Motor fluctuations represent a major challenge in Parkinson’s disease (PD) management. To address them, ADD-ON therapies with monoamine oxidase type B (MAO-B) and catechol-O-methyl transferase (COMT) inhibitors are used to enhance and prolong dopaminergic effects of levodopa, thereby improving motor fluctuations. Despite widespread use, real-life comparative data remain limited. We performed a retrospective, longitudinal study including PD patients referred to two Italian tertiary movement disorder centers. Patients with motor fluctuations requiring ADD-ON therapy (selegiline [SL], rasagiline [RS], safinamide [SF], or opicapone [OP]) and ≥ 12 months of follow-up were included. The primary outcome was treatment stability, defined as months without significant therapy modifications or ADD-ON discontinuation. Secondary outcomes included levodopa dosage changes, initiation of other antiparkinsonian therapies, and ADD-ON discontinuation rates. Cox regression models and Kaplan–Meier survival analyses evaluated the influence of ADD-ON type and clinical-demographic variables on treatment stability. We analyzed 169 patients (SL = 20; RS = 26; SF = 78; OP = 45). Groups differed in age at ADD-ON initiation (p = 0.020; RS > OP), disease duration (p = 0.002; OP > RS and SF), and baseline levodopa equivalent daily dose (p = 0.003; SF and OP > RS). No significant differences in treatment stability were found between groups (p = 0.29). SF group showed higher levodopa increases (p = 0.02) and initiation of new therapies (p = 0.02). ADD-ON discontinuation occurred in 23.1

Background:Preclinical and clinical studies suggest that the multimodal antidepressant vortioxetine may offer a valuable therapeutic option in the treatment of depression associated with neurological disorders, including Parkinson's disease (PD). Objectives:To compare the effect of vortioxetine and the SSRI sertraline in the treatment of PD and comorbid depression, placing emphasis on peripheral inflammation markers. Methods:This is an observational longitudinal study. We have recruited 33 patients affected by PD with comorbid depression, evaluated for motor and non-motor symptoms, depression, and peripheral and soluble markers of inflammation at baseline and at the end of antidepressant treatment. Patients were divided into two groups treated with either vortioxetine (10-20 mg/day) or sertraline (50 mg/day) for 4 months. A group of 12 healthy controls was also used for comparative purposes. Results:At baseline PD patients showed a higher number of "classical" monocytes and a lower number of "non-classical" monocytes and myeloid dendritic cells (mDCs). The number and activity of DCs generated from isolated monocytes were also lower in PD patients. While both sertraline and vortioxetine treatment further reduced the number of mDCs, only vortioxetine had a restorative effect on CD40- and CD54-expressing DCs and their function. Both drugs display an antidepressant activity, but vortioxetine was superior to sertraline in improving cognitive function, anxiety, anhedonia, and apathy. Conclusion:These data evaluate for the first time the immunomodulatory effects of two different treatments in PD patients with comorbid depression, highlighting the greater immunomodulatory capacity of vortioxetine.

Background:Recent studies demonstrated the validity, reliability, and accuracy of consumer smartwatches for measuring daily steps in people with Parkinson disease (PD). However, no study to date has estimated the minimal clinically important difference (MCID) for average daily steps (avDS), measured through a consumer smartwatch in people with PD. Objective:This study aimed to calculate the MCID of avDS, measured through a commercial smartwatch (Garmin Vivosmart 4) in people with PD. Methods:People with PD with a disease stage <4, without cognitive impairment, and who were able to walk unaided, wore a Garmin Vivosmart 4 smartwatch for 5 consecutive days on the wrist least affected by the disease, allowing the computation of avDS. To define the 3 levels of MCID for avDS, we used an anchor-based method linked to: (1) scales capturing subtle changes in global mobility and motor functions, (2) clinical and health-related measures, and (3) disease-related patient-reported outcomes. Linear regressions, Student t test, and ANOVA were used to estimate the minimal change in avDS based on anchors relevant change. For each level, the overall MCID was calculated as the average of the variables included, and the range was reported. Results:A total of 100 people with PD were enrolled. Participants took on average 5949 (SD 3034) daily steps, ranging from 357 to 12,620. The MCID of avDS anchored to standardized measures of motor symptoms and mobility was 581 steps/day (range  554-608) or around 10% of mean avDS in our population. The MCID of avDS anchored to clinical and health-related variables was 1200 steps/day (range  350-1683), or around 20% of mean avDS in our population. Finally, the MCID of avDS anchored to disease-related patient-reported outcomes was 1592 steps/day (range 594-2589), or around 27% of the mean avDS in our population. Conclusions:These findings could be relevant for designing future clinical trials involving avDS as a digital mobility outcome in daily life for people with PD and evaluating the effectiveness of the intervention promoting free-living walking in this population.

