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This article discusses the expanding phenotypic variability of PMPCA-related ataxia, a genetic movement disorder caused by pathogenic variants in the PMPCA gene. The initial description of the disease included 17 patients with a non-progressive cerebellar ataxia syndrome, but since then, eight more cases have been reported, bringing the total to 25 cases from 10 different families. The clinical signs of these patients have expanded the phenotypic variability of the disease, with three phenotypic categories identified: a milder variant with non-progressive ataxia, a severe and progressive variant with multisystemic mitochondrial disease, and an intermediate phenotype with psychomotor regression and intellectual disability. The article presents two new cases of ATX-PMPCA in a previously unreported family, highlighting the clinical variability of the disorder. [Extracted from the article]

Parkinson's disease is characterized by exaggerated beta activity (13–35 Hz) in cortico‐basal ganglia motor loops. Beta activity includes both periodic fluctuations (i.e. oscillatory activity) and aperiodic fluctuations reflecting spiking activity and excitation/inhibition balance (i.e. non‐oscillatory activity). However, the relative contribution, dopamine dependency and clinical correlations of oscillatory vs. non‐oscillatory beta activity remain unclear. We recorded, modelled and analysed subthalamic local field potentials in parkinsonian patients at rest while off or on medication. Autoregressive modelling with additive 1/f noise clarified the relationships between measures of beta activity in the time domain (i.e. amplitude and duration of beta bursts) or in the frequency domain (i.e. power and sharpness of the spectral peak) and oscillatory vs. non‐oscillatory activity: burst duration and spectral sharpness are specifically sensitive to oscillatory activity, whereas burst amplitude and spectral power are ambiguously sensitive to both oscillatory and non‐oscillatory activity. Our experimental data confirmed the model predictions and assumptions. We subsequently analysed the effect of levodopa, obtaining strong‐to‐extreme Bayesian evidence that oscillatory beta activity is reduced in patients on vs. off medication, with moderate evidence for absence of modulation of the non‐oscillatory component. Finally, specifically the oscillatory component of beta activity correlated with the rate of motor progression of the disease. Methodologically, these results provide an integrative understanding of beta‐based biomarkers relevant for adaptive deep brain stimulation. Biologically, they suggest that primarily the oscillatory component of subthalamic beta activity is dopamine dependent and may play a role not only in the pathophysiology but also in the progression of Parkinson's disease. Key points: Beta activity in Parkinson's disease includes both true periodic fluctuations (i.e. oscillatory activity) and aperiodic fluctuations reflecting spiking activity and synaptic balance (i.e. non‐oscillatory activity).The relative contribution, dopamine dependency and clinical correlations of oscillatory vs. non‐oscillatory beta activity remain unclear.Burst duration and spectral sharpness are specifically sensitive to oscillatory activity, while burst amplitude and spectral power are ambiguously sensitive to both oscillatory and non‐oscillatory activity.Only the oscillatory component of subthalamic beta activity is dopamine‐dependent.Stronger beta oscillatory activity correlates with faster motor progression of the disease. [ABSTRACT FROM AUTHOR]

Aim: Impulse‐control disorder is a common neuropsychiatric complication in Parkinson's disease (PD) under dopamine replacement therapy. Prior studies tested the balance between enhanced desire towards reward and cognitive control deficits, hypothesized to be biased towards the former in impulse control disorders. We provide evidence for this hypothesis by measuring behavioral and neural patterns behind the influence of sexual desire over response inhibition and tools towards functional restoration using repetitive transcranial stimulation in patients with hypersexuality as predominant impulsive disorder. Methods: The effect of sexual cues on inhibition was measured with a novel erotic stop‐signal task under on and off dopaminergic medication. Task‐related functional and anatomical connectivity models were estimated in 16 hypersexual and 17 nonhypersexual patients with PD as well as in 17 healthy controls. Additionally, excitatory neuromodulation using intermittent theta‐burst stimulation (sham‐controlled) was applied over the pre‐supplementary motor area in 20 additional hypersexual patients with PD aiming to improve response inhibition. Results: Compared with their nonhypersexual peers, patients with hypersexuality recruited caudate, pre‐supplementary motor area, ventral tegmental area, and anterior cingulate cortex while on medication. Reduced connectivity was found between pre‐supplementary motor area and caudate nucleus in hypersexual compared with nonhypersexual patients (while medicated), a result paralleled by compensatory enhanced anatomical connectivity. Furthermore, stimulation over the pre‐supplementary motor area improved response inhibition in hypersexual patients with PD when exposed to sexual cues. Conclusion: This study, therefore, has identified a specific fronto‐striatal and mesolimbic circuitry underlying uncontrolled sexual responses in medicated patients with PD where cortical neuromodulation halts its expression. [ABSTRACT FROM AUTHOR]

