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BACKGROUND AND PURPOSE: Although there is extensive evidence about the safety of monoclonal antibodies against calcitonin gene-related peptide (anti-CGRP mAbs) in combination with traditional drugs, scarce data are available on the safety of their combination with other mAbs. This study aimed to evaluate the 6-month effectiveness and tolerability of anti-CGRP mAbs in combination with other mAbs for different diseases. METHODS: Patients included in the Italian Headache Registry and treated concomitantly with an anti-CGRP mAb and another mAb were included. Effectiveness outcomes for migraine included reduction from baseline of monthly headache days (MHDs), Migraine Disability Assessment (MIDAS) score, Headache Impact Test-6 (HIT-6) scores, and Patients' Global Impression of Change (PGIC) scale. Adverse events (AEs) were recorded. RESULTS: Thirty-eight patients were included. In 27 patients (71.1%), the anti-CGRP mAb was added to a previously ongoing mAb. Nine patients (23.7%) discontinued one of the two mAbs before the end of treatment (seven discontinued the anti-CGRP mAb and two the other mAb). One patient discontinued for AEs. Anti-CGRP mAbs were discontinued due to ineffectiveness (n = 5, 55.5%) and one each (11.1%) for clinical remission and lost to follow-up. MHDs significantly decreased from baseline to 3 months (p < 0.0001) and 6 months (p < 0.001), as did the MIDAS and the HIT-6 scores at 3 and 6 months (p < 0.001). For anti-CGRP mAbs, 27.4% of patients reported PGIC ≥ 5 at 3 months and 48.3% at 6 months. Mild AEs associated with introduction of a second mAb were detected in six patients (15.8%). CONCLUSIONS: In this real-world study, anti-CGRP mAbs showed safety and effectiveness when administered concomitantly with other mAbs.

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BACKGROUND: Data regarding unequal diagnostic and therapeutic access in patients with acute stroke based on ethnicity and race are inconclusive in Europeans. The objectives of our study were to evaluate the effect of race/ethnicity on access to acute stroke care and treatments and outcomes. METHODS: In this retrospective cohort study, we enrolled adult patients admitted to the emergency department of a comprehensive stroke center for suspected stroke. Based on race/ethnicity, patients were divided into two main groups: Western European Whites (WEW) and non-Western European Whites (nWEW). We also divided the nWEW group into four subgroups based on the Office of Management and Budget classification of human races and ethnicities (White-Others, Hispanic, Asian, Black). Univariate comparisons and logistic regression analyses were also performed. RESULTS: 9167 patients were enrolled in the study: 582 in the nWEW and 8585 in the WEW group. Patients with ischemic stroke in the nWEW group were significantly younger than those in the other group (p < 0.001). Once adjusted for possible confounders, belonging to the nWEW group was found to be an independent predictor of a lower likelihood of receiving revascularization treatments (p = 0.006), regardless similar onset-to-door times. There were no differences in stroke outcomes and prevalence of stroke mimic diagnosis between the groups. CONCLUSIONS: Racial/ethnic disparities in healthcare represent a challenging issue, even in universal healthcare systems, that should be addressed promptly through education campaigns of healthcare personnel and implementation measures, such as integrating readily available interpreter staff for medical emergencies.

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INTRODUCTION: Status Epilepticus (SE) can occur in patients without a previous epilepsy diagnosis, a condition identified as "new-onset status epilepticus" (NOSE). Treatment with benzodiazepine may fail in NOSE termination, requiring anti-seizure medication (ASM) employment. The term "established NOSE" (eNOSE) is generally employed in this context. This study aims to describe the main clinical characteristics of a large sample of patients suffering from eNOSE, compare the ASM efficacy, and explore the risk factors associated with ASM treatment unresponsiveness and eNOSE-associated mortality. METHODS: Adult patients diagnosed with eNOSE were retrospectively selected between January 2016 and December 2022. We reviewed demographics, clinical data, diagnostic work-up, and treatment. We considered the last ASM introduced before the eNOSE termination as effective. RESULTS: 123 patients were included (age: 67.9 ± 17.3). eNOSE acute etiology was mostly reported. In the overall cohort, phenytoin showed the highest response rate (p = 0.01). In the pairwise comparisons, valproate was superior to levetiracetam (p = 0.02) but not to lacosamide (p = 0.50). Phenytoin had a significantly higher resolution rate than levetiracetam (p = 0.001) but not lacosamide (p = 0.14). Thirty patients were refractory to ASM treatment. No predictors of refractoriness were identified. Thirty-nine patients died. Age and GCS were identified as eNOSE-related mortality risk factors. CONCLUSION: eNOSE frequently has an acute etiology with several associated syndromes. Phenytoin is more effective in managing eNOSE, even though lacosamide, valproate, and levetiracetam can represent further therapeutic options. Age and GCS are the main risk factors for eNOSE-associated mortality.

