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Background: Family history of Parkinson's disease (PD) is a common finding in PD patients. However, a few studies have systematically examined this aspect., Objectives: We investigated the family history of PD patients, comparing demographic and clinical features between familial PD (fPD) and sporadic PD (sPD)., Methods: A cross-sectional study enrolling 2035 PD patients was conducted in 28 Italian centers. Clinical data and family history up to the third degree of kinship were collected., Results: Family history of PD was determined in 21.9% of patients. fPD patients had earlier age at onset than sporadic patients. No relevant differences in the prevalence of motor and nonmotor symptoms were detected. Family history of mood disorders resulted more prevalently in the fPD group., Conclusions: fPD was found to recur more frequently than previously reported. Family history collection beyond the core family is essential to discover disease clusters and identify novel risk factors for PD., (© 2024 The Author(s). Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Tremor disorders remain as clinical diagnoses and the rate of misdiagnosis between the commonest non-parkinsonian tremors is relatively high., Objectives: To compare the clinical features of Essential Tremor without other features (pure ET), ET plus soft dystonic signs (ET + DS), and tremor combined with dystonia (TwD)., Methods: We compared the clinical features of patients with pure ET, ET + DS, and TwD enrolled in The ITAlian tremor Network (TITAN). Linear regression models were performed to determine factors associated with health status and quality of life., Results: Three-hundred-eighty-three patients were included. Sex distribution was significantly different between the groups with males being more represented in pure ET and females in TwD. The initial site of tremor was different between the groups with about 40% of TwD having head tremor and ET + DS unilateral upper limb tremor at onset. This pattern mirrored the distribution of overt dystonia and soft dystonic signs at examination. Sensory trick, task-specificity, and position-dependence were more common, but not exclusive, to TwD. Pure ET patients showed the lowest degree of alcohol responsiveness and ET + DS the highest. Midline tremor was more commonly encountered and more severe in TwD than in the other groups. Regression analyses demonstrated that tremor severity, sex, age, and to a lesser degree the variable "group", independently predicted health status and quality of life, suggesting the existence of other determinants beyond tremor., Conclusions: Pure ET and TwD manifest with a phenotypic overlap, which calls for the identification of diagnostic biomarkers. ET + DS shared features with both syndromes, suggesting intra-group heterogeneity., (© 2024 International Parkinson and Movement Disorder Society.)

Spinocerebellar ataxia (SCA)19/22 is a channelopathy caused by mutations in the KCND3 gene encoding for the voltage-gated potassium channel Kv4.3. In the present work, we report an Italian family harboring a novel KCND3 missense mutation characterized by ataxia and mild parkinsonism. Patients underwent dopamine transporter single-photon emission computed tomography to assess dopaminergic degeneration. Normal findings were observed, and treatment with levodopa did not yield any benefit, thus suggesting the involvement of other mechanisms to explain parkinsonian symptoms in SCA19/22. Our cases expand the genetic and imaging spectrum of this rare disease and emphasize a cautious approach in managing parkinsonism in these patients., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background: Although acquired dystonia may develop following ischaemic/haemorrhagic stroke, the relationship between cerebrovascular disease and idiopathic dystonia has been poorly investigated. This cross sectional study aimed at evaluating the impact of cerebrovascular risk factors on the clinical expression of idiopathic adult onset dystonia (IAOD), with reference to dystonia localization and dystonia-associated features., Methods: Data were obtained from the Italian Dystonia Registry. Patients with IAOD were stratified into two groups according to the presence of diabetes mellitus and/or arterial hypertension and/or dyslipidemia and/or heart disease. The two groups were compared for demographic features, dystonia phenotype, and dystonia-associated features (sensory trick, tremor, eye symptoms in blepharospasm, and neck pain in cervical dystonia)., Results: A total of 1108 patients participated into the study. Patients who reported one cerebrovascular factor or more (n = 555) had higher age and longer disease duration than patients who did not. On multivariable logistic regression analysis, blepharospasm was the only localization, and sensory trick was the only dystonia-associated feature that was significantly associated with cerebrovascular risk factors. Linear regression analysis showed that the strength of the association between cerebrovascular factors and blepharospasm/sensory trick increased with increasing the number of cerebrovascular factors per patient., Conclusions: Results of the present study showed that cerebrovascular risk factors may be associated with specific features of IAOD that is development of blepharospasm and sensory trick. Further studies are needed to better understand the meaning and the mechanisms underlying this association., Competing Interests: Declaration of competing interest None, (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Gait abnormalities are common in the elderly and individuals diagnosed with Parkinson's, often leading to reduced mobility and increased fall risk. Monitoring and assessing gait patterns in these populations play a crucial role in understanding disease progression, early detection of motor impairments, and developing personalized rehabilitation strategies. In particular, by identifying gait irregularities at an early stage, healthcare professionals can implement timely interventions and personalized therapeutic approaches, potentially delaying the onset of severe motor symptoms and improving overall patient outcomes. In this paper, we studied older adults affected by chronic diseases and/or Parkinson's disease by monitoring their gait due to wearable devices that can accurately detect a person's movements. In our study, about 50 people were involved in the trial (20 with Parkinson's disease and 30 people with chronic diseases) who have worn our device for at least 6 months. During the experimentation, each device collected 25 samples from the accelerometer sensor for each second. By analyzing those data, we propose a metric for the "gait quality" based on the measure of entropy obtained by applying the Fourier transform.