Metabotropic glutamate (mGlu) receptors are candidate drug targets for therapeutic intervention in Parkinson’s disease (PD). Here we focused on mGlu3, a receptor subtype involved in synaptic regulation and neuroinflammation. mGlu3−/− mice showed an enhanced nigro-striatal damage and microglial activation in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Expression of genes encoding anti-inflammatory proteins and neuroprotective factors was reduced in the striatum of MPTP-treated mGlu3−/− mice. We also examined polymorphic variants of GRM3 (the mGlu3 receptor encoding gene) in 723 PD patients and 826 healthy controls. Two GRM3 haplotypes were associated with PD, and gene variants correlated with motor and non-motor signs. Interestingly, PD patients carrying each of the two haplotypes showed an impaired cortical plasticity in the paired associated stimulation paradigm of magnetic transcranial stimulation. These findings suggest that mGlu3 receptors are neuroprotective in mouse models of parkinsonism and shape mechanisms of cortical plasticity in PD.

Background:Average daily steps (avDS) could be a valuable indicator of real-world ambulation in people with Parkinson disease (PD), and previous studies have reported the validity and reliability of this measure. Nonetheless, no study has considered disease phenotype, stage, and severity when assessing the reliability of consumer wrist-worn devices to estimate daily step count in unsupervised, free-living conditions in PD. Objective:This study aims to assess and compare the reliability of a consumer wrist-worn smartwatch (Garmin Vivosmart 4) in counting avDS in people with PD in unsupervised, free-living conditions among disease phenotypes, stages, and severity groups. Methods:A total of 104 people with PD were monitored through Garmin Vivosmart 4 for 5 consecutive days. Total daily steps were recorded and avDS were calculated. Participants were dichotomized into tremor dominant (TD; n=39) or postural instability and gait disorder (PIGD; n=65), presence (n=57) or absence (n=47) of tremor, and mild (n=65) or moderate (n=39) disease severity. Based on the modified Hoehn and Yahr scale (mHY), participants were further dichotomized into earlier (mHY 1-2; n=68) or intermediate (mHY 2.5-3; n=36) disease stages. Intraclass correlation coefficient (ICC; 3,k), standard error of measurement (SEM), and minimal detectable change (MDC) were used to evaluate the reliability of avDS for each subgroup. The threshold for acceptability was set at an ICC ≥0.8 with a lower bound of 95% CI ≥0.75. The 2-tailed Student t tests for independent groups and analysis of 83.4% CI overlap were used to compare ICC between each group pair. Results:Reliability of avDS measured through Garmin Vivosmart 4 for 5 consecutive days in unsupervised, free-living conditions was acceptable in the overall population with an ICC of 0.89 (95% CI 0.85-0.92), SEM below 10%, and an MDC of 1580 steps per day (27% of criterion). In all investigated subgroups, the reliability of avDS was also acceptable (ICC range 0.84-0.94). However, ICCs were significantly lower in participants with tremor (P=.03), with mild severity (P=.04), and earlier stage (P=.003). Moreover, SEM was below 10% in participants with PIGD phenotype, without tremor, moderate disease severity, and intermediate disease stage, with an MDC ranging from 1148 to 1687 steps per day (18%-25% of criterion). Conversely, in participants with TD phenotype, tremor, mild disease severity, and earlier disease stage, SEM was >10% of the criterion and MDC values ranged from 1401 to 2263 steps per day (30%-33% of the criterion). Conclusions:In mild-to-moderate PD, avDS measured through a consumer smartwatch in unsupervised, free-living conditions for 5 consecutive days are reliable irrespective of disease phenotype, stage, and severity. However, in individuals with TD phenotype, tremor, mild disease severity, and earlier disease stages, reliability could be lower. These findings could facilitate a broader and informed implementation of avDS as an index of ambulatory activity in PD.