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BACKGROUND: Sarcopenia, defined as the loss of skeletal muscle mass, has been associated with a worse functional outcome after stroke. Measurement of temporal muscle thickness (TMT) has been introduced as an easily obtainable surrogate marker to identify patients with sarcopenia. Our study aims to investigate the correlation between pre-stroke sarcopenia, measured by TMT assessment, and functional outcome in patients treated with revascularization procedures for acute ischemic stroke. METHODS: We included consecutive adult patients who underwent thrombolysis, endovascular thrombectomy or both for acute ischemic stroke at our Centre from January 2020 to June 2022. Besides collecting baseline clinical and neuroradiological features, TMT was measured on brain computed tomography scans according to a standardized protocol. Modified Rankin Scale (mRS) scores at 3 months represented the main endpoint of functional outcome. RESULTS: A total of 261 patients were available for the analysis. In univariate models, patients with excellent outcomes (mRS = 0-1) were younger, had higher TMT values and lower pre-event disability and stroke severity. In multivariate models higher TMT values resulted independently associated with reduced mortality (Odds Ratio 0.708, 95% Confidence Interval 0.538-0.930, p = 0.013). Age, diabetes, brain bleeding events and stroke severity were found to be predictors of mortality, too. CONCLUSIONS: Our retrospective analysis shows that in patients who underwent revascularization treatments for ischemic stroke TMT is as an independent predictor of survival easily obtainable from the baseline CT scan. Further investigation is required to confirm the role of sarcopenia assessment and TMT measurement in the prognostication toolkit of this disease.

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A 52-year-old man experienced two seizures in January and June 2021. In October, the neurological examination did not reveal sensory/motor deficits. Brain magnetic resonance imaging (MRI) showed hyperintense lesions with contrast enhancement (CE) involving white matter bilaterally, brainstem, and cerebellum. Spine MRI showed hyperintense C2-C3 and C4-C6 lesions with CE. Anti-aquaporin-4 (AQP4) antibodies were detected, confirming the diagnosis of neuromyelitis optica spectrum disorder (NMOSD). The patient experienced a status epilepticus compatible with Epilepsia Partialis Continua treated with antiseizure medications. He was also treated with methylprednisolone, plasma exchange, and rituximab. Status epilepticus can be a rare manifestation of NMOSD, heightening the broad spectrum of AQP4 autoimmunity.

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BACKGROUND: Automated pupillometry (AP) is a handheld, non-invasive tool that is able to assess pupillary light reflex dynamics and is useful for the detection of intracranial hypertension. Limited evidence is available on acute ischemic stroke (AIS) patients. The primary objective was to evaluate the ability of AP to discriminate AIS patients from healthy subjects (HS). Secondly, we aimed to compute a predictive score for AIS diagnosis based on clinical, demographic, and AP variables. METHODS: We included 200 consecutive patients admitted to a comprehensive stroke center who underwent AP assessment through NPi-200 (NeurOptics®) within 72 h of stroke onset and 200 HS. The mean values of AP parameters and the absolute differences between the AP parameters of the two eyes were considered in the analyses. Predictors of stroke diagnosis were identified through univariate and multivariate logistic regressions; we then computed a nomogram based on each variable's ß coefficient. Finally, we developed a web app capable of displaying the probability of stroke diagnosis based on the predictive algorithm. RESULTS: A high percentage of pupil constriction (CH, p < 0.001), a low constriction velocity (CV, p = 0.002), and high differences between these two parameters (p = 0.036 and p = 0.004, respectively) were independent predictors of AIS. The highest contribution in the predictive score was provided by CH, the Neurological Pupil Index, CV, and CV absolute difference, disclosing the important role of AP in the discrimination of stroke patients. CONCLUSIONS: The results of our study suggest that AP parameters, and in particular, those concerning pupillary constriction, may be useful for the early diagnosis of AIS.

