Immunometabolic Signature and Tauopathy Markers in Blood Cells of Progressive Supranuclear Palsy.

BACKGROUND: Peripheral immune cells critically contribute to the clinical-pathological progression of neurodegenerative diseases and also represent a reliable frame for translational applications. However, data on progressive supranuclear palsy (PSP) are almost scarce in this regard. OBJECTIVE: Our goal is to provide a broad biological characterization of peripheral immune cells in a selected PSP cohort. METHODS: Seventy-one PSP patients scored on the PSP Rating Scale (PSPRS), and 59 controls were enrolled. The blood cell count was collected, together with the neutrophil-to-lymphocyte ratio (NLR) calculation. In a subgroup of patients and controls, the peripheral blood mononuclear cells (PBMCs) were analyzed by the mitochondrial bioenergetic performance and the western blot assay of the nuclear factor erythroid 2-related factor (NRF2)/heme oxygenase 1 (HO-1) pathway and the total tau (t-tau) and phosphorylated tau (p-tau) proteins. Case-control comparison and correlation analyses were performed. RESULTS: PSP patients had a NLR higher than controls, with increased circulating neutrophils. The leukocyte metabolism was also globally increased and the NRF2/HO-1 pathway activated in patients. P-tau, but not t-tau, significantly accumulated in PSP PBMCs and inversely correlated with the PSPRS. CONCLUSIONS: PSP displays a systemic inflammatory shift of the peripheral immunity, which may justify a metabolic reprogramming of the blood leukocytes. Consistently, the NRF2/HO-1 pathway, a master regulator of inflammatory and metabolic response, was activated. PBMCs also engulf tau proteins, especially p-tau, in a way inverse to the disease severity, allowing for a peripheral tracking of tauopathy in patients. Immunometabolic targets may, therefore, gain relevance to PSP in biomarker or therapeutic purposes. © 2024 International Parkinson and Movement Disorder Society.

Safinamide effect on sleep architecture of motor fluctuating Parkinson's disease patients: A polysomnographic rasagiline-controlled study.

INTRODUCTION: Sleep problems commonly occur in Parkinson's disease (PD) and significantly affect patients' quality of life. A possible effect on subjective sleep disturbances of monoamine oxidase-B inhibitors (MAOB-Is) has been described. METHODS: This prospective, observational, single-centre study involved 45 fluctuating PD patients complaining sleep problems as documented by the PD Sleep Scale -2nd version (PDSS-2 ≥18) starting rasagiline 1 mg/daily or safinamide 100 mg/daily, according to common clinical practice, and maintaining antiparkinsonian therapy unchanged. Polysomnography (PSG), sleep questionnaires (PDSS-2, Epworth Sleepiness Scale - ESS), and motor function were evaluated at baseline (T0) and after 4 months of treatment (T1). RESULTS: Safinamide was prescribed in thirty patients and rasagiline in fifteen patients. Both drugs induced a significant improvement in Movement Disorder Society Unified PD Rating Scale III scores. Patients treated with rasagiline showed a significant increase in stage 1 (N1) Non-REM sleep compared to T0, with no significant effects on sleep scales. Patients treated with safinamide showed a significant increase in stage 3 of Non-REM sleep and sleep efficiency and a reduction in the rate of periodic limb movements, matching a significant reduction in PDSS-2 and ESS scales compared to T0. CONCLUSION: This study showed that safinamide, in addition to having a significant effect on PD motor symptoms, like the other MAOB-Is, may exert a specific beneficial effect on subjective and objective sleep, probably driven by its dual mechanism of action, which involves both dopaminergic and glutamatergic neurotransmission.

Stage-dependent phosphoproteome remodeling of Parkinson's disease blood cells.

The complexity and heterogeneity of PD necessitate advanced diagnostic and prognostic tools to elucidate its molecular mechanisms accurately. In this study, we addressed this challenge by conducting a pilot phospho-proteomic analysis of peripheral blood mononuclear cells (PBMCs) from idiopathic PD patients at varying disease stages to delineate the functional alterations occurring in these cells throughout the disease course and identify key molecules and pathways contributing to PD progression. By integrating clinical data with phospho-proteomic profiles across various PD stages, we identify potential stage-specific molecular signatures indicative of disease progression. This integrative approach allows for the discernment of distinct disease states and enhances our understanding of PD heterogeneity.

