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180 m Ta is the longest-lived metastable state presently known. Its decay has not been observed yet. In this work, we report a new result on the decay of 180 m Ta obtained with a 2015.12-g tantalum sample measured for 527.7 d with an ultra-low background HPGe detector in the STELLA laboratory of the Laboratori Nazionali del Gran Sasso (LNGS), in Italy. Before the measurement, the sample has been stored deep-underground for ten years, resulting in subdominant background contributions from cosmogenically activated 182 Ta . We observe no signal in the regions of interest and set half-life limits on the process for the two channels EC and β - : T 1 / 2 , EC > 1.6 × 10 18 year and T 1 / 2 , β - > 1.1 × 10 18 year (90% C. I.), respectively. We also set the limit on the γ de-excitation / IC channel: T 1 / 2 , IC > 4.1 × 10 15 year (90% C. I.). These are, as of now, the most stringent bounds on the decay of 180 m Ta worldwide. Finally, we test the hypothetical scenarios of de-excitation of 180 m Ta by cosmological Dark Matter and constrain new parameter space for strongly-interacting dark-matter particle with mass up to 10 5 GeV. [ABSTRACT FROM AUTHOR]

Background: Gastrointestinal dysfunction (GID) accompanies any phase of Parkinson's disease (PD), underlying differential clinical-pathological trajectories., Objective: To investigate associations between GID and peripheral immune or neurodegeneration-related markers in PD., Methods: One-hundred-and-fourteen patients (n = 55 de novo, DN; n = 59 middle-advanced, MA) completed the Gastrointestinal Dysfunction Scale for PD (GIDS-PD), and other motor and non-motor scales; paired measurement of amyloid-β42, amyloid-β42β/β40, total-tau, phosphorylated-181-tau, total α-synuclein CSF levels, albumin ratio, and peripheral blood cell count were collected. Group and correlation analyses were performed., Results: MA patients had greater GID than DN. GIDS-PD scores directly correlated with MDS-UPDRS-III and non-motor scores in both groups, although more in DN. GIDS-PD scores were directly associated with α-synuclein and inversely with lymphocytes only in DN; conversely, they were positively associated with tau proteins and albumin ratio, and negatively with amyloid-β-peptides in both groups., Conclusions: The burden of GID increases along the PD course with associated stage-specific clinical-biological patterns., (© 2024 International Parkinson and Movement Disorder Society.)

Parkinson's disease (PD) epidemiology and clinical features are sexually dimorphic. However, there are no data based on EEG functional connectivity (FC). Likewise, the contribution of sex hormones on brain FC has never been evaluated. Here, we aimed to investigate the association between biological sex and sex hormones on cortical FC changes in PD using high-density EEG. This study involved 69 early-stage PD patients (F/M 27/42) and 69 age-matched healthy controls (HC) (F/M 30/39). Sex hormone levels (total-testosterone (TT), estradiol (E2), follicle-stimulating hormone (FSH), and luteinizing hormone (LH)) were assessed in PD patients. Data were recorded with a 64-channel EEG system. Source reconstruction method was used to identify brain activity. Cortico-cortical FC was analysed based on the weighted phase-lag index (wPLI) in θ-α-β-low γ bands. Network-based statistic (NBS) was used to compare FC between genders in HC and PD and to study the relationship between FC and sex hormones in PD. PD exhibited a hypoconnected network at θ and α bands and a hyperconnected network at β band compared to HC. Male HC showed a hyperconnected network at α-band compared to female HC. Conversely, males with PD showed a hypoconnected network at α-band compared to females with PD. In females and males with PD, E2 positively correlated with α-FC, while gonadotropins positively correlated with β-FC. TT positively correlated with the θ-FC only in males. Sex hormones shape EEG-FC in both males and females with PD, supporting their major influence on PD pathophysiology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Rapid eye movement (REM) sleep behavior disorder (RBD) may precede motor symptoms in Parkinson's disease (PD) by years. According to a recent hypothesis, premotor RBD (pRBD) is a marker of the PD body-first subtype, where synucleinopathy originates from the peripheral autonomic nervous system. Conversely, in the brain-first subtype, pathology would arise in the brain. Functional connectivity (FC) could provide additional insight into the neurodegenerative process of these putative PD subtypes., Objectives: We aim to analyze the possible FC differences between early-stage PD patients with (PD pRBD+ ) and without (PD pRBD- ) pRBD using high-density electroencephalography (EEG)., Methods: We enrolled 28 PD pRBD+ , 35 PD pRBD- , and 35 healthy controls (HC). Data were recorded with a 64-channel EEG system, and a source-reconstruction method was used to identify brain-region activity. FC was calculated using the weighted phase-lag index in θ, α, β, and low-γ bands. Statistical analysis was conducted using network-based statistic., Results: We found a significant trend of decreased α-FC across PD pRBD+ , PD pRBD- , and HC, mainly in prefrontal and temporal areas. The altered α-FC correlated with Montreal Cognitive Assessment scores in PD pRBD+ and, to a lesser extent, PD pRBD- and with gait/postural disturbances in PD pRBD+ patients only. PD pRBD+ and PD pRBD- had similarly increased FC than HC in a β band network, predominantly involving sensorimotor and limbic areas. The increased β network FC was related to bradykinesia severity in both PD subgroups., Conclusions: Compared to PD pRBD- (brain-first subtype), PD pRBD+ group (body-first subtype) demonstrates specific EEG-FC dysfunctions in the α band, which may reflect early involvement of the cholinergic ascending system. © 2024 International Parkinson and Movement Disorder Society., (© 2024 International Parkinson and Movement Disorder Society.)

