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Multiple system atrophy is a rapidly progressive and fatal neurodegenerative disorder. While numerous preclinical studies suggested efficacy of potentially disease modifying agents, none of those were proven to be effective in large-scale clinical trials. Three major strategies are currently pursued in preclinical and clinical studies attempting to slow down disease progression. These target α-synuclein, neuroinflammation, and restoration of neurotrophic support. This review provides a comprehensive overview on ongoing preclinical and clinical developments of disease modifying therapies. Furthermore, we will focus on potential shortcomings of previous studies that can be avoided to improve data quality in future studies of this rare disease.

These include, among others, two forms of atypical Parkinsonism, multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). This study aimed to assess the potential role of C9orf72 repeat expansions among Serbian patients diagnosed with MSA and PSP. Genomic DNA of 44 MSA patients, 73 PSP patients, and 96 controls was extracted from peripheral blood, and normal C9orf72 alleles were analyzed by standard quantitative fluorescence polymerase chain reaction (QF-PCR) and fragment analysis. Subsequently, for all samples presenting a single allele, repeat-primed PCR was performed with two different sets of primers to avoid a false-negative result. Thirty repeats were used as a pathogenic cut-off and 20-29 repeats for the intermediate alleles. No pathological C9orf72 expansions were detected in the MSA and PSP patients nor the control subjects. In the MSA group, the most common was the allele with 2 repeats, and the largest repeat number was 14. Among PSP patients, the most common allele also had 2 repeats, while the largest detected repeat size within the normal range was 17. Also, we identified one PSP patient that had an intermediate size allele (25 repeats). We did not find correlation between the number of repeats and disease onset, age at the time of examination, or disease duration in MSA or PSP patients. Regarding family history, in PSP the sum of both allele repeats numbers was higher in patients with positive family history than in sporadic cases. The results presented in this study are the first systematic assessment of C9orf72 allele sizes among patients diagnosed with MSA and PSP in the Serbian population. Although the potential role of intermediate C9orf72 repeats in neurodegenerative disorders is still to be elucidated, our results support the current knowledge that C9orf72 repeat expansions are not associated with MSA and PSP.

Multiple system atrophy is considered a sporadic disease, but neuropathologically confirmed cases with a family history of parkinsonism have been occasionally described. Here we report a North-Bavarian (colloquially, Lion’s tail region) six-generation pedigree, including neuropathologically confirmed multiple system atrophy and Parkinson’s disease with dementia. Between 2012 and 2020, we examined all living and consenting family members of age and calculated the risk of prodromal Parkinson’s disease in those without overt parkinsonism. The index case and one paternal cousin with Parkinson’s disease with dementia died at follow-up and underwent neuropathological examination. Genetic analysis was performed in both and another family member with Parkinson’s disease. The index case was a female patient with cerebellar variant multiple system atrophy and a positive maternal and paternal family history for Parkinson’s disease and dementia in multiple generations. The families of the index case and her spouse were genealogically related, and one of the spouse's siblings met the criteria for possible prodromal Parkinson’s disease. Neuropathological examination confirmed multiple system atrophy in the index case and advanced Lewy body disease, as well as tau pathology in her cousin. A comprehensive analysis of genes known to cause hereditary forms of parkinsonism or multiple system atrophy lookalikes was unremarkable in the index case and the other two affected family members. Here, we report an extensive European pedigree with multiple system atrophy and Parkinson`s disease suggesting a complex underlying α-synucleinopathy as confirmed on neuropathological examination. The exclusion of known genetic causes of parkinsonism or multiple system atrophy lookalikes suggests that variants in additional, still unknown genes, linked to α-synucleinopathy lesions underlie such neurodegenerative clustering.

