The chronic use of serotonin norepinephrine reuptake inhibitors facilitates dyskinesia priming in early Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) patients are frequently exposed to antidepressant medications (ADMs). Norepinephrine (NE) and serotonin (5HT) systems have a role in levodopa-induced dyskinesias (LID) pathophysiology. METHODS: We performed a longitudinal analysis on the PPMI cohort including drug-naïve PD patients, who are progressively exposed to dopamine replacement therapies (DRTs) to test the effect of ADM exposure on LID development by the 4th year of follow-up. RESULTS: LID prevalence (according to MDS UPDRS score 4.1 ≥ 1) was 16% (42/251); these patients were more likely women (p = 0.01), had higher motor (p < 0.001) and depression scores (p = 0.01) and lower putaminal DAT binding ratio (p = 0.01). LID were associated with the exposure time to L-DOPA (2.2 ± 1.07 vs 2.6 ± 0.9, p = 0.02) and to the exposure to ADMs, in particular to SNRI (4.8% vs 21.4%, p < 0.001). The latter persisted after correcting for significant covariates (e.g., disease duration, cognitive status, motor impairment, depression, dopaminergic denervation). A similar difference in LID prevalence in PD patients exposed vs non-exposed to SNRI was observed on matched data by the real-world TriNetX repository (22% vs 13%, p < 0.001). DISCUSSION: This study supports the presence of an effect of SNRI on LID priming in patients with early PD. Independent prospective cohort studies are warranted to further verify such association.

Emotional atypical arousal ratings for unpleasant stimuli in patients with Parkinson's disease.

INTRODUCTION: Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms, including alteration in emotional processing and recognition of emotions. We explored the effects of PD on the emotional behavioral ratings using a battery of affective visual stimuli selected from the International Affective Picture System (IAPS). METHODS: Twenty-two patients diagnosed with idiopathic PD and 22 healthy controls (HC), matched by age, gender, and education, were enrolled in the study. Following a clinical assessment, each participant was asked to evaluate the arousal and valence of affective visual stimuli, and response time was recorded. Disease-specific measures including the MDS Unified Parkinson's Disease Rating Scale (MDS UPDRS) and the Non-Motor Symptom Scale (NMSS) were also collected. RESULTS: PD patients exhibited higher arousal responses compared to HC for negative/unpleasant pictures (scoring 7.32 ± 0.88 vs 5.43 ± 2.06, p < 0.001). The arousal response to negative/unpleasant pictures was correlated with measures of non-motor burden in PD (MDS UPDRS I and NMSS, rho = 0.480 and p = 0.023, rho = 0.533 and p = 0.010, respectively). CONCLUSION: Impaired emotional processing characterizes PD patients with mild disease and is related to the non-motor symptom burden. Given the importance of emotional processing for the development and maintenance of close interpersonal relationship and for coping with specific medical situations, it is crucial to direct PD patients towards therapeutic interventions focused on the recognition and processing of emotions.

Restless leg syndrome as a complication of primary hyperparathyroidism: insights from a retrospective study.

INTRODUCTION: Restless leg syndrome (RLS) is an invalidating neurological disorder with a complex, largely unknown pathophysiology. While RLS is observed in Parkinson's disease and in renal failure, idiopathic cases are common. Limited reports associate RLS with parathyroid hormone (PTH). This study analyzes a cohort of patients with primary hyperparathyroidism (PHPT) and chronic post-surgical hypoparathyroidism (hypo PTH), to investigate RLS prevalence, and associated risk factors. METHODS: Ninety-five patients (54 PHPT, 41 hypo PTH) were consecutively enrolled at the bone metabolism outpatient clinic. The revised IRLSSG diagnostic criteria were used to diagnose RLS, with assessments conducted through face-to-face interviews and neurological examination. When RLS was confirmed, the RLS severity scale was applied. Retrospective records included calcium-phosphate metabolism-related parameters, surgery details, renal lithiasis, fragility fractures, and densitometric features (T-score). RESULTS: RLS was diagnosed in 22.2% PHPT patients, compared to 4.9% of patients with hypo PTH (p = 0.02). Of RLS diagnosed patients, 91.7% had a history of parathyroidectomy, compared to 47.6% of patients without RLS (p = 0.01). Most of the operated patients reported that surgery determined an improvement of symptoms; however, mean score severity of RLS at our evaluation was 15/40, defined as moderate. PTH and calcium levels were not statistically associated to the presence of RLS. CONCLUSION: Our study suggests that PHPT may be one of the etiologies of RLS. Parathyroidectomy alleviates symptoms in the vast majority of the cases but does not remove them.