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., Competing Interests: Declaration of competing interest Nothing to report., (Copyright © 2024. Published by Elsevier Inc.)

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., Competing Interests: Declarations. Competing interests: The authors have no relevant financial or non-financial interests to disclose. Ethics approval: This study was conducted in accordance with the principles of the Helsinki Declaration. The local ethics committee approved the study., (© 2024. The Author(s).)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: In this work, we describe a new case of association between SCA2 and MND., Case Report: A 58-year-old man who was diagnosed with spinocerebellar ataxia type 2 presented dysphagia and a significant decline in his ability to walk, with a reduction in autonomy and the need to use a wheelchair. We performed electromyography and electroneurography of the four limbs and of the cranial district and motor-evoked potentials to study upper and lower motor neurons. Referring to the revised El Escorial criteria of 2015, ALS diagnosis was made., Discussion: Considering different cases described in literature over the years, SCA2 could represent an important risk factor for developing ALS. In particular, the presence of alleles of ATXN2 with 27 and 28 CAG repeats seems to slightly decrease the risk of developing the disease, which would instead be progressively increased by the presence of alleles with 29, 30, 31, 32, and 33 repeats. The exact physiopathological mechanism by which the mutation increases the risk of developing the disease is currently unknown. Transcriptomic studies on mouse models have demonstrated the involvement of several pathways, including the innate immunity regulation by STING and the biosynthesis of fatty acid and cholesterol by SREBP., Conclusion: CAG repeat expansions in the ATXN2 gene have been associated with variable neurological presentations, which include SCA2, ALS, Parkinsonism, or a combination of them. Further research is needed to understand the relationship between SCA2 and ALS better and explore molecular underlying mechanisms., (© 2024. The Author(s).)

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., (© 2024. The Author(s).)

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., (© 2024. The Author(s).)

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-β-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., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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-β-42, amyloid-β-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., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

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.

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 (pRBD post , n = 25), without pRBD (pRBD wo , n = 20), and with pre-motor pRBD (pRBD pre , 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). pRBD post patients had a greater rate of motor progression in terms of the H&Y scale compared to pRBD pre and pRBD wo 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., (© 2024. The Author(s).)

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., (© 2023. The Author(s).)

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., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background: Directional deep brain stimulation (DBS) leads allow a fine-tuning control of the stimulation field, however, this new technology could increase the DBS programming time because of the higher number of the possible combinations used in directional DBS than in standard nondirectional electrodes. Neuroimaging leads localization techniques and local field potentials (LFPs) recorded from DBS electrodes implanted in basal ganglia are among the most studied biomarkers for DBS programing., Objective: This study aimed to evaluate whether intraoperative LFPs beta power and neuroimaging reconstructions correlate with contact selection in clinical programming of DBS in patients with Parkinson disease (PD)., Materials and Methods: In this retrospective study, routine intraoperative LFPs recorded from all contacts in the subthalamic nucleus (STN) of 14 patients with PD were analyzed to calculate the beta band power for each contact. Neuroimaging reconstruction obtained through Brainlab Elements Planning software detected contacts localized within the STN. Clinical DBS programming contact scheme data were collected after one year from the implant. Statistical analysis evaluated the diagnostic performance of LFPs beta band power and neuroimaging data for identification of the contacts selected with clinical programming. We evaluated whether the most effective contacts identified based on the clinical response after one year from implant were also those with the highest level of beta activity and localized within the STN in neuroimaging reconstruction., Results: LFPs beta power showed a sensitivity of 67%, a negative predictive value (NPV) of 84%, a diagnostic odds ratio (DOR) of 2.7 in predicting the most effective contacts as evaluated through the clinical response. Neuroimaging reconstructions showed a sensitivity of 62%, a NPV of 77%, a DOR of 1.20 for contact effectivity prediction. The combined use of the two methods showed a sensitivity of 87%, a NPV of 87%, a DOR of 2.7 for predicting the clinically more effective contacts., Conclusions: The combined use of LFPs beta power and neuroimaging localization and segmentations predict which are the most effective contacts as selected on the basis of clinical programming after one year from implant of DBS. The use of predictors in contact selection could guide clinical programming and reduce time needed for it., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Functional connectivity (FC) has shown promising results in assessing the pathophysiology and identifying early biomarkers of neurodegenerative disorders, such as Parkinson's disease (PD)., Objectives: In this study, we aimed to assess possible resting-state FC abnormalities in early-stage PD patients using high-density electroencephalography (EEG) and to detect their clinical relationship with motor and non-motor PD symptoms., Methods: We enrolled 26 early-stage levodopa naïve PD patients and a group of 20 healthy controls (HC). Data were recorded with 64-channels EEG system and a source-reconstruction method was used to identify brain-region activity. FC was calculated using the weighted phase-lag index in θ, α, and β bands. Additionally, we quantified the unbalancing between β and lower frequencies through a novel index (β-functional ratio [FR]). Statistical analysis was conducted using a network-based statistical approach., Results: PD patients showed hypoconnected networks in θ and α band, involving prefrontal-limbic-temporal and frontoparietal areas, respectively, and a hyperconnected network in the β frequency band, involving sensorimotor-frontal areas. The θ FC network was negatively related to Non-Motor Symptoms Scale scores and α FC to the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale part III gait subscore, whereas β FC and β-FR network were positively linked to the bradykinesia subscore. Changes in θ FC and β-FR showed substantial reliability and high accuracy, precision, sensitivity, and specificity in discriminating PD and HC., Conclusions: Frequency-specific FC changes in PD likely reflect the dysfunction of distinct cortical networks, which occur from the early stage of the disease. These abnormalities are involved in the pathophysiology of specific motor and non-motor PD symptoms, including gait, bradykinesia, mood, and cognition. © 2023 International Parkinson and Movement Disorder Society., (© 2023 International Parkinson and Movement Disorder Society.)

