Differential profiles of serum cytokines in Parkinson's disease according to disease duration.

OBJECTIVE: Neurodegeneration and neuroinflammation are two intertwined mechanisms contributing to the pathophysiology of Parkinson's disease. Whether circulating biomarkers reflecting those two processes differ according to disease duration remains to be established. The present study was conducted to characterize the biomarkers individuals with PD with short (≤5 years) or long disease duration (>5 years). METHODS: We consecutively enrolled 104 patients with Parkinson's disease and evaluated them using validated clinical scales (MDS-UPDRS, Hoehn and Yahr staging, MMSE). Serum samples were assayed for the following biomarkers: neurofilament light chain (NfL), brain-derived neurotrophic factor (BDNF), interleukin (IL-) 1ß, 4, 5, 6, 10, 17, interferon-γ, and tumor necrosis factor α. RESULTS: Mean age of participants was 66.0 ± 9.6 years and 45 (34%) were women. The average disease duration was 8 ± 5 years (range 1 to 19 years). Patients with short disease duration (≤ 5 years) showed a pro-inflammatory profile, with significantly higher levels of pro-inflammatory IL-1ß and lower concentrations of IL-5, IL-10 and IL-17 (p < 0.05). NfL serum levels showed a positive correlation with disease duration and age (respectively rho = 0.248, p = 0.014 and rho = 0.559, p < 0.001) while an opposite pattern was detected for BDNF (respectively rho -0,187, p = 0.034 and rho = -0.245, p = 0.014). CONCLUSIONS: Our findings suggest that a pro-inflammatory status may be observed in PD patients in the early phases of the disease, independently from age.

Movement disorders following mechanical thrombectomy resulting in ischemic lesions of the basal ganglia: An emerging clinical entity.

BACKGROUND AND PURPOSE: Post-stroke movement disorders (PMDs) following ischemic lesions of the basal ganglia (BG) are a known entity, but data regarding their incidence are lacking. Ischemic strokes secondary to proximal middle cerebral artery (MCA) occlusion treated with thrombectomy represent a model of selective damage to the BG. The aim of this study was to assess the prevalence and features of movement disorders after selective BG ischemia in patients with successfully reperfused acute ischemic stroke (AIS). METHODS: We enrolled 64 consecutive subjects with AIS due to proximal MCA occlusion treated with thrombectomy. Patients were clinically evaluated by a movement disorders specialist for PMDs onset at baseline, and after 6 and 12 months. RESULTS: None of the patients showed an identifiable movement disorder in the subacute phase of the stroke. At 6 and 12 months, respectively, 7/25 (28%) and 7/13 (53.8%) evaluated patients developed PMDs. The clinical spectrum of PMDs encompassed parkinsonism, dystonia and chorea, either isolated or combined. In most patients, symptoms were contralateral to the lesion, although a subset of patients presented with bilateral involvement and prominent axial signs. CONCLUSION: Post-stroke movement disorders are not uncommon in long-term follow-up of successfully reperfused AIS. Follow-up conducted by a multidisciplinary team is strongly advisable in patients with selective lesions of the BG after AIS, even if asymptomatic at discharge.

Long-term safety and efficacy of frameless subthalamic deep brain stimulation in Parkinson's disease.