BACKGROUND:The outcome of levodopa/carbidopa intestinal gel (LCIG) in Parkinson's disease carriers of GBA1 mutations (GBA-PD) remains uncertain. OBJECTIVE:To evaluate the safety and efficacy of LCIG in a large PD cohort, focusing on GBA1 variants. METHODS:This multicenter, retrospective, longitudinal "real-world" study included consecutive patients with advanced PD treated with LCIG at 31 Italian centers; data were collected at baseline, 1-, 5-year, and last-available follow-up. RESULTS:Data from 512 PD patients (59% male, mean age and disease duration at LCIG initiation 67.0 ± 8.0 and 12.9 ± 5.0 years, respectively) were analyzed. GBA1 genotyping was available for 306 patients (60%), of whom 40 (13%) had GBA1 mutations or risk variants. Mean follow-up on LCIG was 3.9 ± 2.9 years; 5-year follow-up data were available for 159 subjects. At baseline, GBA-PD had a younger age, shorter PD duration, worse cognition, and more hallucinations than noncarriers. At 1- and 5-year follow-up, LCIG improved motor and non-motor symptoms, OFF-time, and dyskinesias in the entire population. In GBA-PD, MDS-UPDRS parts I, II, and III scores did not change, while part IV score improved significantly less than in noncarriers; cognition and orthostatic hypotension symptoms worsened more rapidly. Multivariate analysis of predictors for adverse events and LCIG discontinuation found no significant contribution from GBA1 mutation status. CONCLUSIONS:GBA1 status does not increase the risk of adverse events or LCIG discontinuation. LCIG is a safe option for advanced GBA-PD, even in patients with cognitive impairment at baseline. However, GBA-PD experiences lower efficacy on motor disability and complications and faster cognitive decline than noncarriers.

Autonomic failure has a major impact on the quality of life of individuals with Parkinson’s disease (PD), especially in advanced stages of the disease. Levodopa/carbidopa intestinal gel (LCIG) infusion is a well-established treatment for advanced PD with severe motor fluctuations and provides substantial benefit in managing some non-motor symptoms (NMS), such as sleep, fatigue, and neuropsychiatric issues. The effect of LCIG on autonomic symptoms is by contrast not well known. Here we performed a systematic review on the influence of LCIG therapy on autonomic dysfunction in PD individuals. Following the PRISMA guidelines, we systematically searched for studies that included autonomic outcome measures in LCIG-treated PD individuals, limiting the search to articles written in English and published between January 2005 and June 2023. We evaluated improvement, stability, or worsening of gastrointestinal, urinary, and cardiovascular symptoms at six different timepoints according to clinimetric scale changes compared to baseline. Data on autonomic adverse events (AEs) possibly related to LCIG treatment were also collected. Of the 1476 studies identified in the initial search, 16 ultimately met the inclusion criteria and underwent quality assessment and data extraction, with data from 1361 PD patients (18.3 months mean follow-up). Thirteen studies reported improvement or stability of gastrointestinal, urinary, and cardiovascular symptoms over the interventional period. One study found a worsening of cardiovascular symptoms and two of urological symptoms. Regarding safety, seven studies reported gastrointestinal (8.4

Facial movements are crucial for social and emotional interaction and well-being. Reduced facial expressions (i.e., hypomimia) is a common feature in patients with Parkinson’s disease (PD) and previous studies linked this manifestation to both motor symptoms of the disease and altered emotion recognition and processing. Nevertheless, research on facial motor impairment in PD has been rather scarce and only a limited number of clinical evaluation tools are available, often suffering from poor validation processes and high inter- and intra-rater variability. In recent years, the availability of technology-enhanced quantification methods of facial movements, such as automated video analysis and machine learning application, led to increasing interest in studying hypomimia in PD. In this narrative review, we summarize the current knowledge on pathophysiological hypotheses at the basis of hypomimia in PD, with particular focus on the association between reduced facial expressions and emotional processing and analyze the current evaluation tools and management strategies for this symptom, as well as future research perspectives.