Patients with Parkinson's disease (PD) tend to sleep more frequently in the supine position and less often change head and body position during sleep. Besides sleep quality and continuity, head and body positions are crucial for glymphatic system (GS) activity. This pilot study evaluated sleep architecture and head position during each sleep stage in idiopathic PD patients without cognitive impairment, correlating sleep data to patients' motor and non-motor symptoms (NMS). All patients underwent the multi-night recordings, which were acquired using the Sleep Profiler headband. Sleep parameters, sleep time in each head position, and percentage of slow wave activity (SWA) in sleep, stage 3 of non-REM sleep (N3), and REM sleep in the supine position were extracted. Lastly, correlations with motor impairment and NMS were performed. Twenty PD patients (65.7 ± 8.6 y.o, ten women) were included. Sleep architecture did not change across the different nights of recording and showed the prevalence of sleep performed in the supine position. In addition, SWA and N3 were more frequently in the supine head position, and N3 in the supine decubitus correlated with REM sleep performed in the same position; this latter correlated with the disease duration (correlation coefficient = 0.48, p -value = 0.03) and motor impairment (correlation coefficient = 0.53, p -value = 0.02). These preliminary results demonstrated the importance of monitoring sleep in PD patients, supporting the need for preventive strategies in clinical practice for maintaining the lateral head position during the crucial sleep stages (SWA, N3, REM), essential for permitting the GS function and activity and ensuring brain health.

Introduction: Deep brain stimulation of the subthalamic nucleus (STN-DBS) can exert relevant effects on the voice of patients with Parkinson's disease (PD). In this study, we used artificial intelligence to objectively analyze the voices of PD patients with STN-DBS., Materials and Methods: In a cross-sectional study, we enrolled 108 controls and 101 patients with PD. The cohort of PD was divided into two groups: the first group included 50 patients with STN-DBS, and the second group included 51 patients receiving the best medical treatment. The voices were clinically evaluated using the Unified Parkinson's Disease Rating Scale part-III subitem for voice (UPDRS-III-v). We recorded and then analyzed voices using specific machine-learning algorithms. The likelihood ratio (LR) was also calculated as an objective measure for clinical-instrumental correlations., Results: Clinically, voice impairment was greater in STN-DBS patients than in those who received oral treatment. Using machine learning, we objectively and accurately distinguished between the voices of STN-DBS patients and those under oral treatments. We also found significant clinical-instrumental correlations since the greater the LRs, the higher the UPDRS-III-v scores., Discussion: STN-DBS deteriorates speech in patients with PD, as objectively demonstrated by machine-learning voice analysis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Suppa, Asci, Costantini, Bove, Piano, Pistoia, Cerroni, Brusa, Cesarini, Pietracupa, Modugno, Zampogna, Sucapane, Pierantozzi, Tufo, Pisani, Peppe, Stefani, Calabresi, Bentivoglio, Saggio and Lazio DBS Study Group.)