BACKGROUND: Bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) is standard of care for Parkinson's disease (PD) patients and a correct lead placement is crucial to obtain good clinical outcomes. Evidence demonstrating the targeting accuracy of the frameless technique for DBS, along with the advantages for patients and clinicians, is solid, while data reporting long-term clinical outcomes for PD patients are still lacking. OBJECTIVES: The study aims to assess the clinical safety and efficacy of frameless bilateral STN-DBS in PD patients at 5 years from surgery. METHODS: Consecutive PD patients undergoing bilateral STN-DBS with a frameless system were included in this single-center retrospective study. Clinical features, including the Unified Parkinson's Disease Rating Scale (UPDRS) in its total motor score and axial sub-scores, and pharmacological regimen were assessed at baseline, 1 year, 3 years, and 5 years after surgery. The adverse events related to the procedure, stimulation, or the presence of the hardware were systematically collected. RESULTS: Forty-one PD patients undergone bilateral STN-DBS implantation were included in the study and fifteen patients already completed the 5-year observation. No complications occurred during surgery and the perioperative phase, and no unexpected serious adverse event occurred during the entire follow-up period. At 5 years from surgery, there was a sustained motor efficacy of STN stimulation: STN-DBS significantly improved the off-stim UPDRS III score at 5 years by 37.6% (P < 0.001), while the dopaminergic medications remained significantly reduced compared to baseline (- 21.6% versus baseline LEDD; P = 0.036). CONCLUSIONS: Our data support the use of the frameless system for STN-DBS in PD patients, as a safe and well-tolerated technique, with long-term clinical benefits and persistent motor efficacy at 5 years from the surgery.

Spinal cord stimulation may improve gait and cognition in hereditary spastic paraplegia with mental retardation: a case report.

BACKGROUND: Hereditary spastic paraplegia (HSP) include various sporadic and hereditary neurodegenerative disorders, characterized by progressive spasticity and weakness of lower limbs, possibly associated to additional features. CASE PRESENTATION: We report a male HPS patient in his 40 s, showing mental retardation associated with language impairment, dysarthria, and increased urinary frequency. Three months after treatment with electric chronic high-frequency cervical spinal cord stimulation (HF-SCS), he showed an amelioration of motor symptoms (lower limbs spasticity and gait), dysarthria, cognitive functioning (language and constructive praxic abilities), and urinary symptoms (decreased urinary frequency). Single-photon emission computed tomography (SPECT) showed a postoperative increase of cerebral perfusion in right frontal cortex and temporal cortex bilaterally. CONCLUSION: In our patient, HF-SCS might have induced an activation of ascending neural pathways, resulting in changes in activity in various cortical areas (including sensory-motor cortical areas), which may give rise to a modulation of activity in spared descending motor pathways and in neural networks involved in cognitive functions, including language. Although further studies in patients with HPS are needed to clarify whether HF-SCS can be a suitable treatment option in HSP, our observation suggests that HF-SCS, a minimally invasive neurosurgical procedure, might induce beneficial effects of on various symptoms of such orphan disease.

Intraoperative Local Field Potential Beta Power and Three-Dimensional Neuroimaging Mapping Predict Long-Term Clinical Response to Deep Brain Stimulation in Parkinson Disease: A Retrospective Study.

BACKGROUND: Directional deep brain stimulation (DBS) leads allow a fine-tuning control of the stimulation field, however, this new technology could increase the DBS programming time because of the higher number of the possible combinations used in directional DBS than in standard nondirectional electrodes. Neuroimaging leads localization techniques and local field potentials (LFPs) recorded from DBS electrodes implanted in basal ganglia are among the most studied biomarkers for DBS programing. OBJECTIVE: This study aimed to evaluate whether intraoperative LFPs beta power and neuroimaging reconstructions correlate with contact selection in clinical programming of DBS in patients with Parkinson disease (PD). MATERIALS AND METHODS: In this retrospective study, routine intraoperative LFPs recorded from all contacts in the subthalamic nucleus (STN) of 14 patients with PD were analyzed to calculate the beta band power for each contact. Neuroimaging reconstruction obtained through Brainlab Elements Planning software detected contacts localized within the STN. Clinical DBS programming contact scheme data were collected after one year from the implant. Statistical analysis evaluated the diagnostic performance of LFPs beta band power and neuroimaging data for identification of the contacts selected with clinical programming. We evaluated whether the most effective contacts identified based on the clinical response after one year from implant were also those with the highest level of beta activity and localized within the STN in neuroimaging reconstruction. RESULTS: LFPs beta power showed a sensitivity of 67%, a negative predictive value (NPV) of 84%, a diagnostic odds ratio (DOR) of 2.7 in predicting the most effective contacts as evaluated through the clinical response. Neuroimaging reconstructions showed a sensitivity of 62%, a NPV of 77%, a DOR of 1.20 for contact effectivity prediction. The combined use of the two methods showed a sensitivity of 87%, a NPV of 87%, a DOR of 2.7 for predicting the clinically more effective contacts. CONCLUSIONS: The combined use of LFPs beta power and neuroimaging localization and segmentations predict which are the most effective contacts as selected on the basis of clinical programming after one year from implant of DBS. The use of predictors in contact selection could guide clinical programming and reduce time needed for it.