Background: To date, there are no large studies delineating the clinical correlates of "pure" essential tremor (ET) according to its new definition., Methods: From the ITAlian tremor Network (TITAN) database, we extracted data from patients with a diagnosis of "pure" ET and excluded those with other tremor classifications, including ET-plus, focal, and task-specific tremor, which were formerly considered parts of the ET spectrum., Results: Out of 653 subjects recruited in the TITAN study by January 2022, the data of 208 (31.8%) "pure" ET patients (86M/122F) were analyzed. The distribution of age at onset was found to be bimodal. The proportion of familial cases by the age-at-onset class of 20 years showed significant differences, with sporadic cases representing the large majority of the class with an age at onset above 60 years. Patients with a positive family history of tremor had a younger onset and were more likely to have leg involvement than sporadic patients despite a similar disease duration. Early-onset and late-onset cases were different in terms of tremor distribution at onset and tremor severity, likely as a function of longer disease duration, yet without differences in terms of quality of life, which suggests a relatively benign progression. Treatment patterns and outcomes revealed that up to 40% of the sample was unsatisfied with the current pharmacological options., Discussion: The findings reported in the study provide new insights, especially with regard to a possible inversed sex distribution, and to the genetic backgrounds of "pure" ET, given that familial cases were evenly distributed across age-at-onset classes of 20 years. Deep clinical profiling of "pure" ET, for instance, according to age at onset, might increase the clinical value of this syndrome in identifying pathogenetic hypotheses and therapeutic strategies., Competing Interests: RE receives royalties from the publication of Case Studies in Movement Disorders—Common and Uncommon Presentations (Cambridge University Press, 2017) and of Paroxysmal Movement Disorders (Springer, 2020). He has received consultancies from Sanofi and honoraria for speaking from the International Parkinson's Disease and Movement Disorders Society. PB received consultancies as a member of the advisory board for Zambon, Lundbeck, UCB, Chiesi, Abbvie, and Acorda. APi received grant support from the Ministry of Education, Research and University (MIUR) and IMI H2020 Initiative (IDEA-FAST project- MI2-2018-15-06), received research support from Zambon SrL Italy and Bial Italy; he received speaker honoraria from AbbVie, BioMarin, Bial, and Zambon Pharmaceuticals. APa received grant support from the Ministry of Health (MINSAL) and the Ministry of Education, Research and University (MIUR), from CARIPLO Foundation; personal compensation as a consultant/scientific advisory board member for Biogen 2019-2020-2021 Roche 2019-2020 Nutricia 2020-2021 General Healthcare (GE) 2019; he received honoraria for lectures at meeting ADPD2020 from Roche, lecture at meeting of the Italian Society of Neurology 2020 from Biogen and from Roche, and lecture at meeting AIP 2020 and 2021 from Biogen and from Nutricia, Educational Consulting 2019-2020-2021 from Biogen. AD reports advisory board fees from Sanofi and speaking honoraria from Sanofi, Zambon, and Bial. 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 © 2023 Erro, Lazzeri, Gigante, Pilotto, Magistrelli, Bologna, Terranova, Olivola, Dallocchio, Moschella, Valentino, Di Biasio, Nicoletti, De Micco, Brusa, Sorrentino, Matinella, Bertino, Paparella, Modugno, Contaldi, Padovani, Di Fonzo, Restaino, Barone and TITAN study group.)