Axial postural abnormalities (PA) are invalidating symptoms of Parkinson's disease (PD). Risk factors for PA are unknown. We sought to evaluate PA incidence and risk factors over the first 4–6 years of PD. We included 441 PD patients from the Parkinson's Progression Markers Initiative (PPMI) cohort with data at diagnosis and after 4-year follow-up. PA was defined according to a posture item ≥ 2 at the Movement Disorder Society-sponsored-revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) in Off therapeutic condition. The Kruskal–Wallis test was used to compare characteristics of patients without PA (‘no-PA’), with PA at disease onset (‘baseline-PA’), and PA developed during follow-up (‘develop-PA’). To identify predictors of PA development, univariate and multivariate Cox regression analyses were performed considering demographic, clinical and therapeutic variables. 10.9

The association between cerebral hemodynamics and cognitive impairment has been reported in neurodegenerative and cerebrovascular disorders (CVD). However, it is still unclear whether changes occur in the acute phase of CVD. Here we investigated cognitive and hemodynamic parameters and their association in patients with CVD during the acute and subacute phases. Seventy-three patients with mild stroke, not undergoing endovascular treatment, were recruited. All subjects were devoid of intracranial or external carotid stenosis, significant chronic cerebrovascular pathology, dementia or non-compensated cardiovascular diseases. Patients were evaluated within 7 days from symptoms onset (T1) and after 3 months (T2). Clinical and demographic data were collected. NIHSS, MoCA, FAB, and Word-Color Stroop test (WCST) were used to evaluate disease severity and cognitive functions. Basal hemodynamic parameters in the middle cerebral artery were measured with transcranial Doppler. Differences between T2 and T1, correlations between cognitive and hemodynamic variables at T1 and T2, as well as correlations between the T2-T1 variation in cognitive and hemodynamic parameters were assessed. At T1, cognitive performance of MoCA, FAB, and WCST was lower compared with T2; and pulsatility index, a parameter reflecting distal vascular resistance, was higher. However, no correlations between the changes in cognitive and hemodynamic variables were found; therefore, the two seems to be independent phenomena. In the acute phase, the linear association between cerebral blood flow and cognitive performances was lost, probably due to a differential effect of microenvironment changes and vascular-specific phenomena on cognition and cerebral hemodynamics. This relationship was partially restored in the subacute phase.

Background: Dyskinesias and freezing of gait are episodic disorders in Parkinson’s disease, characterized by a fluctuating and unpredictable nature. This cross-sectional study aims to objectively monitor Parkinsonian patients experiencing dyskinesias and/or freezing of gait during activities of daily living and assess possible changes in spatiotemporal gait parameters. Methods: Seventy-one patients with Parkinson’s disease (40 with dyskinesias and 33 with freezing of gait) were continuously monitored at home for a minimum of 5 days using a single wearable sensor. Dedicated machine-learning algorithms were used to categorize patients based on the occurrence of dyskinesias and freezing of gait. Additionally, specific spatiotemporal gait parameters were compared among patients with and without dyskinesias and/or freezing of gait. Results: The wearable sensor algorithms accurately classified patients with and without dyskinesias as well as those with and without freezing of gait based on the recorded dyskinesias and freezing of gait episodes. Standard spatiotemporal gait parameters did not differ significantly between patients with and without dyskinesias or freezing of gait. Both the time spent with dyskinesias and the number of freezing of gait episodes positively correlated with the disease severity and medication dosage. Conclusions: A single inertial wearable sensor shows promise in monitoring complex, episodic movement patterns, such as dyskinesias and freezing of gait, during daily activities. This approach may help implement targeted therapeutic and preventive strategies for Parkinson’s disease.

