Non-motor symptoms (NMSs) are highly prevalent in Parkinson’s disease (PD) and affect patients’ quality of life. Data on gender differences in NMSs are largely cross-sectional and derived from chronically treated populations. Longitudinal evidence in early, levodopa-naïve PD patients remains limited. This study aims to longitudinally investigate gender differences in a wide range of NMSs in early-stage levodopa-naïve PD patients during the first 2 years following levodopa initiation. This multicenter, prospective study enrolled 216 levodopa-naïve PD patients (139 men, 77 women) from 17 Italian movement disorder centers. Patients were evaluated at baseline and after 24 months (24 M) using validated scales. Baseline gender differences were explored using group comparisons. Gender effects at 24 M were examined using ANCOVA models adjusted for baseline values and levodopa dose at follow-up. At baseline, women showed greater cardiovascular and thermoregulatory autonomic dysfunction, higher anxiety, pain, fatigue, and worse quality of life, whereas men exhibited greater sexual dysfunction, daytime sleepiness, and better attentional performance. At the 24 M, gender differences persisted only for anxiety, pain, mobility, and emotional well-being, while additional significant differences emerged, including hypersexuality, visuo- spatial domain, and orthostatic-hypotension. Women exhibited greater symptom severity than men across all aforementioned variables, with the exception of hypersexuality. Gender significantly influences the expression and early evolution of NMSs in PD, independently of levodopa exposure. Gender-specific NMSs profiles are already evident in the first two years of treatment. These findings highlight the importance of integrating gender considerations into early assessment and personalized management of NMSs in PD.

BACKGROUND AND OBJECTIVES:Idiopathic normal pressure hydrocephalus (iNPH) is characterized by gait disturbance, cognitive decline, and urinary incontinence and may include parkinsonism. The underlying mechanism of parkinsonism in iNPH-whether neurodegenerative or mechanical-remains unclear. This study aimed to assess nigrostriatal integrity in iNPH patients with parkinsonism using dopaminergic transporter imaging (DAT-SPECT) and nigrosome MRI. METHODS:This prospective study was conducted at the Movement Disorders Clinic, Santa Chiara Hospital, Pisa University, from 2021 to 2023. Inclusion criteria for the iNPH group included the following: (1) clinical diagnosis of probable iNPH per the 2021 Japanese Society Guidelines and (2) parkinsonism per United Kingdom Parkinson's Disease Society Brain Bank criteria. An equal number of patients with Parkinson disease (PD), matched for age and sex, served as a comparison group. All participants underwent DAT-SPECT and 3T MRI within 1 month. Statistical analyses included the Student t test or Fisher-Pitman permutation tests for continuous variables and χ2 tests for categorical variables. Multiple linear regression (adjusted for age and sex) compared DAT binding between groups. Pearson correlation assessed relationships between striatal DAT binding and parkinsonism in patients with iNPH evaluated using the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III. RESULTS:A total of 20 patients with iNPH (mean age 75.4 ± 5.1 years, 65% female) and 20 patients with PD (mean age 74 ± 3.7 years, 55% female) were included. Reduced striatal DAT binding was observed in 45% of patients with iNPH, with none exhibiting nigrosome loss. Conversely, all patients with PD showed both reduced DAT binding and nigrosome loss (p < 0.001). After adjusting for age and sex, patients with iNPH exhibited significantly higher putaminal and caudate DAT binding than patients with PD (right putamen: β = -0.644, p < 0.001; left putamen: β = -0.659, p < 0.001; right caudate: β = -0.429, p = 0.006; left caudate: β = -0.391, p = 0.016), with an elevated putaminal/caudate ratio (p = 0.012). In patients with iNPH, striatal DAT binding negatively correlated with motor severity (left: r = -0.626, p = 0.004; right: r = -0.425, p = 0.07). DISCUSSION:Findings suggest that parkinsonism in iNPH may stem from mechanical disruption of the nigrostriatal pathway rather than neurodegeneration, as indicated by preserved nigrosome integrity despite reduced DAT binding. Limitations include the small sample size and lack of postsurgical follow-up data.