Frameless stereotaxy in subthalamic deep brain stimulation: 3-year clinical outcome.

BACKGROUND: In most centers, the surgery of deep brain stimulation (DBS) is performed using a stereotactic frame. Compared with frame-based technique, frameless stereotaxy reduces the duration of surgical procedure and patient's discomfort, with lead placing accuracy equivalent after the learning curve. Although several studies have investigated the targeting accuracy of this technique, only a few studies reported clinical outcomes, with data of short-term follow-up. OBJECTIVE: To assess clinical efficacy and safety of frameless bilateral subthalamic nucleus (STN) DBS in Parkinson's disease (PD) patients at 1- and 3-year follow-up. METHODS: Consecutive PD patients who underwent bilateral STN-DBS with a manual adjustable frameless system were included in the study. The data were collected retrospectively. RESULTS: Eighteen PD patients underwent bilateral STN-DBS implant and were included in the study. All patients completed 1-year observation and ten of them completed 3-year observation. At 1-year follow-up, motor efficacy of STN stimulation in off-med condition was of 30.1% (P = 0.003) and at 3-year follow-up was of 36.3%, compared with off-stim condition at 3-year follow-up (P = 0.005). Dopaminergic drugs were significantly reduced by 31.2% 1 year after the intervention (P = 0.003) and 31.7% 3 years after the intervention (P = 0.04). No serious adverse events occurred during surgery. CONCLUSIONS: Frameless stereotaxy is an effective and safe technique for DBS surgery at 1- and 3-year follow-up, with great advantages for patients' discomfort during surgery.

Effect of the COVID-19 pandemic and the lockdown measures on the local stroke network.

INTRODUCTION: The COVID-19 outbreak highly impacted the acute ischemic stroke care management. The primary end point of the study was to evaluate the impact of the COVID-19 outbreak and the following lockdown measures on our hub-and-spoke network; the secondary end point was to evaluate if the impact of the COVID-19 outbreak was different in hub-and-spoke centers. METHODS: This was a retrospective multicenter observational study conducted at the Stroke Units of Policlinico Gemelli, Ospedale San Filippo Neri, Ospedale di Belcolle, and Ospedale San Camillo de Lellis. We collected clinical reports of all consecutive patients admitted with diagnosis of acute ischemic stroke or transient ischemic attack (TIA) during the phase 1 of the lockdown period (11 March 2020-4 May 2020). As controls, we used all consecutive patients admitted for acute ischemic stroke or TIA in the same period of the previous year. RESULTS: A total of 156 and 142 clinical reports were collected in 2019 and 2020, respectively. During the COVID-19 outbreak, we observed a reduction of number of thrombolysis, a reduction of the length of hospitalization, and an increase of pneumonia. Regarding performance indicators, we observed an increase in onset-to-door time and in door-to-groin time. We did not observe any statistically significant interaction between year (2019 vs 2020) and facility of admission (hub vs spoke) on all variables analyzed. DISCUSSION: Our observational study, involving hub-and-spoke stroke network of a wide regional area, indicates that the COVID-19 outbreak impacted on the acute stroke management. This impact was equally observed in hub as well as in spoke centers.

Heart Rate Variability during Wake and Sleep in Huntington's Disease Patients: An Observational, Cross-Sectional, Cohort Study.