Background: To date, a few studies have systematically investigated differences in the clinical spectrum between acquired and idiopathic dystonias., Objectives: To compare demographic data and clinical features in patients with adult-onset acquired and idiopathic dystonias., Methods: Patients were identified from among those included in the Italian Dystonia Registry, a multicenter Italian dataset of patients with adult-onset dystonia. Study population included 116 patients with adult-onset acquired dystonia and 651 patients with isolated adult-onset idiopathic dystonia., Results: Comparison of acquired and idiopathic dystonia revealed differences in the body distribution of dystonia, with oromandibular dystonia, limb and trunk dystonia being more frequent in patients with acquired dystonia. The acquired dystonia group was also characterized by lower age at dystonia onset, greater tendency to spread, lower frequency of head tremor, sensory trick and eye symptoms, and similar frequency of neck pain associated with CD and family history of dystonia/tremor., Conclusions: The clinical phenomenology of dystonia may differ between acquired and idiopathic dystonia, particularly with regard to the body localization of dystonia and the tendency to spread. This dissimilarity raises the possibility of pathophysiological differences between etiologic categories., (© 2023 International Parkinson and Movement Disorder Society.)

Background: Parkinson's disease (PD) is a common neurodegenerative disease. No disease-modifying treatment is available, and therapy is symptomatic. The histopathologic hallmark is the loss of dopaminergic neurons and accumulation of α-synuclein (α-syn) in surviving neurons, but the underlying pathophysiology is unclear. Inflammatory mechanisms seem to play a prominent role, with an imbalance of immune functions and neurotoxicity caused by reactive oxygen species (ROS). Involvement of peripheral adaptive immunity, with an imbalance in T cell subpopulations and in the expression of transcriptional factors in CD4+ T cells, has also been reported. Although clinical presentation is defined by motor symptoms, patients also report non-motor symptoms, often before the onset of a clinically established disease. Etiopathogenesis of PD is unknown, but an initial aggregation of α-syn in the gut, with subsequent propagation along the vagus nerve to the brain has been hypothesised. Interestingly, in an α-syn overexpressing murine model, the absence of gut microbiota prevented both microglia activation and motor impairment, thus pointing to a fundamental role of microbiota in the development of PD. Magistrelli et al. showed that in peripheral blood mononuclear cells of PD patients, probiotics modulate the in vitro production of cytokines toward an anti-inflammatory profile and reduce the production of ROS., Methods: This is a pilot randomised placebo-controlled clinical trial protocol for a 12-week treatment with probiotics. At least 80 patients affected by PD will be recruited and randomly allocated to either the treatment or placebo group in a 1:1 ratio. General inclusion criteria will be the onset of PD 2 to 5 years before the trial and absence of autoimmune comorbidities or immunomodulating therapy. Our primary endpoint is the assessment of changes in extracellular cytokine levels (Interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-4, and IL-10) and ROS production. Secondary outcomes include changes in lymphocyte subpopulations and transcriptional factors mRNA levels., Discussion: This study is designed to highlight the potential beneficial role of probiotics administration on peripheral immunity through the modulation of gut microbiota. Explorative outcomes will be evaluated to assess variations in motor and non-motor symptoms and the possible correlation with probiotics administration., Trial Registration: ClinicalTrials.gov ID NCT05173701. Registered 08 November 2021., (© 2023. The Author(s).)