INTRODUCTION:For the accurate diagnosis of idiopathic normal pressure hydrocephalus (iNPH) an accurate neuroimaging is essential. Disproportionately enlarged subarachnoid-space hydrocephalus (DESH) is a key neuroradiological feature and novel imaging techniques, including voxel-based morphometry and AI-assisted analyses are emerging as powerful tools to investigate iNPH pathophysiology. Converging evidence also suggests a role for dopaminergic dysfunction in iNPH. Molecular imaging of the dopamine transporter (DaT) enables the investigation of dopaminergic function and holds potential for advancing differential diagnosis and guiding treatment decisions in iNPH. EVIDENCE ACQUISITION:A comprehensive literature search was conducted using MeSH key words. Studies assessing the role of structural and functional neuroimaging in iNPH. The evidence was summarized, and key results were provided. EVIDENCE SYNTHESIS:DESH is crucial for accurate diagnosis and treatment planning. Advanced structural and functional imaging techniques are expanding our understanding of iNPH pathophysiology. Only few functional imaging studies have directly examined the dopaminergic dysfunction in iNPH and severe methodological limitations exist in both clinical classification and imaging processing. Nonetheless, evidence supports the presence of dopaminergic dysfunction in iNPH, which may be linked to specific clinical symptoms, aid in differential diagnosis, and be reversed with shunt surgery treatment. CONCLUSIONS:This review covers the structural and functional imaging data in iNPH, providing a comprehensive outlook of the current knowledge, highlighting the limitations and possible future perspectives.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms. The absence of reliable fluid biomarkers continues to hinder early diagnosis and effective monitoring of disease progression. Circulating microRNAs (cmiRNAs) are potential candidates, given their stability in biofluids and their ability to mirror pathological processes. We conducted a longitudinal study in 30 early-stage levodopa-naive PD patients (22 men, 8 women). Serum samples were collected at baseline (T0) and at a follow-up time point two years later (T2). A panel of MicroRNAs (miRNAs) (miR-146a-5p, miR-34a-5p, miR-155-5p, miR-29a-3p, miR-106a-5p) were quantified by quantitative real-time PCR. Data were expressed as relative expression (2^−ΔCt), and statistical analyses included sex-stratified comparisons and paired tests for longitudinal changes. At baseline, no significant differences were found in the expression of the miRNAs between male and female PD patients. In contrast, longitudinal within-subject analysis revealed a highly significant upregulation in miR-146a-5p expression from T0 to T2 in both sexes (p < 0.0001). No other miRNAs in the panel exhibited significant changes over time. CmiR-146a-5p levels rise markedly over time in PD patients, independent of sex, suggesting that this miRNA could be a dynamic biomarker of disease progression.

BACKGROUND:Evidence suggests that female gender represents a risk factor for the development of motor/nonmotor fluctuations and dyskinesia in Parkinson's disease (PD). So far, no prospective study has analyzed this aspect in relation to the introduction of levodopa treatment. OBJECTIVE:This prospective multicenter study aims to assess the development of motor/nonmotor fluctuations and dyskinesia based on gender over a 2-year observation period in PD patients starting levodopa. METHODS:Two hundred and eighty-nine PD patients requiring levodopa at baseline were enrolled at 17 Movement Disorders Centers and followed for 2 years. Gender differences in the development of fluctuations, defined as a score ≥2 in the 19-item Wearing-Off Questionnaire, and dyskinesia, defined by Movement Disorders Society Unified Parkinson's Disease Rating Scale Part IV (MDS-UPDRS-IV) score >0 on item 4.1 were assessed. Baseline predictors of such complications were evaluated by stepwise multivariate logistic regression analysis. RESULTS:Two hundred and sixteen patients (139 men, 77 women) completed the follow-up (M24). By M24, 53,2% of men and 64.9% of women had fluctuations (P = 0.048), whereas 5% of men and 14.3% of women developed dyskinesia (P = 0.0185). Multivariate analysis showed that female gender significantly predicted wearing-off (Odds ratio [OR] = 1.930; P = 0.0333), whereas older age was a significant protective factor (for 5-year increase: OR = 0.712; P < 0.0001). Multivariate analysis showed that gender (OR = 3.405; P = 0.0228) and MDS-UPDRS Part III score (for a 5-unit increase: OR = 1.281; P = 0.0239) were significant predictors of dyskinesia at M24. CONCLUSIONS:Female gender was the strongest predictor of fluctuations and dyskinesia after 2-year intake of levodopa. This finding could have important implications for the development of gender-oriented therapeutic recommendations in early PD.