INTRODUCTION: Autonomic dysfunction has been reported as one of nonmotor manifestations of both presymptomatic and manifest Huntington's disease (HD). The aim of our study was to evaluate heart rate variability (HRV) during wake and sleep in a cohort of patients with manifest HD. METHODS: Thirty consecutive patients with manifest HD were enrolled, 14 men and 16 women, mean age 57.3 ± 12.2 years. All patients underwent full-night attended video polysomnography. HRV was analyzed during wake, NREM sleep, and REM sleep, in time and frequency domain. Results were compared with a control group of healthy volunteers matched for age and sex. RESULTS: During wake, HD patients presented significantly higher mean heart rate than controls (72.4 ± 9.6 vs. 58.1 ± 7.3 bpm; p < 0.001). During NREM sleep, HD patients showed higher mean heart rate (65.6 ± 11.1 vs. 48.8 ± 4.6 bpm; p < 0.001) and greater low frequency (LF) component of HRV (52.9 ± 22.6 vs. 35.5 ± 17.3 n.u.; p = 0.004). During REM sleep, we observed lower standard deviation of the RR interval in HD subjects (3.4 ± 2.2 vs. 3.7 ± 1.3 ms; p = 0.015). CONCLUSION: Our results show that HD patients have higher heart rate than controls, during wake and NREM, but not during REM sleep. Among HRV parameters, the most relevant difference regarded the LF component, which reflects, at least partially, the ortho-sympathetic output. Our results confirm the involvement of autonomic nervous system in HD and demonstrate that it is evident during both wake and sleep.

Should We Consider Deep Brain Stimulation Discontinuation in Late-Stage Parkinson's Disease?

BACKGROUND: Subthalamic deep brain stimulation (STN-DBS) effects may decrease with Parkinson's disease (PD) progression. There is no indication if, when, and how to consider the interruption of DBS treatment in late-stage PD. The objective of the current study was to investigate the percentage of "poor stimulation responders" among late-stage PD patients for elaborating an algorithm to decide whether and when DBS discontinuation may be considered. METHODS: Late-stage PD patients (Hoehn Yahr stage ≥4 and Schwab and England Scale <50 in medication on/stimulation on condition) treated with STN-DBS for at least 5 years underwent a crossover, double-blind, randomized evaluation of acute effects of stimulation. Physicians, caregivers, and patients were blinded to stimulation conditions. Poor stimulation responders (MDS-UPDRS part III change <10% between stimulation on/medication off and stimulation off/medication off) maintained the stimulation off/medication on condition for 1 month for open-label assessment. RESULTS: Thirty-six patients were included. The acute effect of stimulation was significant (17% MDS-UPDRS part III), with 80% of patients classified as "good responders." Seven patients were classified as "poor stimulation responders," and the stimulation was switched off, but in 4 cases the stimulation was switched back "on" because of worsening of parkinsonism and dysphagia with a variable time delay (up to 10 days). No serious adverse effects occurred. CONCLUSIONS: The vast majority of late-stage PD patients (92%) show a meaningful response to STN-DBS. Effects of stimulation may take days to disappear after its discontinuation. We present a safe and effective decisional algorithm that could guide physicians and caregivers in making challenging therapeutic decisions in late-stage PD. © 2020 International Parkinson and Movement Disorder Society.

Effect of lockdown on the management of ischemic stroke: an Italian experience from a COVID hospital.

OBJECTIVE: To evaluate the impact of the lockdown measures, consequent to the outbreak of COVID-19 pandemic, on the quality of pre-hospital and in-hospital care of patients with acute ischemic stroke. METHODS: This is an observational cohort study. Data sources were the clinical reports of patients admitted during the first month of lockdown and discharged with a confirmed diagnosis of stroke or TIA. Data were collected in the interval ranging from March 11th to April 11th 2020. As controls, we evaluated the clinical reports of patients with stroke or TIA admitted in the same period of 2019. RESULTS: The clinical reports of patients eligible for the study were 52 in 2020 (71.6 ± 12.2 years) and 41 in 2019 (73.7 ± 13.1 years). During the lockdown, we observed a significant increase in onset-to-door time (median = 387 vs 161 min, p = 0.001), a significant reduction of the total number of thrombolysis (7 vs 13, p = 0.033), a non-significant increase of thrombectomy (15 vs 9, p = 0.451), and a significant increase in door-to-groin time (median = 120 vs 93 min, p = 0.048). No relevant difference was observed between 2019 and 2020 in the total number of patients admitted. CONCLUSIONS: Due to the COVID-19 pandemic and lockdown measures, the stroke care pathway changed, involving both pre-hospital and in-hospital performances.