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PURPOSE: To evaluate ophthalmological, neurological, radiological, and laboratory data in patients with multiple sclerosis (MS) and to identify new ophthalmological factors that could be helpful as biomarkers of the disease, potentially leading to an earlier prediction of disease course and disability progression. DESIGN: Retrospective, cross-sectional-study. METHODS: Best-corrected visual acuity (BCVA), ophthalmological biomicroscopy of the anterior segment and fundus, structural optical coherence tomography (OCT) with retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC), and OCT angiography (OCTA) with vascular density (VD) were performed. The following clinical and neuro-radiological features were assessed: MS phenotype, disease duration, clinical severity, type of treatment, and T2-weighted lesion and T1-weighted Gd+ enhancing lesion number on the brain and spinal cord MRI. RESULTS: One hundred and six patients (212 eyes) were analyzed. Sixty-six of them (62.2%) had MS and 40 (37.8%) were matched healthy controls (HCs). patients with MS showed lower RNFL, GCC, and VD in the radial peripapillary capillary plexus than controls in both eyes (P < .05). By Performing a logistic regression with a distinct MS outcome for both eyes, we were able to demonstrate that the value that was most predictive of MS was the average GCC thickness (P = .009). Regression analysis demonstrated that patients with a higher T2-weighted lesions showed a lower RNFL thickness value and reduced GCC and VD values than those with a low lesion load (P < .01 and P < .05, respectively). Similarly, relapsing MS patients showed lower RNFL values (P < .05). CONCLUSIONS: Several OCT and OCTA-optic nerve parameters could be useful prognostic biomarkers for the MS disease course in clinical practice. However, it is necessary to do additional research with larger sample sizes in order to validate these findings.

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Background: The Free and Cued Selective Reminding Test (FCSRT), assessing verbal episodic memory with controlled learning and semantic cueing, has been recommended for detecting the genuine encoding and storage deficits characterizing AD-related memory disorders. Objective: The present study aims at investigating the ability of FCSRT in predicting cerebrospinal fluid (CSF) evidence of amyloid-ß positivity in subjects with amnestic mild cognitive impairment (aMCI) and exploring its associations with amyloidopathy, tauopathy and neurodegeneration biomarkers. Methods: 120 aMCI subjects underwent comprehensive neurological and neuropsychological examinations, including the FCSRT assessment, and CSF collection; CSF Aß42/40 ratio, p-tau181, and total-tau quantification were conducted by an automated CLEIA method on Lumipulse G1200. Based on the Aß42/40 ratio value, subjects were classified as either A+ or A-. Results: All FCSRT subitem scores were significantly lower in A+ group and significantly predicted the amyloid-ß status, with Immediate Total Recall (ITR) being the best predictor. No significant correlations were found between FCSRT and CSF biomarkers in the A- aMCI group, while in the A+ aMCI group, all FCSRT subitem scores were negatively correlated with CSF p-tau181 and total-tau, but not with the Aß42/40 ratio. Conclusions: FCSRT confirms its validity as a tool for the diagnosis of AD, being able to predict the presence of amyloid-ß deposition with high specificity. The associations between FCSRT subitem scores and CSF p-tau-181 and total-tau levels in aMCI due to AD could further encourage the clinical use of this simple and cost-effective test in the evaluation of individuals with aMCI.