BACKGROUND:Glioblastoma (GBM) represents an aggressive and common tumor of the central nervous system. The prognosis of GBM is poor, and despite a refined genetic and molecular characterization, pharmacological treatment is largely suboptimal. OBJECTIVE:Contribute to defining a therapeutic line in GBM targeting the mGlu3 receptor in line with the principles of precision medicine. METHODS:Here, we performed a computational analysis focused on the expression of type 3 and 5 metabotropic glutamate receptor subtypes (mGlu3 and mGlu5, respectively) in high- and low-grade gliomas. RESULTS:The analysis allowed the identification of a particular high-grade glioma type, characterized by a high expression level of both receptor subtypes and by other markers of excitatory and inhibitory neurotransmission. This so-called neurotransmitter-GBM (NT-GBM) also shows a distinct immunological, metabolic, and vascularization gene signature. CONCLUSION:Our findings might lay the groundwork for a targeted therapy to be specifically applied to this putative novel type of GBM.

Type-B monoamine oxidase inhibitors, encompassing selegiline, rasagiline, and safinamide, are available to treat Parkinson's disease. These drugs ameliorate motor symptoms and improve motor fluctuation in the advanced stages of the disease. There is also evidence supporting the benefit of type-B monoamine oxidase inhibitors on non-motor symptoms of Parkinson's disease, such as mood deflection, cognitive impairment, sleep disturbances, and fatigue. Preclinical studies indicate that type-B monoamine oxidase inhibitors hold a strong neuroprotective potential in Parkinson's disease and other neurodegenerative diseases for reducing oxidative stress and stimulating the production and release of neurotrophic factors, particularly glial cell line-derived neurotrophic factor, which support dopaminergic neurons. Besides, safinamide may interfere with neurodegenerative mechanisms, counteracting excessive glutamate overdrive in basal ganglia motor circuit and reducing death from excitotoxicity. Due to the dual mechanism of action, the new generation of type-B monoamine oxidase inhibitors, including safinamide, is gaining interest in other neurological pathologies, and many supporting preclinical studies are now available. The potential fields of application concern epilepsy, Duchenne muscular dystrophy, multiple sclerosis, and above all, ischemic brain injury. The purpose of this review is to investigate the preclinical and clinical pharmacology of selegiline, rasagiline, and safinamide in Parkinson's disease and beyond, focusing on possible future therapeutic applications.

Daily steps could be a valuable indicator of real-world ambulation in Parkinson’s disease (PD). Nonetheless, no study to date has investigated the minimum number of days required to reliably estimate the average daily steps through commercial smartwatches in people with PD. Fifty-six patients were monitored through a commercial smartwatch for 5 consecutive days. The total daily steps for each day was recorded and the average daily steps was calculated as well as the working and weekend days average steps. The intraclass correlation coefficient (ICC) (3,k), standard error of measurement (SEM), Bland–Altman statistics, and minimum detectable change (MDC) were used to evaluate the reliability of the step count for every combination of 2–5 days. The threshold for acceptability was set at an ICC ≥ 0.8 with a lower bound of CI 95% ≥ 0.75 and a SAM < 10%. ANOVA and Mann–Whitney tests were used to compare steps across the days and between the working and weekend days, respectively. Four days were needed to achieve an acceptable reliability (ICC range: 0.84–0.90; SAM range: 7.8–9.4%). In addition, daily steps did not significantly differ across the days and between the working and weekend days. These findings could support the use of step count as a walking activity index and could be relevant to developing monitoring, preventive, and rehabilitation strategies for people with PD.