Contribution of testosterone and estradiol in sexual dimorphism of early-onset Parkinson's disease.

Early-onset Parkinson's disease (EOPD) occurs during the fertile life, when circulating neuroactive sex hormones might enhance the sexual dimorphism of the disease. Here, we aimed to examine how sex hormones can contribute to sex differences in EOPD patients. A cohort of 34 EOPD patients, 20 males and 14 females, underwent comprehensive clinical evaluation of motor and non-motor disturbances. Blood levels of estradiol, total testosterone, follicle-stimulating hormone, and luteinizing hormone were measured in all patients and correlated to clinical features. We found that female patients exhibited greater non-motor symptoms and a relatively higher rate of dystonia than males. In females, lower estradiol levels accounted for higher MDS-UPDRS-II and III scores and more frequent motor complications, while lower testosterone levels were associated with a major occurrence of dystonia. In male patients, no significant correlations emerged. In conclusion, this study highlighted the relevance of sex hormone levels in the sexual dimorphism and unique phenotype of EOPD.

Insular and limbic abnormal functional connectivity in early-stage Parkinson's disease patients with autonomic dysfunction.

Autonomic symptoms in Parkinson's disease result from variable involvement of the central and peripheral systems, but many aspects remain unclear. The analysis of functional connectivity has shown promising results in assessing the pathophysiology of Parkinson's disease. This study aims to investigate the association between autonomic symptoms and cortical functional connectivity in early Parkinson's disease patients using high-density EEG. 53 early Parkinson's disease patients (F/M 18/35) and 49 controls (F/M 20/29) were included. Autonomic symptoms were evaluated using the Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction score. Data were recorded with a 64-channel EEG system. We analyzed cortical functional connectivity, based on weighted phase-lag index, in θ-α-ß-low-γ bands. A network-based statistic was used to perform linear regression between Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction score and functional connectivity in Parkinson's disease patients. We observed a positive relation between the Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction score and α-functional connectivity (network τ = 2.8, P = 0.038). Regions with higher degrees were insula and limbic lobe. Moreover, we found positive correlations between the mean connectivity of this network and the gastrointestinal, cardiovascular, and thermoregulatory domains of Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction. Our results revealed abnormal functional connectivity in specific areas in Parkinson's disease patients with greater autonomic symptoms. Insula and limbic areas play a significant role in the regulation of the autonomic system. Increased functional connectivity in these regions might represent the central compensatory mechanism of peripheral autonomic dysfunction in Parkinson's disease.

Multidisciplinary care use in neurodegenerative complex diseases: The example of progressive supranuclear palsy and advanced Parkinson's disease in real-life.

BACKGROUND: In spite of being considered the gold-standard of care, little is known about the real-life use of in-home and multidisciplinary care in atypical parkinsonism. OBJECTIVE: Primary: Examine real-life multidisciplinary care use for Progressive Supranuclear Palsy (PSP). Secondary: a) Compare PSP care to advanced Parkinson's disease (APD) care; (b) Explore demographic and clinical variables associated with care needs in both groups. METHODS: A cross-sectional multicenter observational study enrolled 129 PSP patients and 65 APD patients (Hoehn and Yahr ≥3), matched for sex and age. Univariate and multivariate regression analysis were performed. RESULTS: Over the previous year, 40 % of PSP patients did not encounter a physical therapist, while only one-third met a speech and language therapist and 5 % an occupational therapist. More than 20 % received in-home care and 32 % needed home structural changes. Compared to APD, PSP patients required more day-time, night-time and home structural changes. When considering both PSP and APD in multivariate analysis, reduced functional autonomy and living without a family caregiver were both related to day-time home assistance and to the need of at least one home care service. A PSP diagnosis compared to APD was a risk factor for having at least four multidisciplinary visits in a year. Finally, PSP diagnosis and being from the Northern Italy were significantly related with home structural changes. CONCLUSIONS: There's a significant gap in providing multidisciplinary care for PSP patients. Our findings emphasize the need for a shared, integrated care plan at a national level for patients with atypical parkinsonism.

