Background: Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease and gender differences have been described on several aspects of PD. In the present commentary, we aimed to collect and discuss the currently available evidence on gender differences in PD regarding biomarkers, genetic factors, motor and non-motor symptoms, therapeutic management (including pharmacological and surgical treatment) as well as preclinical studies. Methods: A systematic literature review was performed by searching the Pubmed and Scopus databases with the search strings “biomarkers’’, ‘‘deep brain stimulation’’, “female”, ‘‘gender’’, ‘‘genetic”, ‘‘levodopa’’, ‘‘men’’, “male”, ‘‘motor symptoms’’, ‘‘non-motor symptoms’’, ‘‘Parkinson disease’’, ‘‘sex’’, ‘‘surgery’’, and ‘‘women’’. Results: The present review confirms the existence of differences between men and women in Parkinson Disease, pointing out new information regarding evidence from animal models, genetic factors, biomarkers, clinical features and pharmacological and surgical treatment. Conclusions: The overall goal is to acquire new informations about sex and gender differences in Parkinson Disease, in order to develop tailored intervetions.

BackgroundLevodopa (LD) is the most effective drug in the treatment of Parkinson’s disease (PD). Unfortunately, prolonged use of LD leads to complications, mainly motor/non-motor fluctuations (MNMF) and dyskinesias (DYS). Women seem more prone to develop such LD-related complications. Nonetheless, there is a paucity of prospective studies examining gender-related predictors of MNMF and DYS. Among several factors, which concur with a very complex scenario, changes in LD pharmacokinetics influence the drug’s effectiveness. The present study aimed to assess gender-related differences in LD pharmacokinetics in patients with PD at their first-ever intake of LD.Materials and MethodsThis is a multicentric study enrolling patients with PD, who were LD-naïve and received a single dose of LD/benserazide (100/25 mg) formulation. All participants gave their written informed consent, and the study was approved by the local Ethics Committees. To measure plasma LD concentrations and pharmacokinetic parameters (AUC, Cmax, Tmax, t1/2), fasting blood samples were collected before drug intake and then at 8-time points until 260 min. LD concentrations were measured by ultra-high-performance liquid chromatography coupled with mass spectrometry (UHPLC-MS). Multiple linear regression analyses were performed to identify the predictors of the parameters.ResultsThirty-five patients (16 women and 19 men) were consecutively enrolled. Area under curve (AUC) and maximum plasma concentration (Cmax) were significantly higher in women than men (p = 0.0006 and p = 0.0014, respectively). No statistically significant difference was found regarding Tmax and t1/2. Multiple linear regression analyses revealed that female sex (β = 1.559116, 95% CI 0.8314479 2.286785; p < 0.0001) and body mass index (BMI) (β = −0.0970631, 95% CI −0.1733004 −0.0208258; p = 0.014) significantly predicted AUC. Only female sex significantly predicted Cmax (β = 1,582.499, 95% CI 731.581 2,433.417; p = 0.001). Moreover, only BMI significantly predicted t1/2 (β = 0.0756267, 95% CI 0.0143407 0.1369126; p = 0.017). Stratifying by gender, BMI was confirmed to significantly predict t1/2 in women (β = 0.1300486, 95% CI 0.0172322 0.242865; p = 0.027), but not in men.ConclusionThis study provides novel insights on gender differences in LD pharmacokinetics, possibly contributing to the later development of motor complications and dyskinesia in PD.

To evaluate intraocular pressure (IOP) and choroidal thickness (ChT) postural changes in multiple system atrophy (MSA), Parkinson’s disease (PD) patients and healthy controls (HC). 20 MSA patients, 21 PD patients and 14 HC, were examined. All subjects underwent a complete examination, including corneal thickness, ChT, IOP and axial length (AL) measurements. IOP measurement was performed in supine, sitting, and standing positions, whereas ChT in sitting and standing positions. Supine to standing IOP variations were significantly higher in MSA vs PD(p = 0.01) and in MSA vs HC (p < 0.0001), whereas no significant differences were observed between PD and HC (p = 0.397). Mean sub-foveal ChT in MSA was 240 ± 92 μm in sitting position, and 215 ± 94 μm in standing position with a significant reduction (p = 0.008). Mean sub-foveal ChT in PD was 258 ± 79 μm in sitting position, and 259 ± 76 μm in standing position (p = 0.887). In HC it was 244 ± 36 μm in sitting position, and 256 ± 37 μm in standing position with a significant increase (p = 0.007). The significant IOP and ChT postural changes can be considered additional hallmarks of autonomic dysfunction in MSA and further studies are needed to consider them as biomarkers in the differential diagnosis with PD.

