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Since the initial description of Essential Tremor (ET), the entity of ET with rest tremor has proven to be a controversial concept. Some authors argued it could be a late manifestation of ET, others suggested it could be a variant of ET, yet others suggested it could represent a transitional state between ET and Parkinson's disease. The novel tremor classification has proposed the construct of ET-plus to differentiate patients with rest tremor from pure ET. However, there is no clarity of what ET-plus rest tremor represents. With the aim of shedding light on this controversial entity, we have, therefore, systematically reviewed all clinical, electrophysiological, imaging and anatomopathological studies indexed in the Medline database published both before and after the new tremor classification and involving patients with ET-plus rest tremor. Forty-four studies involving 4028 patients were included in this review and analyzed in detail by means of descriptive statistics. The results of the current review suggest that ET-plus rest tremor is a heterogenous group of conditions: thus, rest tremor might represent a late feature of ET, might reflect a different disorder with higher age at onset and lower dependance on genetic susceptibility than ET, might suggest the development of Parkinson's disease or might indicate a misdiagnosis of ET. The reviewed lines of evidence refuse recent claims arguing against the construct of ET-plus, which should be viewed as a syndrome with different possible underpinnings, and highlights methodological issues to be solved in future research.

Major progress has occurred during the last decade in the field of tremor. From the clinical standpoint, a new classification has completely revised the nosology of tremor syndromes and has re-conceptualized essential tremor as a syndrome rather than a single disease entity, fueling an ongoing enlightened debate. Significant advances have been obtained in terms of instrumental measurement of tremor, remarking on the possibility of developing novel treatment strategies based on tremor characteristics, namely tremor-phase. Moreover, a better understanding of the pathophysiological mechanisms has further led to the suggestion of refining the classification of tremor syndromes according to their driving underpinnings. Finally, surgical options such as deep brain stimulation and focused ultrasound thalamotomy are now part of the therapeutic portfolio for tremor, but several oral drugs, including long-chain alcohols, T-channel blockers, allosteric modulators of potassium channels, and of GABA-A receptors, are currently being tested and hold promise. This review will discuss the key milestones in tremor research of the last 10 years, with a focus on the most common tremor syndromes, namely essential tremor, dystonic tremor, and Parkinsonian tremor.

Introduction: Progressive supranuclear palsy (PSP) is an atypical parkinsonism characterized by prominent gait and postural impairment. The PSP rating scale (PSPrs) is a clinician-administered tool to evaluate disease severity and progression. More recently, digital technologies have been used to investigate gait parameters. Therefore, object of this study was to implement a protocol using wearable sensors evaluating disease severity and progression in PSP. Methods: Patients were evaluated with the PSPrs as well as with three wearable sensors located on the feet and lumbar area. Spearman coefficient was used to assess the relationship between PSPrs and quantitative measurements. Furthermore, sensor parameters were included in a multiple linear regression model to assess their ability in predicting the PSPrs total score and sub-scores. Finally, differences between baseline and three-month follow-up were calculated for PSPrs and each quantitative variable. The significance level in all analyses was set at ≤ 0.05. Results: Fifty-eight evaluations from thirty-five patients were analyzed. Quantitative measurements showed multiple significant correlations with the PSPrs scores (r between 0.3 and 0.7; p

Introduction Little is known about metabolic changes in progressive supranuclear palsy. Goals of the present study are to: (1) investigate whether early progressive supranuclear palsy is associated with changes in energy expenditure, body composition and dietary intake compared with Parkinson’s disease and healthy controls; (2) assess the accuracy of the Harris–Benedict equation to predict measured rest energy expenditure in progressive supranuclear palsy; (3) verify differences according to sex, phenotypes, disease severity and presence of dysphagia in progressive supranuclear palsy. Methods Twenty-one progressive supranuclear palsy, 41 Parkinson’s disease and nine healthy controls were included. Rest energy expenditure was assessed with indirect calorimeter, body composition with bio-impedance analysis and physical activity and dietary intake were estimated with a validated frequency questionnaire. Parametric testing was used to analyze differences between groups. Results Progressive supranuclear palsy showed reduced total daily energy expenditure and physical activity compared to both other cohorts (p 0.05). Limited accuracy was shown for the Harris–Benedict equation (accurate prediction frequency

Background The evidence about the language performance profile of multiple system atrophy (MSA) is limited, but its definition may lead to a more comprehensive characterization of the disorder and contribute to clarify the involvement of the basal ganglia in language abilities. Objective The objectives of the study were: (1) to evaluate the reliability of the Screening for Aphasia in NeuroDegeneration (SAND) in MSA patients; (2) compare the linguistic profiles among MSA and Parkinson’s disease (PD) patients and healthy controls (HC), and (3) assess relationships between language impairment and cognitive status and MSA motor subtypes. Methods and results Forty patients with a diagnosis of MSA, 22 HC and 17 patients with PD were enrolled in the present study. By excluding the writing task that showed a poor acceptability, we showed that the MSA-tailored SAND Global Score is an acceptable, consistent and reliable tool to screen language disturbances in MSA. MSA patients performed worse than HC, but not than PD, in MSA-tailored SAND Global Score, repetition, reading and semantic association tasks. We did not find significant differences between MSA phenotypes. MSA patients with mild cognitive impairment-multiple domain presented worse language performances as compared to MSA patients with normal cognition and mild cognitive impairment-single domain. Conclusion The MSA-tailored SAND Global Score is a consistent and reliable tool to screen language disturbances in MSA. Language disturbances characterize MSA patients irrespective of disease phenotype, and parallel the decline of global cognitive functions.