Circulating calprotectin as a potential biomarker of persistent olfactory dysfunctions in Post-COVID-19 patients.

BACKGROUND: This longitudinal prospective study aims to investigate the potential of circulating calprotectin (cCLP) as a biomarker in persistent olfactory dysfunctions following COVID-19 infection. METHODS: Thirty-six patients with persistent hyposmia or anosmia post COVID-19 were enrolled (HT0) and re-evaluated after three months of olfactory training (HT1). Two control groups included 18 subjects without olfactory defects post COVID-19 (CG1) and 18 healthy individuals (CG2). Nasal brushing of the olfactory cleft and blood collection were performed to assess circulating calprotectin levels. RESULTS: Higher calprotectin levels were observed in serum and nasal supernatant of hyposmic patients (HT0) compared to control groups (CG1 and CG2). Post-olfactory training (HT1), olfactory function improved significantly, paralleled by decreased calprotectin levels in serum and nasal samples. Circulating calprotectin holds potential as a biomarker in persistent olfactory dysfunctions after COVID-19. The decrease in calprotectin levels post-olfactory training implies a role in monitoring and evaluating treatment responses. DISCUSSION AND CONCLUSIONS: These findings contribute to the growing literature on potential biomarkers in post-COVID-19 olfactory dysfunctions and underscore the importance of investigating novel biomarkers for personalized patient management. Nevertheless, further studies are needed to validate the application of calprotectin assay in nasal diseases and its correlation with nasal cytology.

Increased glucosylsphingosine levels and Gaucher disease in GBA1-associated Parkinson's disease.

INTRODUCTION: Gaucher's disease (GD) is caused by biallelic mutations in the GBA1 gene, leading to reduced glucocerebrosidase (GCase) activity and substrate (glucosylceramide and glucosylsphingosine, GlcSph) accumulation. GBA1 variant carriers are at risk of Parkinson's disease (PD), but only those with biallelic mutations cross the threshold of GCase reduction, leading to substrate accumulation and GD. The link between GBA1 mutations, GD and PD is not fully understood. Here we aimed at reporting the results of a large PD population screening with dried blood spot tests for GD. METHODS: We measured GCase activity and GlcSph levels in 1344 PD patients with dried blood spot tests, and performed GBA1 genetic sequencing. RESULTS: While the GCase activity was reduced in GBA1-PD carriers compared to wild type PD, GlcSph was increased in GBA1-PD compared to GBA1-controls, regardless of the underlying type of GBA1 variant. 13.6 % and 0.4 % of PD patients had mono- or biallelic GBA1 mutations respectively. GCase deficiency, lipid accumulation and clinical manifestations of GD was detected in five PD patients with biallelic GBA1 mutations, of whom four had a risk combined with a GD causing variant. CONCLUSIONS: GlcSph appearing higher in PD may represent a reliable biomarker of the disease and deserves to be further investigated. This study highlights the importance of screening PD patients for possible underlying GD, which is a treatable condition that should not be missed. We diagnosed GD cases carrying a "risk" variant in one allele, which is an unprecedented finding deserving further investigation.

Hearing dysfunction heralds an increase in non-motor burden and a worse quality of life in Parkinson's disease: new insights from non-motor spectrum.