Dopamine depletion affects several aspects of hearing function. Previous work [Wu, Yi, Manca, Javaid, Lauer, and Glowatzki, eLife 9, e52419 (2020)] demonstrated the role of dopamine in reducing the firing rates of inner ear cells, which is thought to decrease synaptic excitotoxicity. Thus, a lack of dopamine could indirectly increase acoustic stimulation of medial olivocochlear efferents. To investigate that, here we studied contralateral suppression of distortion product otoacoustic emissions in a population of Parkinsonian patients, compared to an age-matched control group, both audiometrically tested. To rule out activation of the acoustic reflex, middle ear impedance was monitored during testing. The results show significantly stronger contralateral suppression in the patient group., (© 2023 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).)

Introduction: Early -onset Parkinson's disease (EOPD) labels those cases with onset earlier than fifty. Although peculiarities emerged either in clinical or pathological features, EOPD is managed alike typical, late-onset PD. A customized approach would be, instead, better appropriate. Accordingly, a deeper characterization of the clinical course, with an estimation of the disease progression rate, the therapy flow, and the main motor and non-motor complications occurrence, is needed., Methods: A longitudinal cohort of 193 EOPD patients (selected on a single-centre population of 2000 PD cases) was retrospectively analysed, providing descriptive statics on a series of clinical parameters (genetics, phenotype, comorbidities, therapies, motor and non-motor complications, marital and gender issues) and modelling the trajectories from diagnosis to 10 years later of both Hoehn and Yahr (H&Y) stage and levodopa equivalent daily dose (LEDD)., Results: EOPD had a prevalence of 9.7%, including few monogenic cases. It mostly appeared as a motor syndrome, with asymmetric, rigid-akinetic presentation. H&Y linearly progressed with an increment of 0.92 points/10 years; LEDD flow had a non-linear trend, increasing of 526.90 mg/day in 0-5 years, and 166.83 mg/day in 5-10 years. Motor fluctuations started 6.5 ± 3.2 years from onset, affecting up to 80% of the cohort. Neuropsychiatric troubles interested the 50%, sexual complaints the 12%. Gender-specific motor disturbances emerged., Conclusion: We shaped EOPD course, modelling a "brain-first" PD subtype, slowly progressive, with non-linear dopaminergic requirement. Major burden mostly resulted from motor fluctuations, neuropsychiatric complications, sexual and marital complaints, with a considerable gender-effect., (© 2023. The Author(s).)

Background and Purpose: Parkinson disease (PD) presents relevant sex-related differences in epidemiology, pathophysiology, and clinical features, with males being more vulnerable to the disease. Sex hormones might have a role, as the experimental models suggest; however, human-based evidence is scarce. Here, we integrated multimodal biomarkers to investigate the relationships between circulating sex hormones and clinical-pathological features in male PD patients., Methods: A cohort of 63 male PD patients underwent comprehensive clinical evaluation of motor and nonmotor disturbances; measurement of estradiol, testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) blood levels; and cerebrospinal fluid (CSF) assay of total α-synuclein, amyloid-β-42, amyloid-β-40, total tau, and phosphorylated-181 tau levels. A subgroup of 47 PD patients underwent brain volumetry by 3-T magnetic resonance imaging for further correlations. A control group of 56 age-matched individuals was enrolled for comparative analyses., Results: Male PD patients had higher estradiol and testosterone levels than controls. Estradiol had independent inverse associations with Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part 3 score and disease duration; it was also lower in nonfluctuating patients. Testosterone had inverse independent correlations with CSF α-synuclein and right globus pallidus volume. FSH and LH had age-dependent correlations with cognitive impairment and CSF amyloid-β-42/amyloid-β-40 ratio., Conclusions: The study suggested that sex hormones could differentially contribute to clinical-pathological features of PD in male patients. Whereas estradiol might have a protective role in motor impairment, testosterone might be involved in male vulnerability to PD neuropathology. Gonadotropins instead might mediate age-dependent phenomena of amyloidopathy and cognitive decline., (© 2023 European Academy of Neurology.)