Stroke and COVID19: Not only a large-vessel disease.

Recent evidence has underlined the association between large-vessel stroke and COVID-19, probably due to a proinflammatory and prothrombotic microenvironment induced by SARS-CoV-2. Here, we report the case of a young fit woman affected by COVID-19 without any flu-like symptom, who suffered from speech disorder and left hemiparesis. Brain magnetic resonance evidenced two small acute brain infarctions in right perirolandic cortex without signs of previous ischemic lesions and hemorrhagic infarction. Diagnostic workup excluded cardiac embolic sources, acquired and inherited thrombophilia or autoimmune diseases. Two positive nasopharyngeal swab tests and high titers of serum specific IgA/IgM confirmed COVID-19 diagnosis. In our case stroke seems to be the only manifestation of SARS-COV-2 infection. Therefore the hypothesis of an underlying viral infection, as COVID-19, should be investigated in all the cases of small vessel cryptogenic stroke.

Frequency and phenotypic spectrum of KMT2B dystonia in childhood: A single-center cohort study.

BACKGROUND: Childhood-onset dystonia is often genetically determined. Recently, KMT2B variants have been recognized as an important cause of childhood-onset dystonia. OBJECTIVE: To define the frequency of KMT2B mutations in a cohort of dystonic patients aged <18 years at onset, the associated clinical and radiological phenotype, and the natural history of disease. METHODS: Whole-exome sequencing or customized gene panels were used to screen a cohort of 65 patients who had previously tested negative for all other known dystonia-associated genes. RESULTS: We identified 14 patients (21.5%) carrying KMT2B variants, of which 1 was classified as a variant of unknown significance. We also identified 2 additional patients carrying pathogenic mutations in GNAO1 and ATM. Overall, we established a definitive genetic diagnosis in 23% of cases. We observed a spectrum of clinical manifestations in KMT2B variant carriers, ranging from generalized dystonia to short stature or intellectual disability alone, even within the same family. In 78.5% of cases, dystonia involved the lower limbs at onset, with later caudocranial generalization. Eight patients underwent pallidal DBS with a median decrease of Burke-Fahn-Marsden Dystonia Rating Scale-Motor score of 38.5% in the long term. We also report on 4 asymptomatic carriers, suggesting that some KMT2B mutations may be associated with incomplete disease penetrance. CONCLUSIONS: KMT2B mutations are frequent in childhood-onset dystonia and cause a complex neurodevelopmental syndrome, often featuring growth retardation and intellectual disability as additional phenotypic features. A dramatic and long-lasting response to DBS is characteristic of DYT-KMT2B dystonia. © 2019 International Parkinson and Movement Disorder Society.

Subjective Assessment of Sleep in Huntington Disease: Reliability of Sleep Questionnaires Compared to Polysomnography.