Background: Dopamine replacement therapy reduces most motor and nonmotor features of Parkinson's disease. However, with disease progression, adjustments of dopaminergics and the application of advanced therapies must be considered. Objectives: To validate the OPTIMIPARK questionnaire as a tool to help clinicians make therapeutic decisions on patients treated with levodopa. Methods: We tested a questionnaire including 9 items encompassing motor and nonmotor signs, complications, and disability in a multicenter, observational, cross‐sectional study. A neurologist (neurologist 1 [N1]) assessed patients according to regular clinical practice and blinded to the OPTIMIPARK questionnaire score. Therapeutic decisions were classified as "no changes," "adjustment of conventional treatment," and "advanced therapy indicated." External neurologists (neurologist 3 [N3] and neurologist 4 [N4]), who only knew the patient age, years of disease, and current treatment, made their therapeutic decisions based on the OPTIMIPARK score. Concordance between the criterion of the N1 versus the OPTIMIPARK‐based N3–N4 consensus was analyzed applying weighted κ. The area under Receiving Operating Characteristic (ROC) curves was calculated for OPTIMIPARK scores. Results: A total of 113 patients with Parkinson's disease were included. The OPTIMIPARK‐based decision led to a higher proportion of patients requiring therapeutic modification than N1 assessment (74% vs. 60%; P = 0.002). Concordance between the N1 and N3–N4 decisions was moderate, whereas interobserver agreement among N3 and N4 was high. Area Under the Curve(AUC) values of 0.83 and 0.82 were found for "no changes" and "advanced therapy indicated" decisions by the N1 neurologist. Conclusions: OPTIMIPARK might be more sensitive than regular clinical practice in suggesting the need for a therapeutic change. Furthermore, the low and high scores identify with high accuracy well‐adjusted patients and candidates for advanced therapy, respectively. [ABSTRACT FROM AUTHOR]

Objective: To define the motor onset and progression of Parkinson's disease (PD) in a prospective cohort of early unmedicated patients. Methods: We enrolled a consecutive cohort of recently diagnosed (<18 months) PD patients with unilateral manifestations using age and gender‐matched controls. The most affected body region was determined using various clinical standard metrics and objective quantitative kinematic measurements. Parkinson's Progression Markers Initiative data were used for external validation of the results. Results: Twenty‐five drug‐naive patients and 21 controls were studied. Upper limbs were (92%) the most affected body region at onset as ascertained by patients' self‐assessment, neurologists' impression, and Movement Disorders Society Unified Parkinson's Disease Rating Scale score. The upper limb (ie, hand) was the site of onset in 80% of patients. Motor features progressed to involve the lower limb but remained limited to the initially affected body side over a 2‐year follow‐up. Agreement among the different metrics (96%) confirmed focal upper limb predominant motor impairment at onset. The findings were confirmed by quantitative kinematic analyses and from a cohort of 34 similar patients from the Parkinson's Progression Markers Initiative database. Conclusions: Motor manifestations in PD start distally in one upper limb. The complexity of the motor repertoire and, consequently, the presumed larger dopaminergic striatal demand for maintaining skillful motor function in the upper limb, may contribute to greater vulnerability of dopaminergic striatal terminals. Recognition of this motor pattern could be used to monitor the evolution of nigrostriatal degeneration and the putative impact of therapies. © 2021 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background: Diphasic dyskinesias are a subtype of levodopa-induced dyskinesias that appear typically at the onset and end of levodopa antiparkinsonian action. The pathophysiology of diphasic dyskinesias is not well understood. Methods: We analyzed local field potentials recorded from the subthalamic nucleus in 7 Parkinson's disease (PD) patients who showed typical diphasic dyskinesias during postoperative recordings through a deep brain stimulation electrode. The evolution of the different oscillatory activities related to the onset and end of diphasic dyskinesias was studied by windowed fast Fourier transforms. Results: Typical 'off'-state beta activity disappeared with the onset of diphasic dyskinesias, whereas gamma activity was absent or minimal until their end. Theta activity during diphasic dyskinesias was similar to that observed during peak-dose dyskinesias. Conclusions: From a neurophysiological viewpoint, patients exhibited oscillatory activity typical of the 'on' medication state during diphasic dyskinesias. The minimal presence of gamma activity during diphasic dyskinesias, however, suggests that this 'on' state might be incomplete or limited to dopaminergic mechanisms affecting the lower limbs. © 2012 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Continuous subcutaneous apomorphine infusion (CSAI) is, at present, an alternative option for advanced Parkinson's disease (PD) with motor fluctuations. We studied the evolution of patients with PD and severe motor fluctuations long-term treated with CSAI. We reviewed data from 82 patients with PD (mean age, 67 ± 11.07; disease duration, 14.39 ± 5.7 years) and severe motor fluctuations referred to 35 tertiary hospitals in Spain. These patients were long-term treated (for at least 3 months) with CSAI and tolerated the procedure without serious side effects. We compared the baseline data of these 82 patients (before CSAI) with those obtained from the last follow-up visit of each patient. The mean follow-up of CSAI was 19.93 ± 16.3 months. Mean daily dose of CSAI was 72.00 ± 21.38 mg run over 14.05 ± 1.81 hours. We found a statistically significant reduction in off-hours, according to self-scoring diaries (6.64 ± 3.09 vs. 1.36 ± 1.42 hours/day, P < 0.0001), total and motor UPDRS scores ( P < 0.0001), dyskinesia severity ( P < 0.0006), and equivalent dose of antiparkinsonian therapy (1,405 ± 536.7 vs. 800.1 ± 472.9 mg of levodopa equivalent units P < 0.0001). CSAI is an effective option for patients with PD and severe fluctuations, poorly controlled by conventional oral drug treatment. © 2008 Movement Disorder Society. [ABSTRACT FROM AUTHOR]