Background: Dysregulation of the CD4 + T cell compartment occurs in Parkinson's Disease (PD). Nonetheless, the exact relationship with dopamine transporter (DAT) SPECT denervation patterns is currently unknown., Methods: Expression of transcription factors and levels of circulating CD4 + T cell subsets were assessed in peripheral blood mononuclear cells (PBMC) from 23 newly diagnosed drug-naïve PD patients. Semi-quantitative [ 123 I]-FP-CIT SPECT data, i.e. uptake in the most and least affected putamen (maP, laP) and caudate (maC, laC), total striatal binding ratio (tSBR), and total putamen-to-caudate ratio (tP/C) were obtained., Results: FOXP3 mRNA levels correlated with the uptake in maC (r = - 0.542, P = 0.011), laP (r = - 0.467, P = 0.033), and tSBR (r = - 0.483, P = 0.027). Concerning flow cytometry analysis of circulating CD4 + T cell subsets, a significant relationship between tP/C, caudate uptake, and the levels of both T helper (Th)1 and 2, was detected. Furthermore, we found significant correlations between the uptake in maP and the total count of naïve and activated T regulatory cells (Treg) (r = - 0.717, P = 0.001; r = - 0.691, P = 0.002), which were confirmed after the Benjamini-Hochberg correction for multiple comparisons using a false discovery rate at level q = 0.10. Levels of circulating naïve Treg were higher (P = 0.014) in patients with more extensive dopaminergic denervation, suggesting a compensatory phenomenon., Conclusions: Peripheral CD4 + T cell immunity is involved in early-stage PD and novel correlations with striatal DAT loss were observed., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Effects of dopaminergic medications used to treat Parkinson's disease (PD) may be compared with each other by using conversion factors, calculated as Levodopa equivalent dose (LED). However, current LED proposals on MAO-B inhibitors (iMAO-B) safinamide and rasagiline are still based on empirical approaches., Objectives: To estimate LED of safinamide 50 and 100 mg., Methods: In this multicenter, longitudinal, case-control study, we retrospectively reviewed clinical charts of 500 consecutive PD patients with motor complications and treated with (i) safinamide 100 mg ( N  = 130), safinamide 50 mg ( N  = 144), or rasagiline 1 mg ( N  = 97) for 9 ± 3 months and a control group of patients never treated with any iMAO-B ( N  = 129)., Results: Major baseline features (age, sex, disease duration and stage, severity of motor signs and motor complications) were similar among the groups. Patients on rasagiline had lower UPDRS-II scores and Levodopa dose than control subjects. After a mean follow-up of 8.8-to-10.1 months, patients on Safinamide 50 mg and 100 mg had lower UPDRS-III and OFF-related UPDRS-IV scores than control subjects, who in turn had larger increase in total LED than the three iMAO-B groups. After adjusting for age, disease duration, duration of follow-up, baseline values and taking change in UPDRS-III scores into account (sensitivity analysis), safinamide 100 mg corresponded to 125 mg LED, whereas safinamide 50 mg and rasagiline 1 mg equally corresponded to 100 mg LED., Conclusions: We used a rigorous approach to calculate LED of safinamide 50 and 100 mg. Large prospective pragmatic trials are needed to replicate our findings., (© 2023 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Parkinson's disease (PD) is a common neurodegenerative disease characterized by loss of dopaminergic neurons and intraneuronal accumulation of protein aggregates. The exact mechanisms leading to neuronal death in PD are not fully understood, but several different molecular pathways are involved, leading to the concept that molecular subtypes may coexist in the nosological spectrum of PD. To this respect, immune system activation, both in the periphery and inside the central nervous system, was detected as a common trait of several pathogenic pathways of PD. The current working hypothesis implies that immune cells shift towards a proinflammatory phenotype and trigger the production of neurotoxic cytokines, ultimately contributing to neurodegeneration. While it is very important to understand how commonly used antiparkinson drugs interact with such changes, the search for treatments that may directly or indirectly modulate immune function is a great opportunity for disease modification., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

In recent years, the contraposition between inflammatory and neurodegenerative processes has been increasingly challenged. Inflammation has been emphasized as a key player in the onset and progression of Parkinson disease (PD) and other neurodegenerative disorders. The strongest indicators of the involvement of the immune system derived from evidence of microglial activation, profound imbalance in phenotype and composition of peripheral immune cells, and impaired humoral immune responses. Moreover, peripheral inflammatory mechanisms (e.g., involving the gut-brain axis) and immunogenetic factors are likely to be implicated. Even though several lines of preclinical and clinical studies are supporting and defining the complex relationship between the immune system and PD, the exact mechanisms are currently unknown. Similarly, the temporal and causal connections between innate and adaptive immune responses and neurodegeneration are unsettled, challenging our ambition to define an integrated and holistic model of the disease. Despite these difficulties, current evidence is providing the unique opportunity to develop immune-targeted approaches for PD, thus enriching our therapeutic armamentarium. This chapter aims to provide an extensive overview of past and present studies that explored the implication of the immune system in neurodegeneration, thus paving the road for the concept of disease modification in PD., (Copyright © 2023 Elsevier B.V. All rights reserved.)