INTRODUCTION: The aim of the study was to evaluate the clinical reliability of subjective sleep evaluation, based on sleep and psychometric questionnaires, by comparing the results with those obtained with laboratory-based video-polysomnography (V-PSG). PATIENTS AND METHODS: Thirty consecutive Huntington disease (HD) patients were enrolled. Subjective evaluation of sleep included the Pittsburgh Sleep Quality Index (PSQI), the sleep questionnaire for HD (HDQ), the Epworth Sleepiness Scale, the Bologna questionnaire for sleepiness (BQ), the Berlin questionnaire, and the RBD questionnaire; the International Restless Legs Syndrome Study Group scale was administered to patients with positive screening. The psychometric evaluation included the Zung Anxiety Scale, the short form of the Beck Depression Inventory, and the Maudsley Obsessive-Compulsive Inventory. All patients underwent V-PSG. RESULTS: In sleepiness evaluation, the Epworth score was above the cutoff in 6 subjects, and the BQ detected a "high risk" of sleepiness in 7 cases. The results were concordant in 24 and discordant in 5 cases. In the evaluation of sleep quality, the PSQI score was above the cutoff in 18 subjects. According to the HDQ, 10 subjects were poor sleepers. The results were concordant with the PSQI in 20 subjects. DISCUSSION: All comparisons between scale scores and PSG results showed poor or totally absent concordance between subjective and objective measures. SIGNIFICANCE: The subjective evaluation of sleep in HD patients shows a poor correlation with PSG results.

The role of small intestinal bacterial overgrowth in Parkinson's disease.

Parkinson's disease is associated with gastrointestinal motility abnormalities favoring the occurrence of local infections. The aim of this study was to investigate whether small intestinal bacterial overgrowth contributes to the pathophysiology of motor fluctuations. Thirty-three patients and 30 controls underwent glucose, lactulose, and urea breath tests to detect small intestinal bacterial overgrowth and Helicobacter pylori infection. Patients also underwent ultrasonography to evaluate gastric emptying. The clinical status and plasma concentration of levodopa were assessed after an acute drug challenge with a standard dose of levodopa, and motor complications were assessed by Unified Parkinson's Disease Rating Scale-IV and by 1-week diaries of motor conditions. Patients with small intestinal bacterial overgrowth were treated with rifaximin and were clinically and instrumentally reevaluated 1 and 6 months later. The prevalence of small intestinal bacterial overgrowth was significantly higher in patients than in controls (54.5% vs. 20.0%; P = .01), whereas the prevalence of Helicobacter pylori infection was not (33.3% vs. 26.7%). Compared with patients without any infection, the prevalence of unpredictable fluctuations was significantly higher in patients with both infections (8.3% vs. 87.5%; P = .008). Gastric half-emptying time was significantly longer in patients than in healthy controls but did not differ in patients based on their infective status. Compared with patients without isolated small intestinal bacterial overgrowth, patients with isolated small intestinal bacterial overgrowth had longer off time daily and more episodes of delayed-on and no-on. The eradication of small intestinal bacterial overgrowth resulted in improvement in motor fluctuations without affecting the pharmacokinetics of levodopa. The relapse rate of small intestinal bacterial overgrowth at 6 months was 43%. © 2013 Movement Disorder Society.

Functional Movement Disorders during COVID-19: Psychological Distress, Affective Temperament and Emotional Dysregulation.

Background and objective: Functional movement disorders (FMD) represent a spectrum of psychosomatic symptoms particularly sensitive to stress. The COVID-19 pandemic has increased psychological distress worldwide and may have worsened FMD. The study aimed to confirm this hypothesis and to test whether in FMD there is a relationship between affective temperament, emotional dysregulation and psychological distress due to the pandemic. Methods: We recruited individuals with FMD, diagnosed them according to validated criteria and matched them with healthy controls (HC). Psychological distress and temperament were obtained using the Kessler-10 and the Temperament Evaluation of Memphis, Pisa and San Diego Autoquestionnaire, respectively. We used bootstrapped mediation analysis to test the mediator role of emotional dysregulation on the effect of temperament on psychological distress. Results: The sample consisted of 96 individuals. During the pandemic, 31.3% of the patients reported the need for urgent neurological care, and 40.6% reported a subjective worsening neurological condition. Patients with FMD presented with more psychological distress during the COVID-19 pandemic (F = 30.15, df = 1, p ≤ 0.001) than HC. They also reported more emotional dysregulation (F = 15.80, df = 1, p ≤ 0.001) and more cyclothymic traits (F = 14.84, df = 1, p ≤ 0.001). Cyclothymic temperament showed an indirect effect on COVID-19-related psychological distress, mediated by deficits in emotion regulation mechanisms (Bootstrapped LLCI = 0.41, ULCI = 2.41). Conclusion: Our results suggest that emotional dysregulation may represent a dimension mediating cyclotimic temperament response to the stressful effect of the pandemic and provide insight for developing intervention policies.