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INTRODUCTION: Formulating reliable prognosis for ischemic stroke patients remains a challenging task. We aimed to develop an artificial intelligence model able to formulate in the first 24 h after stroke an individualized prognosis in terms of NIHSS. PATIENTS AND METHODS: Seven hundred ninety four acute ischemic stroke patients were divided into a training (597) and testing (197) cohort. Clinical and instrumental data were collected in the first 24 h. We evaluated the performance of four machine-learning models (Random Forest, K-Nearest Neighbors, Support Vector Machine, XGBoost) in predicting NIHSS at discharge both in terms of variation between discharge and admission (regressor approach) and in terms of severity class namely NIHSS 0-5, 6-10, 11-20, >20 (classifier approach). We used Shapley Additive exPlanations values to weight features impact on predictions. RESULTS: XGBoost emerged as the best performing model. The classifier and regressor approaches perform similarly in terms of accuracy (80% vs 75%) and f1-score (79% vs 77%) respectively. However, the regressor has higher precision (85% vs 68%) in predicting prognosis of very severe stroke patients (NIHSS > 20). NIHSS at admission and 24 hours, GCS at 24 hours, heart rate, acute ischemic lesion on CT-scan and TICI score were the most impacting features on the prediction. DISCUSSION: Our approach, which employs an artificial intelligence based-tool, inherently able to continuously learn and improve its performance, could improve care pathway and support stroke physicians in the communication with patients and caregivers. CONCLUSION: XGBoost reliably predicts individualized outcome in terms of NIHSS at discharge in the first 24 hours after stroke.

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The frequency of corticospinal tract (CST) T2/FLAIR hyperintensity in disorders with neuroglial antibodies is unclear. Herein, we retrospectively reviewed brain MRIs of 101 LGI1-antibody encephalitis patients, and observed CST hyperintensity in 30/101 (30%). It was mostly bilateral (93%), not associated with upper motor neuron signs/symptoms (7%), and frequently decreased over time (39%). In a systematic review including patients with other neuroglial antibodies, CST hyperintensity was reported in 110 with neuromyelitis optica (94%), myelin oligodendrocyte glycoprotein-associated disease (2%), Ma2-antibody (3%) and GAD65-antibody paraneoplastic neurological syndrome (1%). CST hyperintensity is not an infrequent finding in LGI1-Ab encephalitis and other disorders with neuroglial antibodies.

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A few cases of multiple sclerosis (MS) onset after COVID-19 vaccination have been reported, although the evidence is insufficient to establish causality. The aim of this study is to compare cases of newly diagnosed relapsing-remitting MS before and after the outbreak of the COVID-19 pandemic and the impact of COVID-19 vaccination. Potential environmental and genetic predisposing factors were also investigated, as well as clinical patterns. This is a single-centre retrospective cohort study including all patients who presented with relapsing-remitting MS onset between January 2018 and July 2022. Data on COVID-19 vaccination administration, dose, and type were collected. HLA-DRB1 genotyping was performed in three subgroups. A total of 266 patients received a new diagnosis of relapsing-remitting MS in our centre, 143 before the COVID-19 pandemic (until and including March 2020), and 123 during the COVID-19 era (from April 2020). The mean number of new MS onset cases per year was not different before and during the COVID-19 era and neither were baseline patients' characteristics, type of onset, clinical recovery, or radiological patterns. Fourteen (11.4%) patients who subsequently received a new diagnosis of MS had a history of COVID-19 vaccination within one month before symptoms onset. Patients' characteristics, type of onset, clinical recovery, and radiological patterns did not differ from those of patients with non-vaccine-related new diagnoses of MS. The allele frequencies of HLA-DRB1*15 were 17.6% and 22.2% in patients with non-vaccine-related disease onset before and during the COVID-19 era, respectively, while no case of HLA-DRB1*15 was identified among patients with a new diagnosis of MS post-COVID-19 vaccine. In contrast, HLA-DRB1*08+ or HLA-DRB1*10+ MS patients were present only in this subgroup. Although a causal link between COVID-19 vaccination and relapsing-remitting MS cannot be detected, it is interesting to note and speculate about the peculiarities and heterogeneities underlying disease mechanisms of MS, where the interactions of genetics and the environment could be crucial also for the follow-up and the evaluation of therapeutic options.