The exact pathophysiology of cognitive impairment in multiple system atrophy (MSA) is unclear. In our longitudinal study, we aimed to analyze (I) the relationships between cognitive functions and some subcortical structures, such as putamen and cerebellum assessed by voxel-based morphometry (VBM) and T1-weighted/T2-weighted (T1w/T2w) ratio, and (II) the neuroimaging predictors of the progression of cognitive deficits. Twenty-six patients with MSA underwent a comprehensive neuropsychological battery, motor examination, and brain MRI at baseline (T0) and 1-year follow-up (T1). Patients were then divided according to cognitive status into MSA with normal cognition (MSA-NC) and MSA with mild cognitive impairment (MCI). At T1, we divided the sample according to worsening/non worsening of cognitive status compared to baseline evaluation. Logistic regression analysis showed that age (β = − 9.45, p = .02) and T1w/T2w value in the left putamen (β = 230.64, p = .01) were significant predictors of global cognitive status at T0, explaining 65% of the variance. Logistic regression analysis showed that ∆-values of WM density in the cerebellum/brainstem (β = 2188.70, p = .02) significantly predicted cognitive worsening at T1, explaining 64% of the variance. Our results suggest a role for the putamen and cerebellum in the cognitive changes of MSA, probably due to their connections with the cortex. The putaminal T1w/T2w ratio may deserve further studies as a marker of cognitive impairment in MSA.

Background Dystonia may have different neuroanatomical substrates and pathophysiology. This is supported by studies on the motor system showing, for instance, that plasticity is abnormal in idiopathic dystonia, but not in dystonia secondary to basal ganglia lesions. Objective The aim of this study was to test whether somatosensory inhibition and plasticity abnormalities reported in patients with idiopathic dystonia also occur in patients with dystonia caused by basal ganglia damage. Methods Ten patients with acquired dystonia as a result of basal ganglia lesions and 12 healthy control subjects were recruited. They underwent electrophysiological testing at baseline and after a single 45-minute session of high-frequency repetitive somatosensory stimulation. Electrophysiological testing consisted of somatosensory temporal discrimination, somatosensory-evoked potentials (including measurement of early and late high-frequency oscillations and the spatial inhibition ratio of N20/25 and P14 components), the recovery cycle of paired-pulse somatosensory-evoked potentials, and primary motor cortex short-interval intracortical inhibition. Results Unlike previous reports of patients with idiopathic dystonia, patients with acquired dystonia did not differ from healthy control subjects in any of the electrophysiological measures either before or after high-frequency repetitive somatosensory stimulation, except for short-interval intracortical inhibition, which was reduced at baseline in patients compared to control subjects. Conclusions The data show that reduced somatosensory inhibition and enhanced cortical plasticity are not required for the clinical expression of dystonia, and that the abnormalities reported in idiopathic dystonia are not necessarily linked to basal ganglia damage. © 2020 International Parkinson and Movement Disorder Society.

Background The clinical differentiation between Parkinson disease (PD) and multiple system atrophy (MSA) is difficult. Objectives Arterial spin labeling (ASL) is an advanced MRI technique that obviates the use of an exogenous contrast agent for the estimation of cerebral perfusion. We explored the value of ASL in combination with structural MRI for the differentiation between PD and MSA. Methods Ninety-four subjects (30 PD, 30 MSA and 34 healthy controls) performed a morphometric and ASL-MRI to measure volume and perfusion values within basal ganglia and cerebellum. A region-of-interest analysis was performed to test for structural atrophy and regional blood flow differences between groups. Results MSA patients showed higher subcortical atrophy than both PD patients and HC, while no differences were observed between the latter. MSA and PD showed lower volume-corrected perfusion values than HC in several cerebellar areas (Crus I, Crus II, right VIIb, right VIIIa, right VIIIb), right caudate and both thalami. MSA and PD patients displayed similar perfusion values in all aforementioned areas, but the right cerebellar area VIIIb (lower in MSA) and right caudate and both thalami (lower in PD). Similar results were obtained when comparing PD and MSA patients with the parkinsonian variant. Conclusions A perfusion reduction was equally observed in both MSA and PD patients in cerebellar areas that are putatively linked to cognitive (i.e., executive) rather than motor functions. The observed hypo-perfusion could not be explained by atrophy, suggesting the involvement of the cerebellum in the pathophysiology of both MSA and PD.

Introduction Cognitive deficits and neuropsychiatric symptoms occur in parkinsonian and cerebellar subtypes of Multiple System Atrophy (MSA-P and MSA-C). These symptoms have been investigated mainly in cross-sectional studies. The present 1-year follow-up study aimed at evaluating the evolution of cognitive and neuropsychiatric profile in patients with MSA-C and MSA-P. Methods Twenty-nine patients with MSA-P, 21 with MSA-C and 30 healthy subjects (HCs) underwent a neuropsychological battery and questionnaires assessing depression and apathy (T0). After 1 year (T1), patients with MSA-C and MSA-P underwent the same neuropsychological and neuropsychiatric tools employed at T0. Results At T0, MSA-P and MSA-C groups were more depressed and apathetic and performed worse on tests assessing repetition abilities, executive and attentive functions than HCs. MSA-P and MSA-C groups did not differ on cognitive variables and neuropsychiatric scales. At T1, a significant worsening in spatial planning and psychomotor speed in MSA-C group and a significant worsening in memory, spatial planning, repetition abilities and functional autonomy in MSA-P group were found. The prevalence of apathy increased in both subtypes, whereas the prevalence of depression was reduced in MSA-C and relatively consistent in MSA-P. Conclusions The finding revealed a wide-ranging worsening of cognitive functions in MSA-P and a significant decline in processing speed in MSA-C. These results underline the relevance of evaluating cognitive and psychiatric features of MSA over the course of the disease in the daily clinical practice.