Effects of deep brain stimulation of the subthalamic nucleus on patients with Parkinson's disease: a machine-learning voice analysis.

Introduction: Deep brain stimulation of the subthalamic nucleus (STN-DBS) can exert relevant effects on the voice of patients with Parkinson's disease (PD). In this study, we used artificial intelligence to objectively analyze the voices of PD patients with STN-DBS. Materials and methods: In a cross-sectional study, we enrolled 108 controls and 101 patients with PD. The cohort of PD was divided into two groups: the first group included 50 patients with STN-DBS, and the second group included 51 patients receiving the best medical treatment. The voices were clinically evaluated using the Unified Parkinson's Disease Rating Scale part-III subitem for voice (UPDRS-III-v). We recorded and then analyzed voices using specific machine-learning algorithms. The likelihood ratio (LR) was also calculated as an objective measure for clinical-instrumental correlations. Results: Clinically, voice impairment was greater in STN-DBS patients than in those who received oral treatment. Using machine learning, we objectively and accurately distinguished between the voices of STN-DBS patients and those under oral treatments. We also found significant clinical-instrumental correlations since the greater the LRs, the higher the UPDRS-III-v scores. Discussion: STN-DBS deteriorates speech in patients with PD, as objectively demonstrated by machine-learning voice analysis.

STN-DBS does not increase the risk of sialorrhea in patients with advanced Parkinson's disease.

The aims of this study were to assess the incidence rate and risk factors for sialorrhea in the long-term follow-up in a cohort of 132 patients with advanced Parkinson's disease [88 with deep brain stimulation (DBS) and 44 on medical treatment]. The incidence rate of sialorrhea did not differ between the two groups; male sex, Hoehn and Yahr stage and dysphagia resulted risk factors for sialorrhea. These findings indicate that DBS does not increase the risk of developing sialorrhea.

Beyond the CAG triplet number: exploring potential predictors of delayed age of onset in Huntington's disease.

OBJECTIVE: Huntington's disease (HD) is a genetic neurodegenerative disease characterized by cognitive, motor, and psychiatric dysfunction. It is caused by an expansion of the trinucleotide repeat sequence cytosine-adenine-guanine (CAG) in the Huntingtin gene on chromosome 4. Onset typically occurs in the fourth or fifth decade, ranging from childhood to late adulthood. The CAG triplet number is generally inversely proportional to the age of onset (AOO), but the repeat number only accounts for ∼70% of the variability in AOO. Several studies demonstrated the impact of genetic modifiers on age of disease onset. In addition to genetics, we also explored the demographic, anamnestic, and socio-environmental factors that can affect AOO, to help us understand the non-genetic variability of age of onset in HD. METHODS: We analyzed the retrospective data of the ENROLL-HD global registry study, particularly focusing on the continuum of ages, to include sociodemographic, genetic, and anamnestic psychobehavioral variables in a multivariate regression model aimed at identifying the potential predictors of age of motor onset (n = 5053). We ran the same regression model in the sample of subjects who had the same number of triplets (41 CAG, n = 593) and in the sample whose family history was absent/unknown (n = 630). RESULTS: Patients with delayed onset more frequently have unknown/missing family history, are married or widowed, live in larger urbanized contexts and have a lower educational level. Individuals with earlier onset more frequently develop psychobehavioral symptoms. CONCLUSIONS: In the past, the HD gene was considered the epitome of genetic determinism. Our results are consistent with recent evidence that other factors might modulate its impact. These findings allow characterizing the determinants of AOO beyond the CAG expansions and provide valuable information for stratifying patients for future clinical trial designs.