Introduction:According to the higher-level gait disorder (HLGD) pattern, patients with idiopathic normal pressure hydrocephalus (iNPH) can be divided into two motor phenotypes; a disequilibrium (wide-based gait) subtype and a parkinsonian (locomotor) subtype. We aimed to understand the neuroimaging correlates of iNPH phenotyping into different gait patterns, by assessing specific radiological features and their correlations with clinical scores. Methods:We enrolled 86 probable iNPH patients (53 males; age range: 69-88 years), who underwent a comprehensive clinical assessment, including neuropsychological tests, and a conventional MRI scan. The cohort was subdivided into disequilibrium subtype (29 subjects) and parkinsonian subtype of HLGD (57 patients) based on gait evaluation. We compared the iNPH subtypes assessing differences in eight linear radiological indexes and their clinical correlates. Results:The Height of the third ventricle was the only radiological feature that differed between the two motor phenotypes (p < 0.05), being higher in the parkinsonian subtype and showing a trend of correlation with the motor score of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale and with the continence score of the iNPH Rating Scale. Among several clinical-radiological correlations, a reduced callosal angle correlated with the severity of motor and urinary symptoms (p < 0.05). Discussion:A greater height of the third ventricle possibly leading to a top-down compressive effect on the midbrain could be a neuroimaging marker of the parkinsonian phenotype of iNPH. The extensive correlations between linear radiological indices and clinical scales suggest a potential role for radiological features in clinical monitoring.

INTRODUCTION:Idiopathic normal pressure hydrocephalus (iNPH) is a treatable neurodegenerative disorder characterized by a triad of gait disturbance, cognitive impairment, and urinary incontinence. Early diagnosis and timely intervention are crucial for optimal outcomes. However, the diagnosis of iNPH remains challenging due to its variable presentation and overlap with other neurological conditions. EVIDENCE ACQUISITION:A comprehensive review of the literature was conducted to identify current diagnostic criteria and treatment strategies for iNPH. Based on this review, a novel, six-step algorithm was developed to streamline the diagnostic process and improve patient outcomes. EVIDENCE SYNTHESIS:The proposed algorithm includes the following six steps: 1) suspect diagnosis of iNPH: Identification of core clinical features (gait disturbance, cognitive impairment, and urinary incontinence) and radiological evidence of ventricular enlargement; 2) investigate probable iNPH: detailed neuropsychological assessment, gait analysis, and urodynamic studies to confirm the diagnosis; 3) high-volume lumbar puncture: evaluation of the clinical response to CSF drainage, including improvements in gait, cognition, and urinary function; 4) evaluation after HVLP: assessment of the duration and magnitude of symptom improvement after lumbar puncture; 5) shunt surgery: indication for shunt surgery in patients with a positive response to CSF drainage; 6) infusion test and intracranial pressure measurement: alternative diagnostic tools for cases where the diagnosis remains uncertain. CONCLUSIONS:The proposed algorithm provides a structured approach to the diagnosis and management of iNPH. By combining clinical, radiological, and neurophysiological assessments, clinicians can improve diagnostic accuracy and optimize patient outcomes. Further research is needed to validate this algorithm in larger patient populations and to develop more sensitive and specific biomarkers for iNPH.

BACKGROUND AND OBJECTIVES:Deep brain stimulation (DBS) is an established treatment for Parkinson disease (PD). In patients carrying GBA1 variants (GBA-PD), concerns persist that DBS may accelerate cognitive decline. This study investigated the potential additive effects of GBA1 genotype and DBS on long-term motor and nonmotor outcomes. METHODS:This multicenter retrospective, controlled, Italian study included 3 groups: DBS-treated PD patients either carrying or noncarrying GBA1 variants (DBS-nonGBA-PD and DBS-GBA-PD) and GBA-PD patients who fulfilled DBS criteria but eventually were not operated. As secondary aims, we assessed the clinical outcomes of DBS-GBA-PD stratified by GBA1 variant classes and by different DBS targets. Cognitive, motor, and other nonmotor features were collected at baseline and after 1, 3 and, when available, 5 years. Between-group comparisons used χ2 and Kruskal-Wallis tests with Bonferroni correction. Longitudinal changes were analyzed with linear mixed-effects models. Subgroup analyses were performed by GBA1 variant class and DBS target. RESULTS:A total of 615 participants were included: 430 DBS-nonGBA-PD (age 57.4 ± 7.7 years, 32% female), 109 DBS-GBA-PD (age 53.5 ± 8.4 years, 38% female), and 76 nonDBS-GBA-PD (age 57.7 ± 8.1 years, 37% female). At baseline, groups were largely matched for clinical features. Longitudinally, both DBS groups showed marked motor improvement (dyskinesias, on-off phenomenon, and wearing-off, all p vs T0 < 0.001), a benefit which was absent in nonDBS-GBA-PD. At 5 years, dementia occurred more frequently in DBS-GBA-PD and nonDBS-GBA-PD compared with DBS-nonGBA-PD (25.5% vs 36.8% vs 10.8%, p < 0.001). Hallucinations and urinary problems increased in both GBA-PD groups than nonGBA-PD (p-between <0.001 and 0.02, respectively), regardless of DBS. No relevant differences emerged on stratification for variant classes or DBS targets, up to 3 years postsurgery. DISCUSSION:Despite its retrospective design, this study supports DBS as a valid therapeutic option for GBA-PD, providing prolonged benefits on motor symptoms and quality of life. The accelerated cognitive decline observed in GBA-PD, compared with non-mutated participants, was similarly present in both operated and non-operated groups, suggesting it is driven by the genotype rather than DBS itself. CLASSIFICATION OF EVIDENCE:This study provides Class III evidence that DBS does not worsen cognitive function in patients with GBA1-associated PD.