Left Vagus Stimulation Modulates Contralateral Subthalamic ß Power Improving the Gait in Parkinson's Disease.

BACKGROUND: Transcutaneous vagus nerve stimulation (VNS) showed early evidence of efficacy for the gait treatment of Parkinson's disease (PD). OBJECTIVES: Providing data on neurophysiological and clinical effects of transauricular VNS (taVNS). METHODS: Ten patients with recording deep brain stimulation (DBS) have been enrolled in a within participant design pilot study, double-blind crossover sham-controlled trial of taVNS. Subthalamic local field potentials (ß band power), Unified Parkinson's Disease Rating Scales (UPDRS), and a digital timed-up-and-go test (TUG) were measured and compared with real versus sham taVNS during medication-off/DBS-OFF condition. RESULTS: The left taVNS induced a reduction of the total ß power in the contralateral (ie, right) subthalamic nucleus and an improvement of TUG time, speed, and variability. The taVNS-induced ß reduction correlated with the improvement of gait speed. No major clinical changes were observed at UPDRS. CONCLUSIONS: taVNS is a promising strategy for the management of PD gait, deserving prospective trials of chronic neuromodulation. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Epidemiology and geographic clustering of Erdheim-Chester disease in Italy and France.

This geoepidemiological study, performed in Italy and France, shows that Erdheim-Chester disease is increasingly diagnosed and cases cluster in specific geographic areas, namely southern Italy and central France. Disease frequency inversely correlates with the Human Development Index.

Circadian profile, daytime activity, and the Parkinson's phenotype: A motion sensor pilot study with neurobiological underpinnings.

Circadian rhythm impairment may play a role in Parkinson's disease (PD) pathophysiology. Recent literature associated circadian rhythm features to the risk of developing Parkinson and to its progression through stages. The association between the chronotype and the phenotype should be verified on a clinical and biological point of view. Herein we investigate the chronotype of a sample of 50 PD patients with the Morningness Eveningness Questionnaire and monitor their daily activity with a motion sensor embedded in a smartphone. Fibroblasts were collected from PD patients (n = 5) and from sex/age matched controls (n = 3) and tested for the circadian expression of clock genes (CLOCK, BMAL1, PER1, CRY1), and for cell morphology, proliferation, and death. Our results show an association between the chronotype and the PD phenotype. The most representative clinical chronotypes were "moderate morning" (56%), the "intermediate" (24%) and, in a minor part, the "definite morning" (16%). They differed for axial motor impairment, presence of motor fluctuations and quality of life (p < 0.05). Patients with visuospatial dysfunction and patients with a higher PIGD score had a blunted motor daily activity (p = 0.006 and p = 0.001, respectively), independently by the influence of age and other motor scores. Fibroblasts obtained by PD patients (n = 5) had an impaired BMAL1 cycle compared to controls (n = 3, p = 0.01). Moreover, a PD flat BMAL1 profile was associated with the lowest cell proliferation and the largest cell morphology. This study contributes to the growing literature on CR abnormalities in the pathophysiology of Parkinson's disease providing a link between the clinical and biological patient chronotype and the disease phenomenology.

Leg restlessness and hyperparathyroidism in Parkinson's disease, a further clue to RLS pathogenesis?

Background: Non-motor manifestations are the main features of Parkinson's disease (PD). These have been associated with vitamin D abnormalities, but the role of parathormone (PTH) is still obscure. Among the non-motor symptoms of PD, the pathogenesis of restless leg syndrome (RLS) is still debated, but it has been associated with the vitamin D/PTH axis in other disease models. Our study deepens the association between vitamin D and PTH with the prevalence of non-motor symptoms of PD and explores such a relationship in patients reporting leg restlessness. Methods: Fifty patients with PD were extensively investigated with motor and non-motor scales. Data on serum levels of vitamin D, PTH, and related metabolites were obtained, and patients were stratified as having vitamin D deficiency or hyperparathyroidism according to standardized criteria. Results: Overall, 80% of patients with PD exhibited low vitamin D levels, and hyperparathyroidism was diagnosed in 45%. The analysis of the non-motor symptoms profile using the non-motor symptom questionnaire (NMSQ) revealed 36% of leg restlessness, a main feature of RLS. This was significantly associated with worse motor symptoms, quality of sleep, and quality of life. Moreover, it was associated with hyperparathyroidism (OR: 3.48) and with PTH levels, independent of vitamin D, calcium/phosphate levels, and motor status. Conclusion: Our results suggest a significant association between the vitamin D/PTH axis and leg restlessness in PD. PTH has a putative role in nociceptive modulation, and previous evidence on hyperparathyroidism has suggested a possible interrelation with RLS. Further investigations are necessary to add PTH to the non-dopaminergic non-motor landscape of PD.