Although tremor is deemed to be the commonest movement disorder, in adults the differential diagnosis usually boils down to whether the patient has Essential Tremor or Parkinson's Disease, which has likely led to an overdiagnosis of these conditions; yet, many important rare syndromes should be considered in the differential diagnosis of patients with tremor. The aim of this review is to focus on rare forms of tremor, also in view of the new tremor classification, as well as on tremor occurring in other neurological disorders to aid their recognition. Some of the conditions reviewed here are treatable and therefore should not be missed. This review includes orthostatic tremor, focal and task-specific tremors, Holmes tremor, palatal and oculopalatal tremor, cortical tremor, some genetic forms of tremor including fragile X-associated tremor/ataxia syndrome as well as tremor associated with neuromuscular disorders, multiple sclerosis and Wilson's disease, providing an array of demonstrative videos. The recognition of these disorders should aid the physician to make a correct diagnosis and guide a prompt intervention. This article is part of the Special Issue "Tremor" edited by Daniel D. Truong, Mark Hallett, and Aasef Shaikh.

IntroductionFunctional Motor Disorders (FMDs) represent nosological entities with no clear phenotypic characterization, especially in patients with multiple (combined FMDs) motor manifestations. A data-driven approach using cluster analysis of clinical data has been proposed as an analytic method to obtain non-hierarchical unbiased classifications. The study aimed to identify clinical subtypes of combined FMDs using a data-driven approach to overcome possible limits related to “a priori” classifications and clinical overlapping.MethodsData were obtained by the Italian Registry of Functional Motor Disorders. Patients identified with multiple or “combined” FMDs by standardized clinical assessments were selected to be analyzed. Non-hierarchical cluster analysis was performed based on FMDs phenomenology. Multivariate analysis was then performed after adjustment for principal confounding variables.ResultsFrom a study population of n = 410 subjects with FMDs, we selected n = 188 subjects [women: 133 (70.7%); age: 47.9 ± 14.4 years; disease duration: 6.4 ± 7.7 years] presenting combined FMDs to be analyzed. Based on motor phenotype, two independent clusters were identified: Cluster C1 (n = 82; 43.6%) and Cluster C2 (n = 106; 56.4%). Cluster C1 was characterized by functional tremor plus parkinsonism as the main clinical phenotype. Cluster C2 mainly included subjects with functional weakness. Cluster C1 included older subjects suffering from anxiety who were more treated with botulinum toxin and antiepileptics. Cluster C2 included younger subjects referring to different associated symptoms, such as pain, headache, and visual disturbances, who were more treated with antidepressants.ConclusionUsing a data-driven approach of clinical data from the Italian registry, we differentiated clinical subtypes among combined FMDs to be validated by prospective studies.

The aim of this study is to assess changes in the body distribution and the semeiology of functional motor disorder (FMD) in patients who reported only one or more than one body site affected at FMD onset. Data were obtained from the Italian Registry of Functional Motor Disorders, which included patients with a diagnosis of clinically definite FMDs. The relationship between FMD features and spread to other body sites was estimated by multivariate Cox regression analysis. We identified 201 (49%) patients who reported only one body site affected at FMD onset and 209 (51%) who reported multiple body sites affected at onset. FMD spread from the initial site to another site in 43/201 (21.4%) patients over 5.7 ± 7.1 years in those with only one site affected at FMD onset; FMD spread to an another body site in 29/209 (13.8%) over 5.5 ± 6.5 years. The spread of FMD was associated with non-motor functional symptoms and psychiatric comorbidities only in the patients with one body site affected at FMD onset. Our findings provide novel insight into the natural history of FMD. The number of body sites affected at onset does not seem to have a consistent influence on the risk of spread. Furthermore, our findings suggest that psychiatric comorbidities and non-motor functional symptoms may predict the spread of FMD symptoms, at least in patients with one body site affected at onset.

Several MRI techniques have become available to support the early diagnosis of multiple system atrophy (MSA), but few longitudinal studies on both MSA variants have been performed, and there are no established MRI markers of disease progression. We aimed to characterize longitudinal brain changes in 26 patients with MSA (14 MSA-P and 12 MSA-C) over a 1-year follow-up period in terms of local tissue density and T1w/T2w ratio in a-priori regions, namely, bilateral putamen, cerebellar gray matter (GM), white matter (WM), and substantia nigra (SN). A significant GM density decrease was found in cerebellum and left putamen in the entire group (10.7 and 33.1% variation, respectively) and both MSA subtypes (MSA-C: 15.4 and 33.0% variation; MSA-P: 7.7 and 33.2%) and in right putamen in the entire group (19.8% variation) and patients with MSA-C (20.9% variation). A WM density decrease was found in the entire group (9.3% variation) and both subtypes in cerebellum-brainstem (MSA-C: 18.0% variation; MSA-P: 5% variation). The T1w/T2w ratio increase was found in the cerebellar and left putamen GM (6.6 and 24.9% variation), while a significant T1w/T2w ratio decrease was detected in SN in the entire MSA group (31% variation). We found a more progressive atrophy of the cerebellum in MSA-C with a similar progression of putaminal atrophy in the two variants. T1w/T2w ratio can be further studied as a potential marker of disease progression, possibly reflecting decreased neuronal density or iron accumulation.