Whether distinct blood metabolomic profiles can distinguish Parkinson’s disease (PD) patients from healthy controls (HC) is still a matter of debate. Here, we employed ¹H-NMR and UPLC/MS analyses on serum samples from a cohort of PD patients and HC. Compared to HC, PD patients showed: (1) higher glutamine, serine, pyruvate and lower α-ketoglutarate levels (1H-NMR); (2) higher glycine and lower glutamic acid concentrations (UPLC/MS). Several pathways associated with amino acids, mitochondrial and antioxidant metabolism emerged as dysregulated in PD. Our findings highlight a prominent disruption of cellular bioenergetic pathways and amino acid homeostasis 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.

We recently described increased D- and l-serine concentrations in the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys, the post-mortem caudate-putamen of human Parkinson's disease (PD) brains and the cerebrospinal fluid (CSF) of de novo living PD patients. However, data regarding blood D- and l-serine levels in PD are scarce. Here, we investigated whether the serum profile of D- and l-serine, as well as the other glutamate N-methyl-d-aspartate ionotropic receptor (NMDAR)-related amino acids, (i) differs between PD patients and healthy controls (HC) and (ii) correlates with clinical-demographic features and levodopa equivalent daily dose (LEDD) in PD. Eighty-three consecutive PD patients and forty-one HC were enrolled. PD cohort underwent an extensive clinical characterization. Serum levels of D- and l-serine, L-glutamate, l-glutamine, l-aspartate, L-asparagine and glycine were determined using High Performance Liquid Chromatography. In age- and sex-adjusted analyses, no differences emerged in the serum levels of d-serine, l-serine and other NMDAR-related amino acids between PD and HC. However, we found that d-serine and D−/Total serine ratio positively correlated with age in PD but not in HC, and also with PD age at onset. Moreover, we found that higher LEDD correlated with lower levels of d-serine and the other excitatory amino acids. Following these results, the addition of LEDD as covariate in the analyses disclosed a selective significant increase of d-serine in PD compared to HC (Δ ≈ 38%). Overall, these findings suggest that serum d-serine and D−/Total serine may represent a valuable biochemical signature of PD.

Frailty is a common age-related clinical syndrome characterized by a decline in the function of multiple organ systems, increased vulnerability to stressors, and a huge socio-economic burden. Despite recent research efforts, the physiopathological mechanisms underlying frailty remain elusive and biomarkers able to predate its occurrence in the early stages are still lacking. Beyond its physical component, cognitive decline represents a critical domain of frailty associated with higher risk of adverse health outcomes. We measured by High-Performance Liquid Chromatography (HPLC) a pool of serum amino acids including L-glutamate, L-aspartate, glycine, and D-serine, as well as their precursors L-glutamine, L-asparagine, and L-serine in a cohort of elderly subjects encompassing the entire continuum from fitness to frailty. These amino acids are known to orchestrate excitatory and inhibitory neurotransmission, and in turn, to play a key role as intermediates of energy homeostasis and in liver, kidney, muscle, and immune system metabolism. To comprehensively assess frailty, we employed both the Edmonton Frail Scale (EFS), as a practical tool to capture the multidimensionality of frailty, and the frailty phenotype, as a measure of physical function. We found that D-serine and D-/Total serine ratio were independent predictors of EFS but not of physical frailty. Furthermore, higher levels of glycine, glycine/L-serine and D-/Total serine were associated with worse cognition and depressive symptoms in the frail group. These findings suggest that changes in peripheral glycine and serine enantiomers homeostasis may represent a novel biochemical correlate of frailty.