BACKGROUND: Sensorial non-motor symptoms (NMSs) in Parkinson's disease (PD) still lack appropriate investigation in clinical practice. This study aimed to assess if and to what extent auditory dysfunction is associated with other NMSs in PD and its impact on patient's quality of life (QoL). METHODS: We selected patients with idiopathic PD, without other concomitant neurological diseases, dementia, or diagnosis of any audiological/vestibular disease. Demographic and clinical data were collected. Patients underwent otoscopic examination, audiological testing with pure tone audiometry (PTA) and distortion product otoacoustic emissions (DPOAEs) and completed Non-Motor Symptoms Scale (NMSS) and Parkinson's Disease Questionnaires-39 (PDQ-39). ANCOVA and partial correlation analysis have been used for statistical analysis. RESULTS: 60 patients were enrolled and completed PTA and DPOAEs. 32 patients with hearing impairment (HI), assessed by PTA, (hearing threshold ≥ 25 dB) showed similar disease duration, motor impairment, and staging, compared to patients without HI, but higher scores both in NMSS and in PDQ-39, except for cardiovascular (CV), gastrointestinal (GI), urogenital (U) and sexual function (SF) of NMSS. In addition, DPOAEs showed a significant correlation with higher scores both in NMSS and PDQ-39, except for CV, SF, GI, U and perceptual problem subdomains of NMSS. CONCLUSION: This study demonstrated that PD patients with HI have a greater burden of NMS and lower related QoL and functioning. Our results highlight the importance to reconsider HI as a NMS, in parallel with the others. HI evaluation, even in asymptomatic patients, may reveal a wider pathology with a worse QoL.

Post-COVID-19 Hyposmia Does Not Exhibit Main Neurodegeneration Markers in the Olfactory Pathway.

The biological substrate of persistent post-COVID-19 hyposmia is still unclear. However, as many neurodegenerative diseases present with smell impairment at onset, it may theoretically reflect degeneration within the central olfactory circuits. However, no data still exist regarding the post-COVID-19 patients. As the olfactory neurons (ONs) mirror pathological changes in the brain, allowing for tracking the underlying molecular events, here, we performed a broad analysis of ONs from patients with persistent post-COVID-19 OD to identify traces of potential neurodegeneration. ONs were collected through the non-invasive brushing of the olfactory mucosa from ten patients with persistent post-COVID-19 hyposmia (lasting > 6 months after infection) and ten age/sex-matched controls. Immunofluorescence staining for protein quantification and RT-PCR for gene expression levels were combined to measure ONs markers of α-synuclein, amyloid-ß, and tau pathology, axonal injury, and mitochondrial network. Patients and controls had similar ONs levels of oligomeric α-synuclein, amyloid-ß peptide, tau protein, neurofilament light chain (NfL), cytochrome C oxidase subunit 3 (COX3), and the heat shock protein 60 (HSP60). Our findings thus did not provide evidence for synucleinopathy and amyloid-ß mismetabolism or gross traces of neuronal injury and mitochondrial dysfunction within the olfactory system in the early phase of persistent post-COVID-19 hyposmia.

Sex differences in Parkinson's disease-related non motor symptoms: a focus on sleep problems.

Parkinson's disease (PD) symptomatology differs between females and males, yet the contribution of sex on sleep problems needs further analysis. Here, we aimed to investigate sex-specific patterns in the relationship between sleep problems, assessed using the Parkinson's disease sleep scale (PDSS-2), non motor symptoms (NMS), measured by the NMS scale (NMSS), and health-related quality of life (HR-QoL), evaluated by the Parkinson's disease questionnaire (PDQ-39), in a large cohort of PD patients. One-hundred-fifty-four PD patients were included in the study. Female PD patients (n = 62) exhibited a higher prevalence of sleep problems than males (n = 92), with nocturnal motor-related sleep issues being the most frequent. Sleep disturbances differently correlated with a range of NMS between the two sexes. In females, sleep problems mostly correlated with pain; on the other hand, sleep disturbances were linked to a frailer phenotype characterized by global dysautonomia, perception disturbances, and impaired cognitive function in males. Whether female PD patients experienced a lower HR-QoL than males, sleep disturbances were associated with a worse HR-QoL in both sexes. In conclusion, sleep problems in PD differently burden the two sexes, suggesting possible different etiopathogenesis, diagnostic investigations, and possibly tailored approaches.

A biological characterization of patients with postmenopausal Parkinson's disease.

Menopause increases the risk for Parkinson's disease (PD), although the underlying biological mechanisms have not been established in patients. Here, we aimed to understand the basis of menopause-related vulnerability to PD. Main motor and non-motor scores, blood levels of estradiol, testosterone, follicle-stimulating hormone, and luteinizing hormone, CSF levels of total α-synuclein, amyloid-ß-42, amyloid-ß-40, total tau, and phosphorylated-181-tau were examined in 45 women with postmenopausal-onset PD and 40 age-matched controls. PD patients had higher testosterone and lower estradiol levels than controls, and the residual estradiol production was associated with milder motor disturbances and lower dopaminergic requirements. In PD but not in controls, follicle-stimulating hormone levels correlated with worse cognitive scores and CSF markers of amyloidopathy and neuronal loss. In conclusion, menopause-related hormonal changes might differentially contribute to clinical-pathological trajectories of PD, accounting for the peculiar vulnerability to the disease.