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BACKGROUND: Recent randomized trials have shown the benefit of mechanical thrombectomy (MT) also in patients with an established large ischemic core. AIMS: The purpose of this study was to define baseline predictors of clinical outcome in patients with large vessel occlusion (LVO) in the anterior circulation and an Alberta Stroke Program Early CT score (ASPECTS) ⩽ 5, undergoing MT. MATERIAL AND METHODS: The databases of 16 comprehensive stroke centers were retrospectively screened for patients with LVO and ASPECTS ⩽5 that received MT. Baseline clinical and neuroradiological features, including the differential contribution of all ASPECTS regions to the composite score, were collected. Primary clinical outcome measure was a 90-day modified Rankin Scale (mRS) score of 0-2. Statistical analysis used a logistic regression model and random forest algorithm. RESULTS: A total of 408 patients were available for analysis. In multivariate model, among baseline features, lower age (odd ratio (OR) = 0.962, 95% confidence interval (CI) = 0.943-0.982) and lower National Institute of Health Stroke Scale (NIHSS) score (OR = 0.911, 95% CI = 0.862-0.963) were associated with the mRS score 0-2. Involvement of the M2 (OR = 0.398, 95% CI = 0.206-0.770) or M4 (OR = 0.496, 95% CI = 0.260-0.945) ASPECTS regions was associated with an unfavorable outcome. Random forest analysis confirmed that age and baseline NIHSS score are the most important variables influencing clinical outcome, whereas involvement of cortical regions M5, M4, M2, and M1 can have a negative impact. CONCLUSION: Our retrospective analysis shows that, along with age and baseline clinical impairment, presence of early ischemic changes involving cortical areas has a role in clinical outcome in patients with large ischemic core undergoing MT. DATA ACCESS STATEMENT: The data that support the findings of this study are available upon reasonable request.

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Multiple sclerosis is a debilitating autoimmune disease, characterized by chronic inflammation of the central nervous system. While the significance of the gut microbiome on multiple sclerosis pathogenesis is established, the underlining mechanisms are unknown. We found that serum levels of the microbial postbiotic tryptophan metabolite indole-3-carboxaldehyde (3-IAld) inversely correlated with disease duration in multiple sclerosis patients. Much like the host-derived tryptophan derivative L-Kynurenine, 3-IAld would bind and activate the Aryl hydrocarbon Receptor (AhR), which, in turn, controls endogenous tryptophan catabolic pathways. As a result, in peripheral lymph nodes, microbial 3-IAld, affected mast-cell tryptophan metabolism, forcing mast cells to produce serotonin via Tph1. We thus propose a protective role for AhR-mast-cell activation driven by the microbiome, whereby natural metabolites or postbiotics will have a physiological role in immune homeostasis and may act as therapeutic targets in autoimmune diseases.

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BACKGROUND: Among university students, migraine is notably prevalent and is linked to compromised academic performance and daily functioning. Medical students are a particularly vulnerable category due to the demanding nature of their training, as they are often exposed to headache trigger factors. We therefore aimed to determine the prevalence, characteristics, and healthcare-seeking practices of primary headaches among Italian medical students. METHODS: We conducted a cross-sectional study among medical students attending the Università Cattolica del Sacro Cuore in Rome who completed a self-administered questionnaire designed following the International Classification of Headache Disorders-3 criteria. The questionnaire assessed sociodemographic and headache features, healthcare utilization, the use of symptomatic and preventive treatment, and headache trigger factors. RESULTS: Five hundred thirty-six students filled out the questionnaire. The lifetime and last-year prevalence of headache in this cohort was 76.7% (n = 411). Among the students surveyed, migraine had a prevalence of 26.9%, probable migraine of 12.9%, and tension-type headache (TTH)/probable TTH of 36.9%. Two hundred and forty-six students (59.8%) reported that their headache worsened after starting university. All students reporting headache had at least one trigger factor. In students fulfilling the criteria for migraine (n = 144), 137 (95.1%) had previously used acute non-prescription treatments, and eight concurrently used a preventive treatment. Thirty-five students fulfilling the criteria for migraine underwent a brain MRI scan (24.3%), 43 performed a neurological evaluation (29.9%), 36 received a diagnosis of migraine (25%), and 20 (13.9%) accessed the emergency room. DISCUSSION: Migraine and TTH are common among medical students in Italy despite low healthcare resource utilization. These results support the need to promote public health policies and strategies in order to reduce the disability and burden associated with primary headaches among medical students.