Botulinum toxin in clinical practice: state of the art of administration provisions in Italy.

Botulinum neurotoxin type A is a remarkable therapeutic approach for muscle hyperactivity syndromes, pain, and related disorders. Despite its wide application in neurology, there is a poor knowledge on delivery protocols and dispatch from the healthcare providers. In this study, we reported the result of a 2020 survey about the administration provisions of botulinum neurotoxin type A in Italy. Seven questions including information on characteristics of botulinum neurotoxin facilities, prescription, reimbursement, and execution modalities were adopted. Sixty participants answered the survey. Despite the wide availability of dedicated centers all over the national territory, there was a surprising lack of standardized and shared administration provisions. Most of the Italian medical structures delivered botulinum neurotoxin through outpatient clinics located in public hospital facilities, through the "F file" reimbursement modality. However, there was no agreement on the reimbursement request modality, creating differences in public costs relative to the botulinum toxin consumption across Italy.

Deep brain stimulation of the dentato-rubro-thalamic tract in a case of Holmes tremor: a constrained spherical deconvolution (CSD)-guided procedure.

Deep brain stimulation (DBS) is an established treatment for movement disorders, including Holmes tremor (HT). HT is a rest and action tremor that occurs as a late symptom of brainstem lesions such as stroke. Unfortunately, it is frequently refractory to medical treatment, hence DBS surgery may be a good option. Due to variable results, the ideal target for DBS in HT still remains to be established, ranging from the thalamus to the globus pallidus internus, to the subthalamic nucleus. Pre-operative imaging also is very challenging, as the complexity of brain fiber architecture may prevent the correct positioning of the directional lead. Herein, we describe the case of a patient affected by a rubral tremor secondary to a brain hemorrhage, who had advanced pre-operative neuroimaging with constrained spherical deconvolution (CSD)-based tractography obtained from diffusion-weighted imaging (DWI) to identify the dentato-rubro-thalamic tract, involved in the pathophysiology of HT. The patient was then addressed to an awake DBS surgery, and with the help of intraoperative microelectrode recordings, a tailored DRTT-targeted procedure was performed. The stimulation determined an almost complete tremor suppression, with no significant side effects at a follow-up of 6 months, paving the way towards new effective techniques for the planning, i.e., CSD-based tractography and the treatment of refractory tremors.

Oligomeric α-synuclein and tau aggregates in NDEVs differentiate Parkinson's disease from atypical parkinsonisms.

The early differential diagnosis of Parkinson's disease (PD) and atypical Parkinsonian syndromes (APS), including corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), is challenging because of an overlap of clinical features and the lack of reliable biomarkers. Neural-derived extracellular vesicles (NDEVs) isolated from blood provide a window into the brain's biochemistry and may assist in distinguishing between PD and APS. We verified in a case-control study whether oligomeric α-Synuclein and Tau aggregates isolated from NDEVs could allow the differential diagnosis of these conditions. Blood sampling and clinical data, including disease duration, motor severity, global cognition, and levodopa equivalent daily dose (LEDD), were collected from patients with a diagnosis of either PD (n = 70), PSP (n = 21), or CBD (n = 19). NDEVs were isolated from serum by immunocapture using an antibody against the neuronal surface marker L1CAM; oligomeric α-Synuclein and aggregated Tau were measured by ELISA. NDEVs analyses showed that oligomeric α-Synuclein is significantly augmented in PD compared to APS, whereas Tau aggregates are significantly increased in APS compared to PD (p < 0.0001). ROC analyses showed that these two biomarkers have a "good" power of classification (p < 0.0001 for both proteins), with high sensitivity and specificity, with NDEVs concentration of Tau aggregates and oligomeric α-Synuclein being respectively the best biomarker for PD/PSP and PD/CBD diagnostic differentiation. Logistic and multiple regression analysis confirmed that NDEVs-derived oligomeric α-Synuclein and Tau aggregates differentiate PD from CBD and PSP (p < 0.001). Notably, a positive correlation between NDEVs oligomeric α-Synuclein and disease severity (disease duration, p = 0.023; Modified H&Y, p = 0.015; UPDRS motor scores, p = 0.004) was found in PD patients and, in these same patients, NDEVs Tau aggregates concentration inversely correlated with global cognitive scores (p = 0.043). A minimally invasive blood test measuring the concentration of α-synuclein and Tau aggregates in NDEVs can represent a promising tool to distinguish with high sensitivity and specificity PD from CBD or PSP patients. Optimization and validation of these data will be needed to confirm the diagnostic value of these biomarkers in distinguishing synucleinopathies from taupathies.