Does sex influence the natural history of idiopathic adult-onset dystonia?

BACKGROUND: Several earlier studies showed a female predominance in idiopathic adult-onset dystonia (IAOD) affecting the craniocervical area and a male preponderance in limb dystonia. However, sex-related differences may result from bias inherent to study design. Moreover, information is lacking on whether sex-related differences exist in expressing other dystonia-associated features and dystonia spread. OBJECTIVE: To provide accurate information on the relationship between sex differences, motor phenomenology, dystonia-associated features and the natural history of IAOD. METHODS: Data of 1701 patients with IAOD from the Italian Dystonia Registry were analysed. RESULTS: Women predominated over men in blepharospasm, oromandibular, laryngeal and cervical dystonia; the sex ratio was reversed in task-specific upper limb dystonia; and no clear sex difference emerged in non-task-specific upper limb dystonia and lower limb dystonia. This pattern was present at disease onset and the last examination. Women and men did not significantly differ for several dystonia-associated features and tendency to spread. In women and men, the absolute number of individuals who developed dystonia tended to increase from 20 to 60 years and then declined. However, when we stratified by site of dystonia onset, different patterns of female-to-male ratio over time could be observed in the various forms of dystonia. CONCLUSIONS: Our findings provide novel evidence on sex as a key mediator of IAOD phenotype at disease onset. Age-related sexual dimorphism may result from the varying exposures to specific age-related and sex-related environmental risk factors interacting in a complex manner with biological factors such as hormonal sex factors.

Assessment of Psychometric Characteristics of Parkinson's Disease Sleep Scale 2 and Analysis of a Cut-Off Score for Detecting Insomnia in Italian Patients with Parkinson's Disease: A Validation Study.

INTRODUCTION: Sleep disorders are frequent non-motor symptoms affecting patients with Parkinson's disease (PD). Insomnia represents the most common sleep disorder. Parkinson's disease Sleep Scale 2 (PDSS-2) is a specific tool to investigate sleep problems in PD. The General Sleep Disturbances Scale (GSDS) was a general scale validated for the Italian population. Our goal was to assess the psychometric characteristics of PDSS-2 and the GSDS in this population, calculating a cut-off score for insomnia symptoms by using subitems of PDSS-2. METHODS: Patients admitted at the PD Unit of the Hospital of Rome Tor Vergata outpatient clinic and those afferent to PD associations were asked to complete PDSS-2 and GSDS to be correlated to identify a cut-off for insomnia symptoms. Items 1,2,3,8,13 of PDSS-2 were used to detect insomnia. An ROC curve to assess a cut-off score for insomnia was determined. A cross-cultural analysis of PD population characteristics was performed. RESULTS: In total, 350 PD patients were recruited. Cronbach's alpha was high for the total score (0.828 for PDSS-2 and 0.832 for GSDS). A cross-cultural analysis did not show any significant p-value. The ROC curve yielded an AUC of 0.79 (CI: 0.75-0.84). The cut-off value for insomnia disorder based on items 1,2,3,8,13 of PDSS-2 was >10, demonstrating a sensitivity of 76% and a specificity of 69% in determining the presence of subjective insomnia symptoms in PD. DISCUSSION: PDSS-2 is demonstrated to be a valid, specific tool to address sleep disturbances in PD patients. A cut-off score of 10 for items 1,2,3,8,13 was identified for detecting insomnia symptoms in PD patients.

Does thyroid diseases contribute to the natural history of idiopathic adult-onset dystonia? Data from the Italian Dystonia Registry.