Purpose The unified multiple system atrophy (MSA) rating scale (UMSARS) was developed almost 20 years ago as a clinical rating scale to capture multiple aspects of the disease. With its widespread use, the shortcomings of the UMSARS as a clinical outcome assessment (COA) have become increasingly apparent. We here summarize the shortcomings of the scale, confirm some of its limitations with data from the Natural History Study of the Synucleinopathies (NHSS), and suggest a framework to develop and validate an improved COA to be used in future clinical trials of disease-modifying drugs in patients with MSA. Methods Expert consensus assessment of the limitations of the UMSARS and recommendations for the development and validation of a novel COA for MSA. We used UMSARS data from the ongoing NHSS (ClinicalTrials.gov: NCT01799915) to showcase some of these limitations. Results The UMSARS in general, and specific items in particular, have limitations to detect change resulting in a ceiling effect. Some items have specific limitations including unclear anchoring descriptions, lack of correlation with disease severity, susceptibility to improve with symptomatic therapies (e.g., orthostatic hypotension, constipation, and bladder dysfunction), and redundancy, among others. Conclusions Because of the limitations of the UMSARS, developing and validating an improved COA is a priority. The time is right for academic MSA clinicians together with industry, professional societies, and patient advocacy groups to develop and validate a new COA.

Introduction: Although one of the most common monogenic late-onset neurodegenerative disorders, fragile-X-associated tremor/ataxia syndrome (FXTAS) is still underdiagnosed. The aim of the present s...

BackgroundThe second consensus criteria for the diagnosis of multiple system atrophy (MSA) are widely recognized as the reference standard for clinical research, but lack sensitivity to diagnose the disease at early stages.ObjectiveTo develop novel Movement Disorder Society (MDS) criteria for MSA diagnosis using an evidence-based and consensus-based methodology.MethodsWe identified shortcomings of the second consensus criteria for MSA diagnosis and conducted a systematic literature review to answer predefined questions on clinical presentation and diagnostic tools relevant for MSA diagnosis. The criteria were developed and later optimized using two Delphi rounds within the MSA Criteria Revision Task Force, a survey for MDS membership, and a virtual Consensus Conference.ResultsThe criteria for neuropathologically established MSA remain unchanged. For a clinical MSA diagnosis a new category of clinically established MSA is introduced, aiming for maximum specificity with acceptable sensitivity. A category of clinically probable MSA is defined to enhance sensitivity while maintaining specificity. A research category of possible prodromal MSA is designed to capture patients in the earliest stages when symptoms and signs are present, but do not meet the threshold for clinically established or clinically probable MSA. Brain magnetic resonance imaging markers suggestive of MSA are required for the diagnosis of clinically established MSA. The number of research biomarkers that support all clinical diagnostic categories will likely grow.ConclusionsThis set of MDS MSA diagnostic criteria aims at improving the diagnostic accuracy, particularly in early disease stages. It requires validation in a prospective clinical and a clinicopathological study. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Multiple system atrophy (MSA) is a rare neurodegenerative disease that is characterized by neuronal loss and gliosis in multiple areas of the central nervous system including striatonigral, olivopontocerebellar and central autonomic structures. Oligodendroglial cytoplasmic inclusions containing misfolded and aggregated α-synuclein are the histopathological hallmark of MSA. A firm clinical diagnosis requires the presence of autonomic dysfunction in combination with parkinsonism that responds poorly to levodopa and/or cerebellar ataxia. Clinical diagnostic accuracy is suboptimal in early disease because of phenotypic overlaps with Parkinson disease or other types of degenerative parkinsonism as well as with other cerebellar disorders. The symptomatic management of MSA requires a complex multimodal approach to compensate for autonomic failure, alleviate parkinsonism and cerebellar ataxia and associated disabilities. None of the available treatments significantly slows the aggressive course of MSA. Despite several failed trials in the past, a robust pipeline of putative disease-modifying agents, along with progress towards early diagnosis and the development of sensitive diagnostic and progression biomarkers for MSA, offer new hope for patients.