In a previous study, we observed: (i) significant hearing function impairment, assessed with pure tone audiometry and distortion product otoacoustic emissions, in patients with Parkinson's disease, compared with a matched control group, and (ii) lateralization of the hearing dysfunction, worse on the side affected by more pronounced Parkinson's disease motor symptoms. This study investigates the association between the basal ganglia dopamine transporter availability and the hearing function in Parkinson's disease patients, focusing also on the lateralization of both dysfunctions, with respect to that of the motor symptoms, and introducing a further distinction between patients with left-sided and right-sided predominant motor symptoms. Patients with right-handed Parkinson's disease with a recent estimation of 123 I-FP-CIT striatal uptake were audiologically tested with pure tone audiometry and distortion product otoacoustic emissions. Thirty-nine patients were included in the study. A statistically significant association was found, in the left-side predominant group only, between the distortion product otoacoustic emission levels and the contralateral dopamine transporter availability, and between the hearing threshold and the dopamine transporter availability difference between the ipsi- and the contralateral sides. The hearing impairment lateralization correlated to the motor symptom asymmetry was found significant only in the left-side predominant patients. The association between hearing function and basal ganglia dopamine transporter availability supports the hypothesis that the peripheral hearing function decline associated with dopamine depletion is involved in Parkinson's disease development, with a significant difference between patients with left- and right-sided predominant motor symptoms. These findings also suggest that peripheral hearing function evaluation and its lateralization could be key elements for subtyping the disease., Competing Interests: The authors report no conflict of interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Non-motor symptoms (NMS) characterize the Parkinson's disease (PD) clinical picture, and as well as motor fluctuations, PD patients can also experience NMS fluctuations (NMF). The aim of this observational study was to investigate the presence of NMS and NMF in patients with PD using the recently validated Non-Motor Fluctuation Assessment questionnaire (NoMoFa) and to evaluate their associations with disease characteristics and motor impairment. Patients with PD were consecutively recruited, and NMS, NMF, motor impairment, motor fluctuations, levodopa-equivalent daily dose, and motor performance were evaluated. One-third of the 25 patients included in the study (10 females, 15 males, mean age: 69.9 ± 10.3) showed NMF, and patients with NMF presented a higher number of NMS ( p < 0.01). Static NMS and NoMoFa total score were positively associated with motor performance assessed with the Global Mobility Task ( p < 0.01 and p < 0.001), and the latter was also correlated with motor impairment ( p < 0.05) but not with motor fluctuations. Overall, this study shows evidence that NMF are frequently reported by mild-to-moderate PD patients and associated with an increased number of NMS. The relationship between NoMoFa total score and motor functioning highlights the importance of understanding the clinical role of NMS and NMF in the management of PD patients.

Subthalamic nucleus deep-brain stimulation (STN-DBS), in addition to a rapid improvement of Parkinson's disease (PD) motor symptoms, can exert fast, local, neuromodulator activity, reducing β-synchronous oscillations between STN and the motor cortex with possible antikinetic features. However, STN-DBS modulation of β-band synchronization in extramotor cortical areas has been scarcely explored. For this aim, we investigated DBS-induced short-term effects on EEG-based cortical functional connectivity (FC) in β bands in six PD patients who underwent STN-DBS within the past year. A 10 min, 64-channel EEG recording was performed twice: in DBS-OFF and 60 min after DBS activation. Seven age-matched controls performed EEG recordings as the control group. A source-reconstruction method was used to identify brain-region activity. The FC was calculated using a weighted phase-lag index in β bands. Group comparisons were made using the Wilcoxon test. The PD patients showed a widespread cortical hyperconnectivity in β bands in both DBS-OFF and -ON states compared to the controls. Moreover, switching on STN-DBS determined an acute reduction in β FC, primarily involving corticocortical links of frontal, sensorimotor and limbic lobes. We hypothesize that an increase in β-band connectivity in PD is a widespread cortical phenomenon and that STN-DBS could quickly reduce it in the cortical regions primarily involved in basal ganglia-cortical circuits.

Parkinson's disease (PD) is characterized by motor symptoms often experienced in concomitance with non-motor symptoms (NMS), such as depression, apathy, pain, sleep disorders, and urinary dysfunction. The present study aimed to explore the effect of safinamide treatment on NMS and quality of life in motor-fluctuating PD patients. VALE-SAFI is an observational single-centre study performed in fluctuating PD patients starting safinamide treatment and followed for 6 months. The effects of safinamide on NMS, sleep, fatigue, depression and pain were assessed through validated sales. Changes in the scales from baseline to the 6-month follow-up visit were analysed. 60 PD patients (66.67% males) were enrolled at baseline, and 45 patients completed the 6-month follow-up. PD patients improved motor symptoms at follow-up, with the significant reduction of motor fluctuations. The global score of the NMS Scale significantly decreased between baseline and the follow-up. Regarding pain domains, patients reported a significant improvement in discolouration and oedema/swelling. Further, a significant improvement was observed from baseline to follow-up in sleep quality measured through the Pittsburgh Sleep Quality Index, while no changes were documented in daytime sleepiness. No differences were found in depression and fatigue between baseline and follow-up. Finally, the patient's perception of the impact of PD on functioning and well-being decreased from baseline to follow-up. The present findings confirmed the beneficial effect of safinamide on both motor and non-motor symptoms, also improving the quality of life of PD patients. Furthermore, these data support the positive effects of safinamide on pain and mood, as well as on sleep quality and continuity., (© 2022. The Author(s).)