BackgroundClinical markers of cognitive decline in Parkinson's disease (PD) encompass several mental non-motor symptoms such as hallucinations, apathy, anxiety, and depression. Furthermore, freezing of gait (FOG) and specific gait alterations have been associated with cognitive dysfunction in PD. Finally, although low cerebrospinal fluid levels of amyloid-β42 have been found to predict cognitive decline in PD, hitherto PET imaging of amyloid-β (Aβ) failed to consistently demonstrate the association between Aβ plaques deposition and mild cognitive impairment in PD (PD-MCI).AimFinding significant features associated with PD-MCI through a machine learning approach.Patients and methodsPatients were assessed with an extensive clinical and neuropsychological examination. Clinical evaluation included the assessment of mental non-motor symptoms and FOG using the specific items of the MDS-UPDRS I and II. Based on the neuropsychological examination, patients were classified as subjects without and with MCI (noPD-MCI, PD-MCI). All patients were evaluated using a motion analysis system. A subgroup of PD patients also underwent amyloid PET imaging. PD-MCI and noPD-MCI subjects were compared with a univariate statistical analysis on demographic data, clinical features, gait analysis variables, and amyloid PET data. Then, machine learning analysis was performed two times: Model 1 was implemented with age, clinical variables (hallucinations/psychosis, depression, anxiety, apathy, sleep problems, FOG), and gait features, while Model 2, including only the subgroup performing PET, was implemented with PET variables combined with the top five features of the former model.ResultsSeventy-five PD patients were enrolled (33 PD-MCI and 42 noPD-MCI). PD-MCI vs. noPD-MCI resulted in older and showed worse gait patterns, mainly characterized by increased dynamic instability and reduced step length; when comparing amyloid PET data, the two groups did not differ. Regarding the machine learning analyses, evaluation metrics were satisfactory for Model 1 overcoming 80% for accuracy and specificity, whereas they were disappointing for Model 2.ConclusionsThis study demonstrates that machine learning implemented with specific clinical features and gait variables exhibits high accuracy in predicting PD-MCI, whereas amyloid PET imaging is not able to increase prediction. Additionally, our results prompt that a data mining approach on certain gait parameters might represent a reliable surrogate biomarker of PD-MCI.

Contains fulltext : 287125.pdf (Publisher’s version ) (Open Access) BACKGROUND AND PURPOSE: Clinical experience suggests that many patients with functional motor disorders (FMD), despite reporting severe balance problems, typically do not fall frequently. This discrepancy may hint towards a functional component. Here, we explored the role of the Shoulder-Touch test, which features a light touch on the patient's shoulders, to reveal a possible functional etiology of postural instability. METHODS: We enrolled consecutive outpatients with a definite diagnosis of FMD. Patients with Parkinson's disease (PD) or progressive supranuclear palsy (PSP) with postural instability served as controls. Each patient underwent a clinical evaluation including testing for postural instability using the retropulsion test. Patients with an abnormal retropulsion test (score ≥ 1) also received a light touch on their shoulders to explore the presence (S-Touch+) or absence (S-Touch-) of an incongruent, exaggerated postural response, defined as taking three or more steps to recover or a fall if not caught by the examiner. RESULTS: From a total sample of 52 FMD patients, 48 patients were recruited. Twenty-five patients (52%) had an abnormal retropulsion test. Twelve of these 25 patients (48%) had an S-Touch+, either because of need to take two or more steps (n = 4) or a fall if not caught by the examiner (n = 8). None of the 23 PD/PSP patients manifested S-Touch+. The sensitivity of the S-Touch test was 48%, whereas its specificity was 100%. CONCLUSION: The S-Touch test has a high specificity, albeit with a modest sensitivity, to reveal a functional etiology of postural instability in persons with FMD.

Objective\ud We aimed to describe the prevalence and clinical-demographical features of patients with functional gait disorders (FGDs) and to compare them to patients with functional motor disorders (FMDs) without FGDs (No-FGDs).\ud \ud Methods\ud In this multicenter observational study, we enrolled patients with a clinically definite diagnosis of FMDs in 25 tertiary movement disorders centers in Italy. Each subject with FMDs underwent a comprehensive clinical assessment, including screening for different subtypes of functional gait disorders. Multivariate regression models were implemented in order to estimate the adjusted odds ratio (OR; 95% confidence interval) of having FGDs in relation to sociodemographic and clinical characteristics.\ud \ud Results\ud Out of 410 FMDs, 26.6% (n = 109) of patients exhibited FGDs. The most frequent FGDs were slow gait (n = 43, 39.4%), astasia-abasia (n = 26, 23.8%), and knee buckling (n = 24, 22%). They exhibited single FGDs in 51.4% (n = 56) or complex FGDs (more than one type of FGDs) in 48.6% (n = 53) of cases. On multivariate regression analysis, the presence of FGDs was more likely associated with older age (OR 1.03, 95% CI 1.01–1.04), functional visual symptoms (OR 2.19, 95% CI 1.08–4.45), and the diagnosis of somatic symptoms disorder (OR 2.97, 95% CI 1.08–8.17). FGDs were also more likely to undergo physiotherapy (OR 1.81, 95% CI 1.08–3.03).\ud \ud Conclusions\ud People with FMDs may present with different and overlapping types of FGDs, which may occur in older age. The association of FGDs with functional visual symptoms and somatic symptoms disorder opens up to new avenues to the understanding of the neural mechanisms of these disorders.

The objective of the present study was to describe gait parameters of progressive supranuclear palsy (PSP) phenotypes at early stage verifying the ability of gait analysis in discriminating between disease phenotypes and between the other variant syndromes of PSP (vPSP) and Parkinson's disease (PD). Nineteen PSP (10 PSP-Richardson's syndrome, five PSP-parkinsonism, and four PSP-progressive gait freezing) and nine PD patients performed gait analysis in single and dual tasks. Although phenotypes showed similar demographic and clinical variables, Richardson's syndrome presented worse cognitive functions. Gait analysis demonstrated worse parameters in Richardson's syndrome compared with the vPSP. The overall diagnostic accuracy of the statistical model during dual task was almost 90%. The correlation analysis showed a significant relationship between gait parameters and visuo-spatial, praxic, and attention abilities in PSP-Richardson's syndrome only. vPSP presented worse gait parameters than PD. Richardson's syndrome presents greater gait dynamic instability since the earliest stages than other phenotypes. Computerized gait analysis can differentiate between PSP phenotypes and between vPSP and PD.