Background White matter hyperintensities (WMHs) have a role in cognitive impairment in normal brain aging, while the effect on Parkinson's disease (PD) progression is still controversial. Objective To investigate the longitudinal evolution of micro- and macrostructural damage of cerebral white matter (WM) and its relationship with the clinical picture in PD. Methods A total of 154 PD patients underwent clinical, cognitive, and magnetic resonance imaging (MRI) assessment once a year for up to 4 years. Sixty healthy controls underwent the same protocol at baseline. WMHs were identified and total WMH volume was measured. WMHs were also used as exclusion masks to define normal-appearing white matter (NAWM). Using tract-based spatial statistics, diffusion tensor (DT) MRI metrics of whole-brain WM and NAWM were obtained. Linear mixed-effects models defined the longitudinal evolution and association between variables. WM alterations were tested as risk factors of disease progression using linear regression and Cox proportional hazards models. Results At baseline, PD patients showed alterations of all DT MRI measures compared to controls. Longitudinally, DT MRI measures did not vary significantly and no association with clinical variables was found. WMH volume changed over time and was associated with impairment in global cognition, executive functions, and language. Baseline WMH volume was a moderate risk factor for progression to mild cognitive impairment. Conclusions Our study suggests an association between WMHs and cognitive deterioration in PD, whereas WM microstructural damage is a negligible contributor to clinical deterioration. WMHs assessed by MRI can provide an important tool for monitoring the development of cognitive impairment in PD patients. © 2021 International Parkinson and Movement Disorder Society.

The Unified Multiple System Atrophy (MSA) Rating Scale was developed to provide a surrogate marker of disease severity and clinical progression in patients with MSA. It is comprised of four subscales: UMSARS-I (12 items) rates patient-reported functional disability; UMSARS-II (14 items) assesses motor impairment based on a clinical examination; UMSARS-III records blood pressure and heart rate in the supine and standing positions; and UMSARS-IV (1 item) rates chore-based disability. Strengths of the UMSARS include its wide acceptance in the field, the comprehensive coverage of motor symptoms and its clinimetric properties (including reliability and validity). However, with its increasing use, potential areas of improvement in the UMSARS have become apparent. To address these limitations, a task force, involving clinicians, researchers, patient groups, and industry representatives, has recently been endorsed by the International Parkinson’s Disease and Movement Disorders Society. The present viewpoint summarizes strengths and weaknesses of the UMSARS and suggests a roadmap to develop an improved MSA clinical outcome assessment.

An expert committee was formed to reach consensus on the use of tilt table testing (TTT) in the diagnosis of disorders that may cause transient loss of consciousness (TLOC) and to outline when other provocative cardiovascular autonomic tests are needed. While TTT adds to history taking, it cannot be a substitute for it. An abnormal TTT result is most meaningful if the provoked event is recognised by patients or eyewitnesses as similar to spontaneous events. The minimum requirements to perform TTT are a tilt table, a continuous beat-to-beat blood pressure monitor, at least one ECG lead, protocols for the indications stated below and trained staff. This basic equipment lends itself to the performance of (1) additional provocation tests, such as the active standing test, carotid sinus massage and autonomic function tests; (2) additional measurements, such as video, EEG, transcranial Doppler, NIRS, end-tidal CO2 or neuro-endocrine tests; and (3) tailor-made provocation procedures in those with a specific and consistent trigger of TLOC. TTT and other provocative cardiovascular autonomic tests are indicated if the initial evaluation does not yield a definite or highly likely diagnosis, but raises a suspicion of (1) reflex syncope, (2) the three forms of orthostatic hypotension (OH), i.e. initial, classic and delayed OH, as well as delayed orthostatic blood pressure recovery, (3) postural orthostatic tachycardia syndrome or (4) psychogenic pseudosyncope. A therapeutic indication for TTT is to teach patients with reflex syncope and OH to recognise hypotensive symptoms and to perform physical counter manoeuvres.

Clinical correlates of autonomic nervous system (ANS) dysfunction in early Parkinson's disease (PD) have been addressed mainly in a cross-sectional way.This is a combined cross-sectional and longitudinal prospective study of ANS dysfunction using the SCOPA-AUT in PD patients at the Hoehn and Yahr stage 1 with disease duration2 years. PD patients (n = 107) were compared to healthy controls (HC, n = 79), and then followed-up for over 3 years. The severity of PD, depression, anxiety, apathy and cognitive impairment were evaluated using rating scales.At least one symptom of ANS dysfunction was present in 71% of PD patients in comparison to 30.4% of HC, and in all PD patients after three years. The overall severity of dysautonomia symptoms was mild (SCOPA-AUT mean ± SD; 4.16 ± 5.0), but worsened by 23%, 86% and 0.3% during the 1st, 2nd and 3rd year respectively. Nighttime voiding (38.3%), constipation (30.8%) and straining for defecation (29%) were the most common symptoms. Prevalence and severity of urinary, gastrointestinal, and orthostatic symptoms increased, in contrast to thermoregulatory and pupillomotor symptoms. Frequency of symptoms suggestive of multi-domain ANS dysfunction rose from 49% to 79%. Psychiatric symptoms and age, but not motor impairment, were associated with dysautonomia symptoms.Symptoms of ANS dysfunction were frequent in the initial motor stage of PD and progressed, yet remaining mild, within 3 years. An independent progression of dysautonomia symptoms from motor disability and its associations with non-motor, mainly psychiatric symptoms and age support the non-motor clustering in PD.