Background: Sleep-related symptoms, especially insomnia, are frequently reported by patients with Parkinson's disease (PD) and can markedly affect motor symptoms and impair patients' quality of life. Melatonin has been shown to improve sleep in PD patients. This pilot study aimed at evaluating the effects of a 3-month treatment with 2 mg melatonin prolonged-release (PR) on sleep and motor disability in PD patients., Materials and Methods: Twelve PD patients under stable antiparkinsonian treatment were enrolled in the study. Before treatment (T0), motor dysfunction was assessed with Unified Parkinson's Disease Rating Scale (UPDRS-III) and sleep architecture with polysomnography. Subjective sleep quality was also assessed through Pittsburgh Sleep Quality Index (PSQI) and daytime somnolence with Epworth Sleepiness Scale (ESS). Patients then started melatonin PR and all measures were repeated at the end of treatment after 3 months (T1)., Results: Sleep latency significantly decreased from T0 to T1, but no other significant differences were found in PSG parameters. Melatonin PR treatment significantly reduced the ESS scores from T0 to T1, while the PSQI scores presented a trend of improvement from T0 to T1. Motor dysfunction was not improved by melatonin PR, although there was a trend in decreasing UPDRS-III. Both clinical global improvement and patient clinical global impression documented an improvement in insomnia symptoms at T1., Conclusions: These findings suggest that melatonin may improve sleep symptoms in PD patients, although further evidence is needed in larger controlled studies to confirm these results and explore the possible direct and indirect influence of sleep improvement on motor dysfunction., (© 2022. The Author(s).)

Most research analyzed gut-microbiota alterations in Parkinson's disease (PD) through cross-sectional studies, as single snapshots, without considering the time factor to either confirm methods and findings or observe longitudinal variations. In this study, we introduce the time factor by comparing gut-microbiota composition in 18 PD patients and 13 healthy controls (HC) at baseline and at least 1 year later, also considering PD clinical features. PD patients and HC underwent a fecal sampling at baseline and at a follow-up appointment. Fecal samples underwent sequencing and 16S rRNA amplicons analysis. Patients'clinical features were valued through Hoehn&Yahr (H&Y) staging-scale and Movement Disorder Society Unified PD Rating Scale (MDS-UPDRS) Part-III. Results demonstrated stability in microbiota findings in both PD patients and HC over a period of 14 months: both alfa and beta diversity were maintained in PD patients and HC over the observation period. In addition, differences in microbiota composition between PD patients and HC remained stable over the time period. Moreover, during the same period, patients did not experience any worsening of either staging or motor impairment. Our findings, highlighting the stability and reproducibility of the method, correlate clinical and microbiota stability over time and open the scenario to more extensive longitudinal evaluations.

Magnetic Resonance-guided Focused Ultrasound (MRgFUS) represents an effective micro-lesioning approach to target pharmaco-resistant tremor, mostly in patients afflicted by essential tremor (ET) and/or Parkinson's disease (PD). So far, experimental protocols are verifying the clinical extension to other facets of the movement disorder galaxy (i.e., internal pallidus for disabling dyskinesias). Aside from those neurosurgical options, one of the most intriguing opportunities of this technique relies on its capability to remedy the impermeability of blood-brain barrier (BBB). Temporary BBB opening through low-intensity focused ultrasound turned out to be safe and feasible in patients with PD, Alzheimer's disease, and amyotrophic lateral sclerosis. As a mere consequence of the procedures, some groups described even reversible but significant mild cognitive amelioration, up to hippocampal neurogenesis partially associated to the increased of endogenous brain-derived neurotrophic factor (BDNF). A further development elevates MRgFUS to the status of therapeutic tool for drug delivery of putative neurorestorative therapies. Since 2012, FUS-assisted intravenous administration of BDNF or neurturin allowed hippocampal or striatal delivery. Experimental studies emphasized synergistic modalities. In a rodent model for Huntington's disease, engineered liposomes can carry glial cell line-derived neurotrophic factor (GDNF) plasmid DNA (GDNFp) to form a GDNFp-liposome (GDNFp-LPs) complex through pulsed FUS exposures with microbubbles; in a subacute MPTP-PD model, the combination of intravenous administration of neurotrophic factors (either through protein or gene delivery) plus FUS did curb nigrostriatal degeneration. Here, we explore these arguments, focusing on the current, translational application of neurotrophins in neurodegenerative diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer AC declared a shared affiliation, with several of the authors AS, MP, LS, RC, MC, and SC to the handling editor at the time of the review., (Copyright © 2022 Stefani, Pierantozzi, Cardarelli, Stefani, Cerroni, Conti, Garasto, Mercuri, Marini and Sucapane.)