A few earlier observations and recent controlled studies pointed to the possible contribution of thyroid diseases in idiopathic adult-onset dystonia (IAOD). The aim of this study was to investigate the association between thyroid status and clinical characteristics of IAOD, focusing on dystonia localization, spread, and associated features such as tremors and sensory tricks. Patients were identified from those included in the Italian Dystonia Registry, a multicentre dataset of patients with adult-onset dystonia. The study population included 1518 IAOD patients. Patients with hypothyroidism and hyperthyroidism were compared with those without any thyroid disease. In the 1518 IAOD patients, 167 patients (11%; 95% CI 9.5-12.6%) were diagnosed with hypothyroidism and 42 (2.8%; 95% CI 1.99-3.74) with hyperthyroidism. The three groups were comparable in age at dystonia onset, but there were more women than men in the groups with thyroid disease. Analysing the anatomical distribution of dystonia, more patients with blepharospasm were present in the hyperthyroidism group, but the difference did not reach statistical significance after the Bonferroni correction. The remaining dystonia-affected body sites were similarly distributed in the three groups, as did dystonia-associated features and spread. Our findings provided novel information indicating that the high rate of thyroid diseases is not specific for any specific dystonia subpopulation and does not appear to influence the natural history of the disease.

Parkinson's disease motor progression in relation to the timing of REM sleep behavior disorder presentation: an exploratory retrospective study.

REM sleep behavior disorder (RBD) is a frequent non-motor symptom of Parkinson's disease (PD), and the timing of its presentation might have a role in the underlying neurodegenerative process. Here, we aimed to define the potential impact of probable RBD (pRBD) on PD motor progression.We conducted a longitudinal retrospective study on 66 PD patients followed up at the University Hospital of Rome Tor Vergata. Patients were divided into three groups: with post-motor pRBD (pRBDpost, n = 25), without pRBD (pRBDwo, n = 20), and with pre-motor pRBD (pRBDpre, n = 21). Hoehn and Yahr (H&Y) scores, Unified PD Rating Scale (UPDRS) motor scores, and levodopa equivalent daily dose were collected at two follow-up visits conducted in a 5-year interval (T0 and T1). pRBDpost patients had a greater rate of motor progression in terms of the H&Y scale compared to pRBDpre and pRBDwo patients, without the influence of anti-parkinsonian treatment.These preliminary findings suggest that the post-motor occurrence of pRBD can be associated with an acceleration in PD motor progression.

Pregnancy, fertile life factors, and associated clinical course in PRKN early-onset Parkinson's disease.

INTRODUCTION: As the most common cause of autosomal recessive early onset Parkinson's disease (EOPD), parkin type Parkinson's disease (PRKN-PD) may affect female patients in childbearing age. Accordingly, issues related to fertility must be adequately addressed. Here, we landscaped fertile life factors and pregnancy course of a PRKN-PD cohort, including both novel cases directly observed at our center and published ones. METHODS: Six patients with confirmed PRKN-PD were examined by a structured interview on reproductive factors and associated modifications of PD disturbances, including one case followed up throughout pregnancy which was described in greater detail. Six studies reporting fertile life factors of nine PRKN-PD patients were reviewed collecting homogeneous data on fertile life and pregnancy course. RESULTS: PRKN-PD female patients experienced motor fluctuations with the menstrual cycle, pregnancy, and puerperium, which suggests a role for sex hormones in PD clinical burden. In some cases, abortion and miscarriages occurred during the organogenesis phase in patients receiving oral antiparkinsonian therapy; however, levodopa/benserazide monotherapy resulted to be the safest choice in pregnancy. CONCLUSION: Collectively these data disclose the importance of pre-conception counseling in childbearing age PRKN-PD patients and EOPD in general.

Constipation and pain in Parkinson's disease: a clinical analysis.