Parkinson's disease (PD) and Multiple System Atrophy (MSA) are progressive neurodegenerative diseases with overlap of symptoms in early stages of disease. No reliable biomarker exists and the diagnosis is mainly based on clinical features. Several studies suggest that miRNAs are involved in PD and MSA pathogenesis. Our goal was to study two serum circulating microRNAs (miR-96-5p and miR-339-5p) as novel biomarkers for the differential diagnosis between PD and MSA. Serum samples were obtained from 51 PD patients, 52 MSA patients and 56 healthy controls (HC). We measured levels of miRNAs using quantitative PCR and compared the levels of miR-96-5p and miR-339-5p among PD, MSA and HC groups using a one-way analysis of variance. Correlations between miRNA expression and clinical data were calculated using Pearson's rho test. We used the miRTarBase to detect miRNA targets and STRING to evaluate co-expression relationship among target genes. MiR-96-5p was significantly increased in MSA patients compared with HC (Fold change (fc): 3.6; p = 0.0001) while it was decreased in PD patients compared with HC (Fold change: 4; p = 0.0002). Higher miR-96-5P levels were directly related to longer disease duration in MSA patients. We observed a significant increase of miR-339-5p in MSA patients compared with PD patients (fc: 2.5; p = 0.00013). miR-339-5p was increased in MSA patients compared with HC (fc: 2.4; p = 0.002). We identified 32 target genes of miR-96-5p and miR-339-5p, some of which are involved in neurodegenerative diseases. The study of those miRNAs could be useful to identify non-invasive biomarkers for early differential diagnosis between PD and MSA.

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Background: There is increasing evidence of gender differences in the epidemiology and clinical manifestation of both motor and non-motor symptoms of Parkinson's disease (PD). Nevertheless, few data are available on gender differences in the response to antiparkinsonian drugs. Safinamide is a multimodal drug with positive effects on motor and non-motor fluctuations that might improve patients' care and quality of life.Objective: To analyze gender differences on clinical effects of safinamide in PD patients treated in real-life conditions during the SYNAPSES trial.Methods: SYNAPSES was a multinational, multicenter, observational study. At baseline, patients with PD diagnosis received safinamide as an add-on to levodopa and were followed up for 12 months, with visits performed every 4 months. A new statistical analysis was performed to describe the efficacy of safinamide in men and women on motor complications, motor symptoms, and adverse events.Results: Six hundred and sixteen (38%) out of 1,610 patients enrolled in the SYNAPSES study were women and 994 (62%) men. Safinamide improved motor symptoms and motor complications (fluctuations and dyskinesia) in both genders, with a good safety profile and without requiring any change in the concomitant dopaminergic therapy. Clinically significant improvements, according to the criteria developed by Shulman et al., were seen in 46% of male and female patients for the UPDRS motor score and 43.5% of men vs. 39.1% of women for the UPDRS total score.Conclusions: Safinamide was effective in improving motor fluctuations and dyskinesia and proved to be safe in both male and female patients with PD. Further prospective studies, specifically addressing potential gender differences in response to PD therapies, are needed to develop tailored management strategies.

Diagnosis of multiple system atrophy (MSA) may be improved by using multimodal imaging approaches. We investigated the use of T1-weighted/T2-weighted (T1w/T2w) images ratio combined with voxel-based morphometry to evaluate brain tissue integrity in MSA compared to Parkinson’s disease (PD) and healthy controls (HC). Twenty-six patients with MSA, 43 patients with PD and 56 HC were enrolled. Whole brain voxel-based and local regional analyses were performed to evaluate gray and white matter (GM and WM) tissue integrity and mean regional values were used for patients classification using logistic regression. Increased mean regional values of T1w/T2w in bilateral putamen were detected in MSA-P compared to PD and HC. The combined use of regional GM and T1w/T2w values in the right and left putamen showed the highest accuracy in discriminating MSA-P from PD and good accuracy in discriminating MSA from PD and HC. A good accuracy was also found in discriminating MSA from PD and HC by either combining regional GM and T1w/T2w values in the cerebellum or regional WM and T1w/T2w in the cerebellum and brainstem. The T1w/T2w image ratio alone or combined with validated MRI parameters can be further considered as a potential candidate biomarker for differential diagnosis of MSA.

Introduction: The aim of this study is to investigate the impact of orthostatic hypotension (OH) on cognitive functions in patients with multiple system atrophy (MSA) followed over time.Methods: Thirty-two MSA patients were enrolled and underwent a comprehensive neuropsychological battery; at baseline (T0) 15 out of 32 patients presented OH, assessed by means of orthostatic standing test. All patients underwent a follow-up (T1) evaluation 12 months after baseline. Thirteen out of 32 patients also underwent a second follow-up (T2) evaluation at 24 months. Changes over time on different neuropsychological tasks were compared between patients with and without OH by means of Mann-Whitney's U-test. Moreover, clinical categories of normal cognition, mild cognitive impairment, and dementia were determined, and changes at T1 and T2 in global cognitive status were compared between patients with and without OH.Results: At T0, patients with OH had better performance on words/non-words repetition task (p = 0.02) compared to patients without OH. Compared to patients without OH, patients with OH performed worse on semantic association task (p &lt; 0.01) at T1 and on Stroop test-error effect (p = 0.04) at T2. The percentage of patients with worsened cognitive status at T1 was higher among patients with OH than among patients without OH (93 vs. 59%, p = 0.03). OH (β = −4.67, p = 0.01), education (β = 0.45, p = 0.02), age (β = 0.19, p = 0.03), and Montreal Cognitive Assessment battery (MOCA) score at T0 (β = −0.26, p = 0.04) were significant predictors of global cognitive status worsening at T1.Discussion: We found that global cognitive status worsened at 1-year follow-up in 93% of patients with OH, and OH, along with age, education, and MOCA score, predicted cognitive worsening over time. To clarify the relationship between OH and cognitive dysfunction in MSA, we suggest the use of clinical categories of normal cognition, mild cognitive impairment, and dementia in further longitudinal studies on MSA patients with and without OH.