In Parkinson's disease (PD), cortical-subcortical interplay plays a relevant role in affecting clinical performance. Functional MRI sequences described changes in functional connectivity at different stages of disease. Scarce are, instead, the investigations examining brain connectivity in patients with PD at early stages of disease. For this aim, here we analyzed the differences in functional connectivity between de novo , never treated, PD patients and healthy controls. The analyses were based upon custom-written scripts on the Matlab platform, combined with high-level functions of Fieldtrip, Brainstorm, and Brain Connectivity toolboxes. First, we proceeded to the spectral analysis of the EEG data in the five frequency bands (δ-θ-α-β-γ). Second, we calculated functional connectivity matrices based on both coherency (COH) and imaginary part of coherency (iCOH), in the δ-θ-α-β-γ frequency bands. Then, four network measures (density, transitivity, global efficiency, and assortativity) were computed in identified connectivity matrices. Finally, we compared the spectral density, functional connectivity matrices, and network measured between healthy controls and de novo PD patients through two-samples T -test. A total of 21 de novo PD patients and 20 healthy subjects were studied. No differences were observed in spectral analysis between the two groups, with the exception of the γ band where a significant increase in power density was found in PD patients. A reduced connectivity in the main EEG frequency bands (α-β frequency bands) was observed in PD patients compared to controls, while a hyperconnectivity was found in PD patients in γ band. Among the network measures, a reduced assortativity coefficient was found in de novo PD patients in α frequency band. Our results show the occurrence of early EEG functional connectivity alterations from the initial stages of PD. From this point of view, connectivity analysis may ease a better understanding of the complexity of PD physiopathology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Conti, Bovenzi, Garasto, Schirinzi, Placidi, Mercuri, Cerroni, Pierantozzi and Stefani.)

Background: Several biomarkers have been evaluated in Parkinson's disease (PD); cerebrospinal fluid (CSF) levels of lactate may reflect cerebral metabolism function and CSF amyloid-β42 (Aβ42), total tau (t-tau) and phosphorylated tau (p-tau) concentrations may detect an underlying neurodegenerative process., Objective: CSF levels of lactate, Aβ42, t-tau, and p-tau were measured in patients with mild to moderate PD. CSF levels of dopamine (DA) and its metabolite 3,4-Dihydroxyphenylacetic acid (DOPAC) were also assessed, exploring their relations with the other CSF biomarkers., Methods: 101 drug-naive PD patients and 60 controls were included. Participants underwent clinical assessments and CSF biomarker analysis. Patients were divided into subgroups according to their Hoehn & Yahr stage (PD-1, PD-2, PD-3)., Results: PD patients showed higher lactate levels (M = 1.91; p = 0.03) and lower Aβ42 (M = 595; p < 0.001) and DA levels (M = 0.32; p = 0.04) than controls (Mlactate = 1.72; MAβ42 = 837; MDA = 0.50), while no significant differences were found in t-tau, p-tau and DOPAC concentrations. Considering the subgroup analysis, PD-3 group had higher lactate (M = 2.12) and t-tau levels (M = 333) than both PD-1 (Mlactate = 1.75, p = 0.006; Mt - tau = 176, p = 0.008) and PD-2 groups (Mlactate = 1.91, p = 0.01; Mt - tau = 176, p = 0.03), as well as the controls (Mlactate = 1.72, p = 0.04; Mt - tau = 205, p = 0.04). PD-2 group showed higher lactate levels than PD-1 group (p = 0.04) and controls (p = 0.03). Finally, CSF lactate levels negatively correlated with DA (r = -0.42) and positively with t-tau CSF levels (r = 0.33)., Conclusion: This CSF-based study shows that lactate levels in PD correlated with both clinical disease progression and neurodegeneration biomarkers, such as tau proteins and DA. Further studies should explore the clinical potential of measuring CSF biomarkers for better understanding the role of brain energy metabolism in PD, for research and therapeutic options.

Background: Adult-onset sporadic chorea includes a wide and heterogeneous group of conditions whose differential diagnosis and treatments are often challenging and extensive., Objectives: To analyse retrospectively cases of adult-onset sporadic chorea from a single Italian centre to provide insights for a practical approach in the management of these patients., Methods: A total of 11,071 medical charts from a 9-year period (2012-2020) were reviewed, identifying 28 patients with adult-onset sporadic chorea (genetic forms excluded). All available data regarding phenomenology, diagnostic workup, aetiology, treatments, and long-term outcome from this cohort were collected and analysed., Results: Adult-onset sporadic chorea occurred more frequently in females and presented with an acute-subacute onset. Cerebrovascular diseases accounted for 68% of aetiology; further causes were structural brain lesions, internal diseases, and other movement disorder syndromes. Clinical course was mild, with spontaneous resolution or minimal disturbances in 82% of cases. Neuroimaging was fundamental to diagnose 76% of adult-onset sporadic chorea, an appropriate clinical examination contributed to the 14% of diagnoses, whereas basic laboratory tests to the 10%., Conclusions: Revision of real-world data of adult-onset sporadic chorea patients from a single Italian cohort suggests that an accurate clinical examination, neuroimaging, and routine laboratory tests are useful to identify those cases underlying potentially severe but treatable conditions. Although in the majority of cases adult-onset sporadic chorea has mild clinical course and good response to symptomatic treatments, it is essential to run a fast diagnostic workup., (© 2021. The Author(s).)

