healthy control subjects sustained a vowel sound (/α/) and received unexpected, brief (200 ms) perturbations in voice loudness (±3 or 6 dB) or pitch (±100 cents) auditory feedback. Results showed that, while all subjects produced compensatory responses in their voice amplitude or fundamental frequency, individuals with PD exhibited larger response magnitudes than the control subjects. Furthermore, for loudness-shifted feedback, upward stimuli resulted in shorter response latencies than downward stimuli in the control subjects but not in individuals with PD.The larger response magnitudes in individuals with PD compared with the control subjects suggest that processing of voice auditory feedback is abnormal in PD. Although the precise mechanisms of the voice feedback processing are unknown, results of this study suggest that abnormal voice control in individuals with PD may be related to dysfunctional mechanisms of error detection or correction in sensory feedback processing

Amantadine for Dyskinesias in Parkinson's Disease: A Randomized Controlled Trial

BACKGROUND: Dyskinesias are some of the major motor complications that impair quality of life for patients with Parkinson's disease. The purpose of the present study was to investigate the efficacy of amantadine in Parkinson's disease patients suffering from dyskinesias. METHODS: In this multi-center, double-blind, randomized, placebo-controlled, cross-over trial, 36 patients with Parkinson's disease and dyskinesias were randomized, and 62 interventions, which included amantadine (300 mg/day) or placebo treatment for 27 days, were analyzed. At 15 days after washout, the treatments were crossed over. The primary outcome measure was the changes in the Rush Dyskinesia Rating Scale (RDRS) during each treatment period. The secondary outcome measures were changes in the Unified Parkinson's Disease Rating Scale part IVa (UPDRS-IVa, dyskinesias), part IVb (motor fluctuations), and part III (motor function). RESULTS: RDRS improved in 64% and 16% of patients treated with amantadine or placebo, respectively, with significant differences between treatments. The adjusted odds-ratio for improvement by amantadine was 6.7 (95% confidence interval, 1.4 to 31.5). UPDRS-IVa was improved to a significantly greater degree in amantadine-treated patients [mean (SD) of 1.83 (1.56)] compared with placebo-treated patients [0.03 (1.51)]. However, there were no significant effects on UPDRS-IVb or III scores. CONCLUSIONS: Results from the present study demonstrated that amantadine exhibited efficacious effects against dyskinesias in 60-70% of patients. TRIAL REGISTRATION: UMIN Clinical Trial Registry UMIN000000780

Levodopa-induced dyskinesia in Parkinson disease: Current and Evolving Concepts.

Levodopa‐induced dyskinesia is a common complication in Parkinson disease. Pathogenic mechanisms include phasic stimulation of dopamine receptors, nonphysiological levodopa‐to‐dopamine conversion in serotonergic neurons, hyperactivity of corticostriatal glutamatergic transmission, and overstimulation of nicotinic acetylcholine receptors on dopamine‐releasing axons. Delay in initiating levodopa is no longer recommended, as dyskinesia development is a function of disease duration rather than cumulative levodopa exposure. We review current and in‐development treatments for peak‐dose dyskinesia but suggest that improvements in levodopa delivery alone may reduce its future prevalence

Physiological and Pathological Role of Alpha-synuclein in Parkinson’s Disease Through Iron Mediated Oxidative Stress; The Role of a Putative Iron-responsive Element

Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder after Alzheimer’s disease (AD) and represents a large health burden to society. Genetic and oxidative risk factors have been proposed as possible causes, but their relative contribution remains unclear. Dysfunction of alpha-synuclein (α-syn) has been associated with PD due to its increased presence, together with iron, in Lewy bodies. Brain oxidative damage caused by iron may be partly mediated by α-syn oligomerization during PD pathology. Also, α-syn gene dosage can cause familial PD and inhibition of its gene expression by blocking translation via a newly identified Iron Responsive Element-like RNA sequence in its 5’-untranslated region may provide a new PD drug target

Discovery of Therapeutic Approaches for Polyglutamine Diseases: A Summary of Recent Efforts