This study aimed to identify functional neuroimaging patterns anticipating the clinical indication for deep brain stimulation (DBS) in patients with Parkinson’s disease (PD). A cohort of prospectively recruited patients with PD underwent neurological evaluations and resting-state functional MRI (RS-fMRI) at baseline and annually for 4 years. Patients were divided into two groups: 19 patients eligible for DBS over the follow-up and 41 patients who did not meet the criteria to undergo DBS. Patients selected as candidates for DBS did not undergo surgery at this stage. Sixty age- and sex-matched healthy controls performed baseline evaluations. Graph analysis and connectomics assessed global and local topological network properties and regional functional connectivity at baseline and at each time point. At baseline, network analysis showed a higher mean nodal strength, local efficiency, and clustering coefficient of the occipital areas in candidates for DBS over time relative to controls and patients not eligible for DBS. The occipital hyperconnectivity pattern was confirmed by regional analysis. At baseline, a decreased functional connectivity between basal ganglia and sensorimotor/frontal networks was found in candidates for DBS compared to patients not eligible for surgery. In the longitudinal analysis, patient candidate for DBS showed a progressively decreased topological brain organization and functional connectivity, mainly in the posterior brain networks, and a progressively increased connectivity of basal ganglia network compared to non-candidates for DBS. RS-fMRI may support the clinical indication to DBS and could be useful in predicting which patients would be eligible for DBS in the earlier stages of PD.

Objective: To study the longitudinal disease course of Parkinson’s disease (PD) patients with glucocerebrosidase (GBA) mutation (GBA-positive) compared to PD non-carriers (GBA-negative) along a 5-year follow-up, evaluating changes in clinical and cognitive outcomes, cortical thickness, and gray-matter (GM) volumes. Methods: Ten GBA-positive and 20 GBA-negative PD patients underwent clinical, neuropsychological, and MRI assessments (cortical thickness and subcortical, hippocampal, and amygdala volumes) at study entry and once a year for 5 years. At baseline and at the last visit, each group of patients was compared with 22 age-matched healthy controls. Clinical, cognitive, and MRI features were compared between groups at baseline and over time. Results: At baseline, GBA-positive and GBA-negative PD patients had similar clinical and cognitive profiles. Compared to GBA-negative and controls, GBA-positive patients showed cortical thinning of left temporal, parietal, and occipital gyri. Over time, compared to GBA-negative, GBA-positive PD patients progressed significantly in motor and cognitive symptoms, and showed a greater pattern of cortical thinning of posterior regions, and frontal and orbito-frontal cortices. After 5 years, compared to controls, GBA-negative PD patients showed a pattern of cortical thinning similar to that showed by GBA-positive cases at baseline. The two groups of patients showed similar patterns of subcortical, hippocampal, and amygdala volume loss over time. Conclusions: Compared to GBA-negative PD, GBA-positive patients experienced a more rapid motor and cognitive decline together with a greater, earlier and faster cortical thinning. Cortical thickness measures may be a useful tool for monitoring and predicting PD progression in accordance with the genetic background.