Background and purpose: Parkinson disease (PD) patients are classically classified according to two alternative motor subtyping methods: (i) tremor-dominant versus postural instability and gait disorder; (ii) tremor-dominant versus akinetic-rigid. The degree of overlap between the two classification systems at diagnosis of PD and their temporal stability, as well as the correspondence between the two systems, were examined over a follow-up period of 4years. Methods: Newly diagnosed, untreated PD patients were classified as tremor-dominant versus postural instability and gait disorder and tremor-dominant versus akinetic-rigid at baseline and after 2 and 4years. Results: There was a poor overlap between the two classification systems at any time point and baseline subtype status could not predict 4-year subtype membership. In fact, about half of our cohort shifted category during the first 2years, regardless of the classification scheme adopted. A lower rate of shift was observed from 2- to 4-year follow-up. Conclusions: The two classical motor subtyping methods of PD poorly overlap, which implies that a patient can be categorized as tremor-dominant in one classification system but not in the other. Moreover, their temporal instability undermines their prognostic value in the early stage of PD.

Cyclic nucleotide phosphodiesterase (PDE) enzymes catalyze the hydrolysis and inactivation of the cyclic nucleotides cyclic adenosine monophosphate and cyclic guanosine monophosphate, which act as intracellular second messengers for many signal transduction pathways in the central nervous system. Several classes of PDE enzymes with specific tissue distributions and cyclic nucleotide selectivity are highly expressed in brain regions involved in cognitive and motor functions, which are known to be implicated in neurodegenerative diseases, such as Parkinson's disease and Huntington's disease. The indication that PDEs are intimately involved in the pathophysiology of different movement disorders further stems from recent discoveries that mutations in genes encoding different PDEs, including PDE2A, PDE8B, and PDE10A, are responsible for rare forms of monogenic parkinsonism and chorea. We here aim to provide a translational overview of the preclinical and clinical data on PDEs, the role of which is emerging in the field of movement disorders, offering a novel venue for a better understanding of their pathophysiology. Modulating cyclic nucleotide signaling, by either acting on their synthesis or on their degradation, represents a promising area for development of novel therapeutic approaches. The study of PDE mutations linked to monogenic movement disorders offers the opportunity of better understanding the role of PDEs in disease pathogenesis, a necessary step to successfully benefit the treatment of both hyperkinetic and hypokinetic movement disorders. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Objectives: Bipolar disorder (BD) has been suggested to be a risk factor for the development of Parkinson's disease (PD). Standard treatment of BD includes drugs that are known to induce drug-induced parkinsonism (DIP). Clinical differentiation between PD and DIP is crucial and might be aided by functional neuroimaging of the dopaminergic nigrostriatal pathway.Methods: Twenty consecutive BD patients with parkinsonism were clinically assessed and underwent 123I-ioflupane dopamine transporter single-photon emission computer tomography (SPECT). Imaging data of BD patients with pathological scans were further compared to a population of 40 de novo PD patients.Results: Four BD patients had abnormal scans, but their clinical features and cumulative exposure to both antipsychotic drugs and lithium were similar to those of BD patients with normal dopamine transporter imaging. BD patients with pathological scans had putaminal binding ratio and putamen-to-caudate ratios higher than those of PD patients despite a similar motor symptom burden.Conclusions: Up to 20% of BD patients with parkinsonism might have an underlying dopaminergic deficit, which would not be due to cumulative exposure to offending drugs and is ostensibly higher than expected in the general population. This supports the evidence that BD represents a risk factor for subsequent development of neurodegenerative parkinsonism, the nature of which needs to be elucidated.

We aimed to study the attitude of Italian neurologists in the use of conventional MRI in patients with idiopathic adult-onset focal dystonia. Patients were included in the Italian Dystonia Registry by experts working in different Italian centers. MRI was available for 1045 of the 1471 (71%) patients included in the analysis. Using logistic regression analysis, we found that MRI was more likely to be performed in patients with cervical dystonia, spasmodic dysphonia, or non-task-specific upper limb dystonia, whereas it was less likely to be performed in patients with blepharospasm or task-specific upper limb dystonia. We did not find differences in the number of MRIs performed between neurological centers in Northern, Central, and Southern Italy. We conclude that although the diagnosis of idiopathic adult-onset dystonia is mainly based on clinical grounds, many movement disorder experts rely on MRI to confirm a diagnosis of idiopathic dystonia. We suggest that neuroimaging should be used in patients with adult-onset focal dystonia to rule out secondary forms.

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

Objectives To explore the impact of sex and age on relationship between prodromal constipation and disease phenotype in Parkinson’s disease at early stages. Methods A total of 385 Parkinson’s disease patients from the PRIAMO study were classified according to the presence of prodromal constipation and followed for 24 months. Multivariable mixed-effect models were applied. All analyses were performed separately for sex (64.1% men) and median age (different by sex: 67 years-old in men and 68 years-old in women). Results As for sex, prodromal constipation was associated with greater odds of attention/memory complaints and apathy symptoms in women only. As for age, prodromal constipation was associated with lower cognitive and higher apathy scores in older patients only. Conclusions Prodromal constipation anticipates lower cognitive performances and more severe apathy since the earliest stages in women and older patients. Sex- and age-related heterogeneity of prodromal markers of Parkinson’s disease may impact disease phenotype.