Background GBA variants increase the risk of developing Parkinson disease (PD) and influence its outcome. Deep brain stimulation (DBS) is a recognised therapeutic option for advanced PD. Data on DBS long-term outcome in GBA carriers are scarce. Objective To elucidate the impact of GBA variants on long-term DBS outcome in a large Italian cohort. Methods We retrospectively recruited a multicentric Italian DBS-PD cohort and assessed: (1) GBA prevalence; (2) pre-DBS clinical features; and (3) outcomes of motor, cognitive and other non-motor features up to 5 years post-DBS. Results We included 365 patients with PD, of whom 73 (20%) carried GBA variants. 5-year follow-up data were available for 173 PD, including 32 mutated subjects. GBA-PD had an earlier onset and were younger at DBS than non-GBA-PD. They also had shorter disease duration, higher occurrence of dyskinesias and orthostatic hypotension symptoms. At post-DBS, both groups showed marked motor improvement, a significant reduction of fluctuations, dyskinesias and impulsive-compulsive disorders (ICD) and low occurrence of most complications. Only cognitive scores worsened significantly faster in GBA-PD after 3 years. Overt dementia was diagnosed in 11% non-GBA-PD and 25% GBA-PD at 5-year follow-up. Conclusions Evaluation of long-term impact of GBA variants in a large Italian DBS-PD cohort supported the role of DBS surgery as a valid therapeutic strategy in GBA-PD, with long-term benefit on motor performance and ICD. Despite the selective worsening of cognitive scores since 3 years post-DBS, the majority of GBA-PD had not developed dementia at 5-year follow-up.

Background: GBA mutations are known to increase risk of Parkinson disease (PD) and to influence mainly its non-motor outcome. Deep brain stimulation (DBS) is a good therapeutic option for advanced PD, with major improvement of motor symptoms also in GBA-PD patients. However, a recent study suggested that DBS could accelerate cognitive decline in GBA carriers, raising concerns on its indication. We elucidated long-term impact of DBS on motor and non-motor features in GBA-PD.

BACKGROUND AND PURPOSE:The pathogenesis of idiopathic normal pressure hydrocephalus (iNPH) remains controversial. Limited studies have indicated a high prevalence of obstructive sleep apnoea (OSA) amongst iNPH patients. The aim was to investigate the clinical correlates of OSA in iNPH patients. METHODS:In this cross-sectional observational study, consecutive iNPH patients were prospectively enrolled. Evaluations included the iNPH Rating Scale, the Movement Disorder Society Unified Parkinson's Disease Rating Scale part III, the time and number of steps to walk 10 m, the Epworth Sleepiness Scale, the Pittsburgh Sleep Quality Index, a complete neuropsychological evaluation, 3-T brain MRI, full-night video-polysomnography, tap test and cerebrospinal fluid (CSF) neurodegeneration biomarkers. RESULTS:Fifty-one patients were screened, of whom 38 met the inclusion criteria. Amongst the recruited patients, 19/38 (50%) exhibited OSA, with 12/19 (63.2%) presenting moderate to severe disorder. OSA+ iNPH patients required more time (p = 0.02) and more steps (p = 0.04) to complete the 10-m walking test, had lower scores on the gait subitem of the iNPH Rating Scale (p = 0.04) and demonstrated poorer performance on specific neuropsychological tests (Rey Auditory Verbal Learning Test immediate recall, p = 0.03, and Rey-Osterrieth Complex Figure, p = 0.01). Additionally, OSA+ iNPH patients had higher levels of total tau (p = 0.02) and phospho-tau (p = 0.03) in their CSF but no statistically significant differences in beta-amyloid (1-42) levels compared to OSA- iNPH patients. CONCLUSION:Obstructive sleep apnoea is highly prevalent in iNPH patients, particularly at moderate to severe levels. OSA is associated with worse motor and cognitive performance in iNPH. The CSF neurodegeneration biomarker profile observed in OSA+ iNPH patients may reflect OSA-induced impairment of cerebral fluid dynamics.

BACKGROUND:SNCA p.V15A was reported in five families. In vitro models showed increased aggregation and seeding activity, mitochondrial damage, and apoptosis. Mutant flies had reduced flying ability and survival. OBJECTIVES:To clinically and functionally evaluate SNCA p.V15A in a large Italian family with Parkinson's disease (PD). METHODS:Genetic diagnosis was reached through next-generation sequencing. Pathogenicity was assessed by molecular dynamics simulation and biochemical studies on peripheral blood mononuclear cells (PBMCs). RESULTS:Five siblings carried SNCA p.V15A; three developed bradykinetic-rigid PD in their 50s with rapid motor progression and variable cognitive impairment. A fourth sibling had isolated mood disturbance, whereas the fifth was still unaffected at age 47. The mutant protein showed decreased stability and an unstable folded structure. Proband's PBMCs showed elevated total and phosphorylated α-synuclein (α-syn) levels and significantly reduced glucocerebrosidase activity. CONCLUSION:This study demonstrates accumulation of α-synV15A in PBMCs and strengthens the link between α-syn pathophysiology and glucocerebrosidase dysfunction. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.