Objective: The prevalence of autonomic involvement in early stage of Parkinson 's disease (PD) is still debated. Aim of this study is to assess the autonomic functions in de novo PD patients (dnPD) in comparison with PD patients on therapy (PDot) and healthy controls (HC)., Methods: Twenty-eight dnPD and 24 PDot, to whom Unified Parkinson's Rating Scale (UPDRS) was administered, and 23 HC underwent electrochemical skin conductance (ESC) measured with sudoscan, cardiovascular reflexes (head-up tilt test HUTT, Valsalva maneuver, deep breathing, hand grip, and cold face),and Scales for Outcomes in Parkinson's Disease-Autonomic Dysfunction (SCOPA-AUT) questionnaire., Results: The mean SCOPA-AUT total score was significantly higher in dnPD group compared with HC group (p < 0.001) and significantly lower than PDot (p = 0.004). No significant difference of ESC mean values were found between dnPD and HC group. DnPD had a significantly lower diastolic blood pressure (BP) response at handgrip test (p = 0.005) compared with HC. Hands and feet ESC significantly negatively correlated with disease duration (p = 0.014; p = 0.025) and feet ESC significantly negatively correlated with UPDRS III (p = 0.039). Systolic and diastolic BP responses at 3rd minute of HUTT correlated significantly negatively with disease duration (p < 0.001; p = 0.003) and with UPDRSIII (p = 0.001; p < 0.001). BP response to Valsalva maneuver negatively correlated with UPDRSIII (p = 0.006)., Conclusion: Although dnPD patients complain of thermoregulatory symptoms, we found no alteration in the sudomotor function investigated with sudoscan. Furthermore, a deficit of the sympathetic vasoconstrictive response to the isometric exercise was detected, suggesting an early involvement of the autonomic cardiovascular components in dnPD., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Non-motor symptoms (NMS), including neuropsychiatric, sleep, autonomic, and sensory domains, are an integral aspect of the clinical presentation of Parkinson disease (PD) and affect neurocognitive functioning as well as patients' and caregivers' well-being. Objective: To describe the occurrence of NMS in PD patients with motor fluctuations in real-life condition. Methods: The present study is a secondary analysis of a previous multinational, multicenter, retrospective-prospective cohort observational study (SYNAPSES). Patients with PD diagnosis and motor fluctuations aged ≥18 years were included. Data collected at the baseline visit were used for this study, and descriptive analyzes were conducted to describe the distribution of NMS in motor-fluctuating PD patients distributed according to different clinical characteristics. Results: Of the 1,610 patients enrolled, 1,589 were included for the analysis (978 males and 611 females), with a mean age of 68.4 (SD = 9.6). Most patients had at least one NMS (88.5%). Sleep problems and psychiatric symptoms were the most prevalent NMS in motor fluctuating PD patients in all H and Y stages. Psychiatric disorders were more frequent in older patients and in patients with a larger number of years of PD diagnosis, while sleep problems were more preeminent in younger patients and with inferior disease duration. Conclusions: The present findings further support the high prevalence of NMS in PD patients with motor fluctuations, thus reinforcing the need for assessing them for diagnostic accuracy and for delivering holistic care., Competing Interests: CC is a Zambon S.p.A. employee; EB is a statistical consultant of Zambon S.p.A.; CL and AS received symposium honoraria from Zambon S.p.A. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Fernandes, Pierantozzi, Stefani, Cattaneo, Bonizzoni, Cerroni, Mercuri and Liguori.)

Objectives: Non-motor symptoms (NMS) frequently impact health-related quality of life (HRQoL) in patients with Parkinson's Disease (PD). Sleep problems represent one of the main NMS complained by PD patients. In this observation study, sleep problems measured by Parkinson's Disease Sleep Scale - 2nd version (PDSS-2), and HRQoL measured by Parkinson's Disease Questionnaire-39 (PDQ39) were quantified in patients with PD ranging from mild to moderate-advanced disease stages, and correlated to motor impairment and anti-PD therapy., Methods: We included idiopathic PD patients who underwent PDSS-2 and PDQ39. Moreover, we assessed patients' motor symptoms by rating the Unified Parkinson's Disease Rating Scale (UPDRS) - III section (motor examination), patients' PD status following H&Y stage, and levodopa equivalent daily dose (LEDD)., Results: One-hundred and fifty-four patients with PD were included and distributed for H&Y stage. PDSS-2 and PDQ39 total and sub-items scores significantly increased with the H&Y stage. PDSS-2 total score significantly correlated with PDQ39 total score (γ = 0.63, P < 0.01). Finally, distributing PD patients according to the PDSS-2 cut-off for detecting sleep disturbances, we found in poor sleepers (n = 58) higher PDQ39 scores than good sleepers (n = 89)., Conclusions: Sleep problems are very common in patients with PD and severely impact on HRQoL. Sleep impairment and low HRQoL occur from the early stages of the disease and deteriorate along disease progression. Further studies investigating sleep and quality of life should be planned for targeting sleep improvement to increase HRQoL and possibly reduce motor impairment., (Copyright © 2021 Elsevier B.V. All rights reserved.)