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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.

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BACKGROUND AND PURPOSE: Myopathies are associated with classic signs and symptoms, but also with possible life-threatening complications that may require assistance in an emergency setting. This phenomenon is understudied in the literature. We aimed to assess the presentation, management, and outcomes of clinical manifestations potentially related to a muscle disorder requiring referral to the adult emergency department (ED) and hospitalization. METHODS: Anonymized patient data retrieved using the International Classification of Diseases, Ninth Revision codes related to muscle disorders over 4 years were retrospectively analyzed. Medical reports were evaluated to extract demographic and clinical variables, along with outcomes. Two groups were defined based on the presence (known diagnosis [KD] group) or absence (unknown diagnosis [UD] group) of a diagnosed muscle disorder at arrival. RESULTS: A total of 244 patients were included, 51% of whom were affected by a known myopathy, predominantly limb-girdle muscular dystrophies and myotonic dystrophies. The main reasons for ED visits in the KD group were respiratory issues, worsening of muscle weakness, and gastrointestinal problems. Heart complications were less prevalent. In the UD group, 27 patients received a new diagnosis of a specific primary muscle disorder after the ED access, mostly an inflammatory myopathy. Death during hospitalization was recorded in 26 patients, with a higher rate in the KD group and in patients affected by mitochondrial and inflammatory myopathies. Sepsis and dyspnea were associated with increased death risk. CONCLUSIONS: Respiratory complications are the most common reason for myopathic patients accessing the ED, followed by gastrointestinal issues. Infections are severe threats and, once hospitalized, these patients have relatively high mortality.

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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.

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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.

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Cognitive disorders are increasingly recognized in Parkinson disease (PD), even in early disease stages, and memory is one of the most affected cognitive domains. Classically, hippocampal cholinergic system dysfunction was associated with memory disorders, whereas nigrostriatal dopaminergic system impairment was considered responsible for executive deficits. Evidence from PD studies now supports involvement of the amygdala, which modulates emotional attribution to experiences. Here, we propose a tripartite model including the hippocampus, striatum and amygdala as key structures for cognitive disorders in PD. First, the anatomo-functional relationships of these structures are explored and experimental evidence supporting their role in cognitive dysfunction in PD is summarized. We then discuss the potential role of α-synuclein, a pathological hallmark of PD, in the tripartite memory system as a key mechanism in the pathogenesis of memory disorders in the disease.

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Levodopa-induced dyskinesias (LIDs) are a common complication in patients with Parkinson's disease (PD). A complex cascade of electrophysiological and molecular events that induce aberrant plasticity in the cortico-basal ganglia system plays a key role in the pathophysiology of LIDs. In the striatum, multiple neurotransmitters regulate the different forms of physiological synaptic plasticity to provide it in a bidirectional and Hebbian manner. In PD, impairment of both long-term potentiation (LTP) and long-term depression (LTD) progresses with disease and dopaminergic denervation of striatum. The altered balance between LTP and LTD processes leads to unidirectional changes in plasticity that cause network dysregulation and the development of involuntary movements. These alterations have been documented, in both experimental models and PD patients, not only in deep brain structures but also at motor cortex. Invasive and non-invasive neuromodulation treatments, as deep brain stimulation, transcranial magnetic stimulation, or transcranial direct current stimulation, may provide strategies to modulate the aberrant plasticity in the cortico-basal ganglia network of patients affected by LIDs, thus restoring normal neurophysiological functioning and treating dyskinesias. In this review, we discuss the evidence for neuroplasticity impairment in experimental PD models and in patients affected by LIDs, and potential neuromodulation strategies that may modulate aberrant plasticity.

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