Polyglutamine (PolyQ) diseases are a group of neurodegenerative disorders caused by the expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the coding region of specific genes. This leads to the production of pathogenic proteins containing critically expanded tracts of glutamines. Although polyQ diseases are individually rare, the fact that these nine diseases are irreversibly progressive over 10 to 30 years, severely impairing and ultimately fatal, usually implicating the full-time patient support by a caregiver for long time periods, makes their economic and social impact quite significant. This has led several researchers worldwide to investigate the pathogenic mechanism(s) and therapeutic strategies for polyQ diseases. Although research in the field has grown notably in the last decades, we are still far from having an effective treatment to offer patients, and the decision of which compounds should be translated to the clinics may be very challenging. In this review, we provide a comprehensive and critical overview of the most recent drug discovery efforts in the field of polyQ diseases, including the most relevant findings emerging from two different types of approaches-hypothesis-based candidate molecule testing and hypothesis-free unbiased drug screenings. We hereby summarize and reflect on the preclinical studies as well as all the clinical trials performed to date, aiming to provide a useful framework for increasingly successful future drug discovery and development efforts.Project ON.2 SR&TD Integrated Program (NORTE-07-0124-FEDER-000021), co-funded by North Portugal Regional Operational Program (ON.2-O Novo Norte), under the National Strategic Reference Framework, through the European Regional Development Fund (ERDF) and also supported by Fundação para a Ciência e Tecnologia through the project POCI-01-0145-FEDER-016818 (PTDC/NEU-NMC/3648/2014)info:eu-repo/semantics/publishedVersio

Using “Functional” Target Coordinates of the Subthalamic Nucleus to Assess the Indirect and Direct Methods of the Preoperative Planning: Do the Anatomical and Functional Targets Coincide?

Objective: To answer the question of whether the anatomical center of the subthalamic nucleus (STN), as calculated indirectly from stereotactic atlases or by direct visualization on magnetic resonance imaging (MRI), corresponds to the best functional target. Since the neighboring red nucleus (RN) is well visualized on MRI, we studied the relationships of the final target to its different borders. Methods: We analyzed the data of 23 PD patients (46 targets) who underwent bilateral frame-based STN deep brain stimulation (DBS) procedure with microelectrode recording guidance. We calculated coordinates of the active contact on DBS electrode on postoperative MRI, which we referred to as the final “functional/optimal” target. The coordinates calculated by the atlas-based “indirect” and “direct” methods, as well as the coordinates of the different RN borders were compared to these final coordinates. Results: The mean ± SD of the final target coordinates was 11.7 ± 1.5 mm lateral (X), 2.4 ± 1.5 mm posterior (Y), and 6.1 ± 1.7 mm inferior to the mid-commissural point (Z). No significant differences were found between the “indirect” X, Z coordinates and those of the final targets. The “indirect” Y coordinate was significantly posterior to Y of the final target, with mean difference of 0.6 mm (p = 0.014). No significant differences were found between the “direct” X, Y, and Z coordinates and those of the final targets. Conclusions: The functional STN target is located in direct proximity to its anatomical center. During preoperative targeting, we recommend using the “direct” method, and taking into consideration the relationships of the final target to the mid-commissural point (MCP) and the different RN borders

Severe topiramate-associated hyperthermia resulting in persistent neurological dysfunction.

Topiramate has recently been reported to cause hyperthermia as a result of oligohydrosis, primarily in pediatric patients. All cases reported to date were clinically mild, without permanent systemic or neurologic dysfunction. We report a case of severe hyperthermia and subsequent ataxia and tremor in an adult treated with topiramate. To our knowledge, this is the first case of topiramate-associated hyperthermia to result in residual cerebellar and cognitive dysfunction

Long-Term Satisfaction and Patient-Centered Outcomes of Deep Brain Stimulation in Parkinson’s Disease

Bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) is an effective and proven treatment option for patients with advanced Parkinson’s disease (PD). Long-term outcomes (>5 years) have demonstrated sustained improvement in objective motor symptoms; however, few studies have evaluated patient-centered outcomes other than quality of life (QOL). A locally developed DBS-patient-centered outcomes questionnaire was administered to PD patients >5 years post-DBS. All questions were scored on a ten-point scale, whereby 0 represented the most ‘positive’ answer and 10 the most ‘negative’ answer. Pre-operative scales were repeated at the time of survey. Fifty-two patients (mean 8.2 ± 2.6 years post-DBS) were included. Satisfaction was high with median score (range) of 1/10 (0–8) at the time of survey. Patients endorsed having made the correct decision by undergoing DBS, with a score of 0 (0–10), would choose to have DBS again, with a score of 0 (0–10), and would recommend DBS to others, with a score of 0 (0–10). Pre-operative expectation target was set at a high level with a score of 2 (0–10). Parkinson’s Disease QOL (PDQ-39) Questionnaire Summary Index (SI) scores were, mean (SD), 2.1 (18.2) above baseline (p = 0.44). Those with worsening in PDQ-39-SI scores had less satisfaction with DBS (rs = 0.57, p ≤ 0.0001). This is the first study to assess long-term patient satisfaction with STN DBS. We are currently collecting data prospectively to confirm the results of these preliminary findings