Background Adult-onset focal dystonia can spread to involve one, or less frequently, two additional body regions. Spread of focal dystonia to a third body site is not fully characterized. Materials and methods We retrospectively analyzed data from the Italian Dystonia Registry, enrolling patients with segmental/multifocal dystonia involving at least two parts of the body or more. Survival analysis estimated the relationship between dystonia features and spread to a third body part. Results We identified 340 patients with segmental/multifocal dystonia involving at least two body parts. Spread of dystonia to a third body site occurred in 42/241 patients (17.4%) with focal onset and 10/99 patients (10.1%) with segmental/multifocal dystonia at onset. The former had a greater tendency to spread than patients with segmental/multifocal dystonia at onset. Gender, years of schooling, comorbidity, family history of dystonia/tremor, age at dystonia onset, and disease duration could not predict spread to a third body site. Among patients with focal onset in different body parts (cranial, cervical, and upper limb regions), there was no association between site of focal dystonia onset and risk of spread to a third body site. Discussion and conclusion Spread to a third body site occurs in a relative low percentage of patients with idiopathic adult-onset dystonia affecting two body parts. Regardless of the site of dystonia onset and of other demographic/clinical variables, focal onset seems to confer a greater risk of spread to a third body site in comparison to patients with segmental/multifocal dystonia at onset.

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

Background Somatosensory temporal discrimination is abnormal in dystonia and reflects reduced somatosensory inhibition. In healthy individuals, both the latter are enhanced by high-frequency repetitive somatosensory stimulation, whereas opposite effects are observed in patients with cervical dystonia. Objectives We tested whether low-frequency repetitive sensory stimulation, which in healthy individuals worsens discrimination, might have the opposite effect in patients with cervical dystonia at the physiological level and, in turn, improve their perceptual performance. Methods Somatosensory temporal discrimination and several electrophysiological measures of sensorimotor inhibition were collected before and after 45 minutes of low-frequency repetitive sensory stimulation. Results As predicted, and opposite to what happened in controls, low-frequency repetitive sensory stimulation in patients enhanced sensorimotor inhibition and normalized somatosensory temporal discrimination. Conclusions Patients with cervical dystonia have an abnormal response to repetitive sensory stimulation, which we hypothesize is attributed to abnormally sensitive homeostatic mechanisms of inhibitory circuitry in both sensory and motor systems. © 2020 International Parkinson and Movement Disorder Society.

Introduction Dystonia occurring in the context of parkinsonism is well-known, e.g. as foot dystonia in young-onset Parkinson's disease (PD), anterocollis in multisystem atrophy (MSA) or blepharospasm (levator inhibition) in progressive supranuclear palsy. We have, however, encountered a series of patients whose phenotype differed from the above described entities. Methods We describe a cohort of patients in whom typical idiopathic isolated (primary) late-onset focal or segmental (predominantly cervical) dystonia preceded the development of parkinsonism by several years, sometimes decades. Results In a cohort of 450 patients followed in our botulinum toxin injections clinic, we identified 11 (2.4%; 7 women) who developed parkinsonism at a median of 14 years after the onset of dystonia. Median age at onset of parkinsonism was 70 years (range 59–87), usually manifesting with a new tremor or a change of tremor pattern, complaints of ‘slowing down’ or new walking difficulties. Parkinsonism resembled PD in 5 (one pathologically confirmed); the remainder had atypical parkinsonism of MSA (n = 3) or indeterminate phenotype (n = 3). Conclusion The relatively frequent occurrence of parkinsonism after long-standing dystonia would suggest a link between the two, in line with evidence from other clinical reports, imaging studies, animal models and genetics. It appears that in some cases of dystonia this could be an antecedent manifestation of a syndrome with parkinsonism developing later, or be a risk factor for parkinsonism. In practice, it is important for clinicians to be alert to new symptoms/signs in patients with long-standing dystonia. From a research point of view, longitudinal case-control studies would be required to further investigate the link between long-standing dystonia and subsequent parkinsonism.

Introduction Functional motor disorders (FMDs) are usually categorized according to the predominant phenomenology; however, it is unclear whether this phenotypic classification mirrors the underlying pathophysiologic mechanisms. Objective To compare the characteristics of patients with different FMDs phenotypes and without co-morbid neurological disorders, aiming to answer the question of whether they represent different expressions of the same disorder or reflect distinct entities. Methods Consecutive outpatients with a clinically definite diagnosis of FMDs were included in the Italian registry of functional motor disorders (IRFMD), a multicenter data collection platform gathering several clinical and demographic variables. To the aim of the current work, data of patients with isolated FMDs were extracted. Results A total of 176 patients were included: 58 with weakness, 40 with tremor, 38 with dystonia, 23 with jerks/facial FMDs, and 17 with gait disorders. Patients with tremor and gait disorders were older than the others. Patients with functional weakness had more commonly an acute onset (87.9%) than patients with tremor and gait disorders, a shorter time lag from symptoms onset and FMDs diagnosis (2.9 ± 3.5 years) than patients with dystonia, and had more frequently associated functional sensory symptoms (51.7%) than patients with tremor, dystonia and gait disorders. Patients with dystonia complained more often of associated pain (47.4%) than patients with tremor. No other differences were noted between groups in terms of other variables including associated functional neurological symptoms, psychiatric comorbidities, and predisposing or precipitating factors. Conclusions Our data support the evidence of a large overlap between FMD phenotypes.