Parkinson's Disease (PD) is a neurodegenerative disorder characterized by both motor and non-motor symptoms (NMS). Among NMS, constipation and pain are both highly prevalent and debilitating affecting up to 80% of PD patients and impairing their quality of life. Here, we investigated the relationship between constipation and pain in PD patients. This is a retrospective study assessing the relationship between pain and constipation in a PD patient population from a clinical database of patients attending the outpatient clinic of the movement disorders division, Neurology Unit of Policlinico Tor Vergata, in Rome. Subjects were assessed with the Unified Parkinson's Disease Rating Scale (UPDRS) part III, Hoehn and Yahr (H&Y) stage, King's Parkinson's Disease Pain Scale (KPPS), Brief Pain Inventory (BPI), Non-Motor Symptoms Scale (NMSS) and Beck Depression Inventory (BDI). Patients were further divided in two groups (Group 1, 32 patients with constipation and Group 2, 35 PD patients without constipation) ANOVA and ANCOVA analysis were used to compare the two groups. PD patients with constipation had significantly higher pain severity and pain interference, as measured by the BPI scale and higher total KPPS score, fluctuation-related pain, nocturnal pain, and radicular pain when compared to PD patients without constipation. This study highlights for the first time a possible interplay between constipation and pain in PD that deserves further investigations.

Motor cortex transcranial direct current stimulation improves non-motor symptoms in early-onset Parkinson's disease: a pilot study.

Early-onset Parkinson's Disease (EOPD) demands tailored treatments. The younger age of patients might account for a higher sensitivity to transcranial direct current stimulation (tDCS) based non-invasive neuromodulation, which may raise as an integrative therapy in the field. Accordingly, here we assessed the safety and efficacy of the primary left motor cortex (M1) anodal tDCS in EOPD. Ten idiopathic EOPD patients received tDCS at 2.0 mA per 20 min for 10 days within a crossover, double-blind, sham-controlled pilot study. The outcome was evaluated by measuring changes in MDS-UPDRS part III, Non-Motor Symptoms Scale (NMSS), PD-cognitive rating scale, and PD Quality of Life Questionnaire-39 scores. We showed that anodal but not sham tDCS significantly reduced the NMSS total and "item 2" (sleep/fatigue) scores. Other parameters were not modified. No adverse events occurred. M1 anodal tDCS might thus evoke plasticity changes in cortical-subcortical circuits involved in non-motor functions, supporting the value as a therapeutic option in EOPD.

Peripheral immunity changes are associated with neurodegeneration and worse clinical outcome in idiopathic normal pressure hydrocephalus.

BACKGROUND AND PURPOSE: Idiopathic normal pressure hydrocephalus (iNPH) pathogenesis is multifactorial. Systemic inflammation might have a role in gathering clinical-pathological trajectories. We aimed to shape the peripheral immune profile of iNPH and establish correlations with cerebrospinal fluid (CSF) markers, ventricular enlargement, and clinical outcomes. METHODS: We conducted a single-center retrospective-longitudinal study, including 38 iNPH patients and 38 controls. Baseline iNPH Grading Scale and modified Rankin Scale (mRS) scores were collected with peripheral blood cell count, CSF amyloid-ß42 (Aß42), total tau (t-tau), phosphorylated-181-tau, and Evans index. Depending on 5-year outcome, iNPH patients were grouped into "poor outcome" (PO; mRS ≥ 5) and "favorable outcome" (FO; mRS < 5). Biomarkers were compared and correlated with each other. Receiver operating characteristic analysis was performed. RESULTS: iNPH patients compared to controls had higher neutrophil-to-lymphocyte ratio (NLR; 2.43 ± 1.04 vs. 1.61 ± 0.47, p < 0.001), higher neutrophils (4.22 ± 0.86 1000/mL vs. 3.48 ± 1.34, p = 0.033), and lower lymphocytes (1.45 ± 0.55 1000/mL vs. 2.07 ± 0.86, p = 0.038), with the expected CSF biomarkers signature. In the patients' cohort, NLR was associated directly with t-tau and inversely with Aß42. NLR directly correlated with Evans index. PO patients compared to those with FO had higher NLR (3.25 ± 1.40 vs. 2.01 ± 0.77, p = 0.035) and higher t-tau (274.76 ± 114.39 pg/mL vs. 150.28 ± 72.62, p = 0.017), with an area under the curve of 0.786 and 0.793, respectively. CONCLUSIONS: iNPH patients present a proinflammatory state associated with neurodegeneration and predicting poor clinical outcome. Systemic inflammation represents a factor in the clinical-pathological progression of iNPH, and the NLR emerges as a potential prognostic index.