Focal vibrations enhance somatosensory facilitation in healthy subjects: A pilot study on Equistasi® and high-frequency oscillations.

Background: Equistasi® is a vibrotactile device composed of nanotechnology fibers that converts temperature change into mechanical energy by self-producing a focal vibration. It is used in non-pharmacological rehabilitation in patients with movement disorders and multiple sclerosis sequelae. Nonetheless, the mechanism underlying such an improvement in motor functions is still poorly understood. Objectives: We designed a small uncontrolled pilot trial to explore the effect of Equistasi® on the somatosensory pathway through the analysis of high-frequency oscillations (HFOs). Methods: For all the included subjects, we recorded somatosensory-evoked potentials (SEPs) at the baseline (T0) and at 60 min after the application of Equistasi® (T1) on the seventh cervical vertebra level and at the forearm over each flexor carpi radialis, bilaterally. Then, we extracted the HFOs from the N20 signal and compared the HFO duration and area under the curve pre- and post-Equistasi® application. Results: In a head-to-head comparison of T0 to T1 data, there was a statistically significant reduction in the total HFO area (p < 0.01), which was prominent for the late component (p = 0.025). No statistical differences have been found between T0 and T1 HFO duration (p > 0.05). We further evaluated the N20 amplitude from the onset to the N20 peak to avoid possible interpretational bias. No statistical differences have been found between T0 and T1 (p = 0.437). Conclusion: Our clinical hypothesis, supported by preliminary data, is that vibrotactile afference delivered by the device could work by interfering with the somatosensory processing, rather than by peripheral effects.

Global Neurocognitive and Frontal Functions Analysis and Precision Intrathecal Pressure Measurement to Settle the Diagnostic Dilemma of the Normal Pressure Hydrocephalus: A Preliminary Experience.

INTRODUCTION: Normal-pressure hydrocephalus (NPH) is a common condition associated with a cognitive deterioration and possibly involving up to 9%-14% of all nursing home residents older than 65 years old. The purpose of the present paper is to introduce an inclusive study protocol aimed at increasing the diagnostic precision and follow-up accuracy. METHODS: A total of 28 patients were operated on for NPH in our institution in the period ranging between January 2015 and December 2019. All the patients underwent magnetic resonance imaging of the brain with standard sequences, calculation of the Evans index and corpus callosum angle, and evaluations by means of Montreal Cognitive Assessment (MOCA), Mini-Mental State Examination, and Frontal Assessment Battery (FAB) neuropsychological tests preoperatively and at 1 and 6 months. A preoperative lumbar test infusion (LIT) with fine measurement of the intrathecal pressures at the beginning and at the end of the procedures was performed. RESULTS: MOCA and FAB proved an overall improvement of the neurocognitive conditions at 1 month postoperatively. The mean pressure at the beginning of the LIT, was negatively associated with the neuropsychological outcome variables (Mini-Mental State Examination, FAB, and MOCA) in the 3 different evaluations, with FAB and MOCA at 6 months. We found a strong positive correlation between the Evans index as measured on the first magnetic resonance imaging scan both with the diastolic and systolic pressure at the beginning of the test. CONCLUSIONS: Neuropsychological assessment, combined with LIT with intrathecal pressure managements aids the diagnostic process in patients affected by NPH. It allows standardizing in a rigorous fashion the follow-up evaluation of patients undergoing surgery for a ventriculoperitoneal shunt.