Introduction One of the latest subtyping systems of Parkinson disease (PD) identifies motor severity, cognitive dysfunction, dysautonomia, and rapid eye movement behavior disorder as key features for phenotyping patients into three different subtypes (i.e., mild motor-predominant, diffuse-malignant and intermediate). Since PD subtypes are clinically most relevant if they are mutually exclusive and consistent over-time, we explored the impact of disease stage and duration on these novel subtypes. Methods One-hundred-twenty-two consecutive patients, with a disease duration ranging from 0 to 20 years, were allocated as suggested into these three subtypes. The relationship between either disease duration or stage, as measured by the Hoehn and Yahr staging, and subtype allocation was explored. Results Significant differences in subtype distribution were observed across patients stratified according to either disease duration or staging, with the diffuse-malignant subtypes increasing in prevalence as the disease advanced. Both disease duration and staging were independent predictors of subtype allocation. Conclusions These novel PD subtypes are significantly influenced by disease duration and staging, which might suggest that they do not represent mutually exclusive disease pathways. This should be taken into account when attempting correlations with putative biomarkers of disease progression.

Background\ud Functional motor disorders (FMDs) are abnormal movements that are significantly altered by distractive maneuvers and are incongruent with movement disorders seen in typical neurological diseases.\ud \ud Objective\ud The objectives of this article are to (1) describe the clinical manifestations of FMDs, including nonmotor symptoms and occurrence of other functional neurological disorders (FND); and (2) to report the frequency of isolated and combined FMDs and their relationship with demographic and clinical variables.\ud \ud Methods\ud For this multicenter, observational study, we enrolled consecutive outpatients with a definite diagnosis of FMDs attending 25 tertiary movement disorders centers in Italy. Each patient underwent a detailed clinical evaluation with a definition of the phenotype and number of FMDs (isolated, combined) and an assessment of associated neurological and psychiatric symptoms.\ud \ud Results\ud Of 410 FMDs (71% females; mean age, 47 ± 16.1 years) the most common phenotypes were weakness and tremor. People with FMDs had higher educational levels than the general population and frequent nonmotor symptoms, especially anxiety, fatigue, and pain. Almost half of the patients with FMDs had other FNDs, such as sensory symptoms, nonepileptic seizures, and visual symptoms. Patients with combined FMDs showed a higher burden of nonmotor symptoms and more frequent FNDs. Multivariate regression analysis showed that a diagnosis of combined FMDs was more likely to be delivered by a movement disorders neurologist. Also, FMD duration, pain, insomnia, diagnosis of somatoform disease, and treatment with antipsychotics were all significantly associated with combined FMDs.\ud \ud Conclusions\ud Our findings highlight the need for multidimensional assessments in patients with FMDs given the high frequency of nonmotor symptoms and other FNDs, especially in patients with combined FMDs.

Background and purpose\ud The aims of this study were to describe the clinical manifestations of functional motor disorders (FMDs) coexisting with other neurological diseases (“comorbid FMDs”), and to compare comorbid FMDs with FMDs not overlapping with other neurological diseases (“pure FMDs”).\ud \ud Methods\ud For this multicenter observational study, we enrolled outpatients with a definite FMD diagnosis attending 25 tertiary movement disorder centers in Italy. Each patient with FMDs underwent a detailed clinical assessment including screening for other associated neurological conditions. Group comparisons (comorbid FMDs vs. pure FMDs) were performed in order to compare demographic and clinical variables. Logistic regression models were created to estimate the adjusted odds ratios (95% confidence intervals) of comorbid FMDs (dependent variable) in relation to sociodemographic and clinical characteristics (independent variables).\ud \ud Results\ud Out of 410 FMDs, 21.7% of patients (n = 89) had comorbid FMDs. The most frequent coexisting neurological diseases were migraine, cerebrovascular disease and parkinsonism. In the majority of cases (86.5%), FMDs appeared after the diagnosis of a neurological disease. Patients with comorbid FMDs were older, and more frequently had tremor, non‐neurological comorbidities, paroxysmal non‐epileptic seizures, major depressive disorders, and benzodiazepine intake. Multivariate regression analysis showed that diagnosis of comorbid FMDs was more likely associated with longer time lag until the final diagnosis of FMD, presence of tremor and non‐neurological comorbidities.\ud \ud Conclusions\ud Our findings highlight the need for prompt diagnosis of FMDs, given the relatively high frequency of associated neurological and non‐neurological diseases.

Theory of Mind is defined as the ability to attribute mental state and emotions to other people and is relevant to social relationships. The cortical and subcortical regions involved in Theory of Mind are damaged by neurodegenerative processes of Parkinsonian syndromes, so the aim of the present study was to explore, for the first time, possible deficits of Theory of Mind and their cognitive correlates in multiple system atrophy (MSA). Twenty-six patients with MSA, 25 patients with Parkinson's disease (PD) and 25 healthy subjects were enrolled. Cognitive and affective subcomponents of Theory of Mind, executive functions, long-term memory and apathy were evaluated. The three groups did not differ on demographic variables. MSA and PD groups performed worse than healthy subjects on both cognitive (advanced test of ToM) and affective (emotion attribution task) ToM tasks, but no significant difference was found between patients' groups. However, when using another affective ToM task (Eyes Test), MSA group had poorer performance than healthy subjects and Parkinsonian patients, whereas Parkinsonian patients had similar performance to healthy subjects. Regression analysis revealed an association between poor cognitive flexibility and dysfunctional cognitive component of Theory of Mind. Deficit of cognitive and affective components of Theory of Mind occurred in MSA. Dysfunction of cognitive component was related to executive dysfunction (i.e. cognitive rigidity). These findings might suggest the usefulness of an early evaluation of social cognition in MSA to identify individuals with impaired Theory of Mind who are at risk of social withdrawal, and reduced quality of life.