: Symptoms of cognitive impairment are rather common since the early stage of Parkinson’s disease (PD); they aggravate with disease progression and may lead to dementia in a significant proportion of cases. Worsening of cognitive symptoms in PD patients depends on the progression of subcortical dopaminergic damage as well as the involvement of other brain neurotransmitter systems in cortical and subcortical regions. Beyond the negative impact on disability and quality of life, the presence and severity of cognitive symptoms may limit adjustments of dopamine replacement therapy along the disease course. : This review focuses on the consequences of the administration of monoamine-oxidase type Binhibitors (MAOB-I) on cognition in PD patients. Two drugs (selegiline and rasagiline) are available for the treatment of motor symptoms of PD as monotherapy or in combination with L-DOPA or dopamine agonists in stable and fluctuating patients; a further drug (safinamide) is usable in fluctuating subjects solely. : The results of available studies indicate differential effects according to disease stage and drug features. In early, non-fluctuating patients, selegiline and rasagiline ameliorated prefrontal executive functions, similarly to other dopaminergic drugs. Benefit on some executive functions was maintained in more advanced, fluctuating patients, despite the tendency of worsening prefrontal inhibitory control activity. Interestingly, high-dose safinamide improved inhibitory control in fluctuating patients. The benefit of high-dose safinamide on prefrontal inhibitory control mechanisms may stem from its dual mechanism of action, allowing reduction of excessive glutamatergic transmission, in turn secondary to increased cortical dopaminergic input.

OBJECTIVE: Opicapone (OPC) is a third-generation peripheral catechol-O-methyl transferase inhibitor (COMT-i) approved as add-on therapy to levodopa/DOPA decarboxylase inhibitors (DDCI) combinations in Parkinson’s disease (PD) patients with end-of-dose motor fluctuations. While the OPC effectiveness on motor symptoms is well known, there is still uncertainty about the timing of introduction, the management of levodopa dose, and the efficacy on non-motor symptoms (NMS). SUBJECTS AND METHODS: A group of PD experts participated in a consensus activity composed of the Nominal Group Technique (NGT) and the Delphi method to better define the role of OPC. A list of statements was defined with the NGT and voted on through an online Delphi process by a panel of 85 Italian clinicians. RESULTS: 24 statements were selected for the Delphi voting. Most statements (n=15, 62%) reached a consensus. A wide agreement was reached about the efficacy of OPC in treating motor fluctuations, including early morning akinesia and nocturnal akinesia. The panel widely agreed about the effectiveness of OPC in early fluctuating patients. The long-lasting inhibitory effect of OPC was recognized as an advantage over other COMT-i, resulting in a single daily dose and greater ease of introduction into the levodopa therapeutic regimen. CONCLUSIONS: The efficacy of OPC observed in the clinical trials for the management of PD patients with motor fluctuations is also experienced in clinical practice. The review of the current positioning of OPC from the late to early stages of the disease may represent an important step in the evolution of the PD therapeutic approach.

Background: Levodopa-carbidopa intestinal gel (LCIG) improves motor and non-motor symptoms in patients with advanced Parkinson’s disease (aPD). Objective: To present the final 36-month efficacy and safety results from DUOGLOBE (DUOdopa/Duopa in Patients with Advanced Parkinson’s Disease – a GLobal OBservational Study Evaluating Long-Term Effectiveness; NCT02611713). Methods: DUOGLOBE was an international, prospective, long-term, real-world, observational study of patients with aPD initiating LCIG in routine clinical care. The primary endpoint was change in patient-reported “Off” time to Month 36. Safety was assessed by monitoring serious adverse events (SAEs). Results: Significant improvements in “Off” time were maintained over 3 years (mean [SD]: –3.3 hours [3.7]; p < 0.001). There were significant improvements to Month 36 in total scores of the Unified Dyskinesia Rating Scale (–5.9 [23.7]; p = 0.044), Non-Motor Symptoms Scale (–14.3 [40.5]; p = 0.002), Parkinson’s Disease Sleep Scale-2 (–5.8 [12.9]; p < 0.001), and Epworth Sleepiness Scale (–1.8 [6.0]; p = 0.008). Health-related quality of life and caregiver burden significantly improved through Months 24 and 30, respectively (Month 24, 8-item Parkinson’s Disease Questionnaire Summary Index, –6.0 [22.5]; p = 0.006; Month 30, Modified Caregiver Strain Index, –2.3 [7.6]; p = 0.026). Safety was consistent with the well-established LCIG profile (SAEs: 54.9% of patients; discontinuations: 54.4%; discontinuations due to an adverse event: 27.2%). Of 106 study discontinuations, 32 patients (30.2%) continued LCIG outside the study. Conclusion: DUOGLOBE demonstrates real-world, long-term, reductions in motor and non-motor symptoms in patients with aPD treated with LCIG.