Objective: To verify the association of midbrain-based MRI measures as well as cortical volumes with disease core features and progression in patients with Progressive Supranuclear Palsy (PSP). Methods: Sixty-seven patients (52.2% with Richardson's syndrome) were included in the present analysis. Available midbrain-based MRI morphometric assessments as well as cortical lobar volumes were computed. Ocular, gait and postural involvement at the time of MRI was evaluated with the PSP rating scale. Specific milestones or death were used to estimate disease progression up to 72 months follow up. Hierarchical regression models and survival analysis were used for analyzing cross-sectional and longitudinal data, respectively. Results: Multivariate models showed vertical supranuclear gaze palsy was associated with smaller midbrain area (OR: 0.02, 95% CI 0.00–0.175, p = 0.006). Cox regression adjusted for age, disease duration, and phenotype demonstrated that lower midbrain area (HR: 0.122, 95% CI 0.030–0.493, p = 0.003) and diameter (HR: 0.313, 95% CI 0.112–0.878, p = 0.027), higher MR Parkinsonism Index (HR: 6.162, 95% CI 1.790–21.209, p = 0.004) and larger third ventricle width (HR: 2.755, 95% CI 1.068–7.108, p = 0.036) were associated with higher risk of dependency on wheelchair. Conclusions: Irrespective of disease features and other MRI parameters, reduced midbrain size is significantly associated with greater ocular motor dysfunction at the time of MRI and more rapid disease progression over follow up. This is the first comprehensive study to systematically assess the association of available midbrain-based MRI measures and cortical volumes with disease severity and progression in a large cohort of patients with PSP in a real-world setting.

Gender differences have been described in several neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. The effects of gender on cognitive and behavioral manifestations in multiple system atrophy and the changes of cognitive functions over time according to gender have not been investigated so far. Fifty-five patients with a diagnosis of multiple system atrophy underwent a comprehensive neuropsychological and neuropsychiatric battery at baseline and 26 of them could be re-evaluated at 1-year follow-up. At baseline women with multiple system atrophy had poorer global cognitive state and visuo-spatial abilities, and a higher prevalence of depression and apathy than males. At follow-up, female patients deteriorated more than males on attention abilities and motor functions, and had a higher prevalence of depression than men. Executive functions and visuo-spatial abilities significantly worsened over time in both groups. Mild Cognitive Impairment single domain was significantly more frequent in females than males. Cognitive and behavioral differences between genders in multiple system atrophy involve global cognition, planning, attention, visual-perceptive skills, and depression, with female patients more compromised than males. Female patients deteriorated more than men over time as for motor functions and attention. Further longitudinal studies are deserved to confirm gender differences in progression of cognitive and behavioral features of multiple system atrophy.

Theory of mind (ToM) refers to an individual's ability to attribute mental states to predict and explain another person's behavior. It has been shown that patients with cervical dystonia (CD) present impaired ToM ability supporting the idea that CD is a network disorder. An emerging hypothesis is that different phenotypes of CD reflect distinct key nodes in the malfunctioning cerebral network. The aim of the present study was to investigate whether the presence of tremor as additional phenotypic feature of CD influences the ability to attribute a cognitive or emotional state to another person. We enrolled 35 patients with CD, 21 with tremor (CD-T) and 14 without tremor (CD-NT) and 47 age-matched healthy subjects (HS). The Emotion Attribution Task (EAT) was adopted to assess the affective ToM ability while the Advanced Test (AT) was used to investigate the cognitive ToM ability. Results showed that CD patients' performance was worse than HS in recognizing the emotional feelings expressed in the EAT situations, with no difference between CD-T and CD-NT. Regarding cognitive ToM, both CD-T and CD-NT performed worse than HS in the AT task. However, it also emerged that CD-T were more impaired in AT task than CD-NT. Our results indicate that both affective and cognitive aspects of ToM are impaired in CD and that cognitive ToM is more impaired in patients presenting tremor respect to those without. These findings support the hypothesis that the cerebral network responsible of motor and non-motor impairments is more widespread in CD-T than CD-NT.

Introduction: Cervical dystonia (CD) is one of the most common forms of adult-onset isolated dystonia. Recently, CD has been classified according to the site of onset and spread, in different clinical subgroups, that may represent different clinical entities or pathophysiologic subtypes. In order to support this hypothesis, in this study we have evaluated whether different subgroups of CD, that clinically differ for site of onset and spread, also imply different sensorimotor features. Methods: Clinical and demographic data from 842 patients with CD from the Italian Dystonia Registry were examined. Motor features (head tremor and tremor elsewhere) and sensory features (sensory trick and neck pain) were investigated. We analyzed possible associations between motor and sensory features in CD subgroups [focal neck onset, no spread (FNO-NS); focal neck onset, segmental spread (FNO-SS); focal onset elsewhere with segmental spread to neck (FOE-SS); segmental neck involvement without spread (SNI)]. Results: In FNO-NS, FOE-SS, and SNI subgroups, head tremor was associated with the presence of tremor elsewhere. Sensory trick was associated with pain in patients with FNO-NS and with head tremor in patients with FNO-SS. Conclusion: The frequent association between head tremor and tremor elsewhere may suggest a common pathophysiological mechanism. Two mechanisms may be hypothesized for sensory trick: a gating mechanism attempting to reduce pain and a sensorimotor mechanism attempting to control tremor.

Cervical dystonia is associated with neck pain in a significant proportion of cases, but the mechanisms underlying pain are largely unknown. In this exploratory study, we compared demographic and clinical variables in cervical dystonia patients with and without neck pain from the Italian Dystonia Registry. Univariable and multivariable logistic regression analysis indicated a higher frequency of sensory trick and a lower educational level among patients with pain.