The autonomic nervous system (ANS) is the part of the central and peripheral nervous system, hierarchically organized into central autonomic network and the peripheral autonomic branches, that regulates functions which are mostly independent of human will. These include vital functions such as breathing, blood pressure maintenance, heart rate regulation, sweating, digestion, urination, sexual functions. Organ systems responsible for these functions are regulated by two inseparable parts of ANS, the sympathetic and parasympathetic systems, that exert the antagonistic effects. Although both the sympathetic and parasympathetic systems exhibit constant tonic activity the predominance of one or the other is determined by the specific external or internal stimuli the person is exposed to. A flight-or-fight reaction is typical for the prevailing sympathetic activity characterized by an increase in heart rate and blood pressure and centralization of the circulation. In contrast, the parasympathetic system is more active in the rest-and-digest circumstances and causes energy conservation and stimulation of the digestive system. The principal neurotransmitter of the sympathetic system is norepinephrine whereas the parasympathetic fibers are cholinergic. A detailed knowledge of ANS physiology is a prerequisite for the diagnosis and treatment of various causes of ANS dysfunction.

Longitudinal connectivity studies might guide our understanding of the underlying neurodegenerative processes. We report the results of a longitudinal study in patients at different stages of Parkinson's disease (PD), who performed motor and non-motor evaluations and serial resting state (RS) functional MRI (fMRI). Cluster analysis was applied to demographic and clinical data of 146 PD patients to define disease subtypes. Brain network functional alterations were assessed at baseline in PD relative to 60 healthy controls and every year for a maximum of 4 years in PD groups. Progression of brain network changes were compared between patient clusters using RS fMRI. The contribution of network changes in predicting clinical deterioration was explored. Two main PD clusters were identified: mild PD (86 patients) and moderate-to-severe PD (60 patients), with the latter group being older and having earlier onset, longer PD duration, more severe motor, non-motor and cognitive deficits. Within the mild patient cluster, two clinical subtypes were further identified: mild motor-predominant (43) and mild-diffuse (43), with the latter being older and having more frequent non-motor symptoms. Longitudinal functional connectivity changes vary across patients in different disease stages with the coexistence of hypo- and hyper-connectivity in all subtypes. RS fMRI changes were associated with motor, cognitive and non-motor evolution in PD patients. Baseline RS fMRI presaged clinical and cognitive evolution. Our network perspective was able to define trajectories of functional architecture changes according to PD stages and prognosis. RS fMRI may be an early biomarker of PD motor and non-motor progression.

Recent research shows that patients with multiple system atrophy (MSA) have significant cognitive and neuropsychiatric comorbidities that can color the clinical presentation of the disease and affect their quality of life. The aims of this study were to determine the neuropsychiatric profile in a cohort of patients with the parkinsonian type of MSA (MSA-P) and their dynamic changes over a 1-year follow-up period and to compare rates of neuropsychiatric symptoms (NPSs) reported by caregivers and the patients themselves.Forty-seven patients were assessed at baseline; of these, 25 were assessed again after 1 year. NPS assessment tools included the Neuropsychiatric Inventory (NPI), the Beck Depression Inventory, the Hamilton Depression Rating Scale, the Hamilton Anxiety Rating Scale, and the Apathy Evaluation Scale.The prevalence of NPSs in patients with MSA-P was very high, with depression, sleep disturbances, apathy, and anxiety being the most frequently occurring features. The evolution of NPSs was found to be independent of motor, autonomic, and cognitive symptoms. None of the scales measuring NPSs, including the NPI, were capable of detecting changes over the 1-year follow-up period. Although the overall prevalence of depression, apathy, and anxiety obtained from caregivers and the patients themselves was similar, reports from these two sources cannot be considered interchangeable.The progression of neuropsychiatric symptoms was not a subject of rapid change in MSA-P, in contrast to the observed motor, autonomic, and cognitive deterioration. These findings suggest the need to investigate the utility of available instruments in capturing the evolution of NPSs in MSA over time.

Background The objectives of this study were to investigate progressive cortical thinning and volume loss in Parkinson's disease (PD) patients with different longitudinal patterns of cognitive decline: with stable normal cognition, with stable mild cognitive impairment, with conversion to mild cognitive impairment, and with conversion to dementia. Methods We recruited 112 patients (37 Parkinson's disease with stable normal cognition, 20 Parkinson's disease with stable mild cognitive impairment, 36 Parkinson's disease with conversion to mild cognitive impairment, 19 Parkinson's disease with conversion to dementia) and 38 healthy controls. All patients underwent at least 2 visits within 4 years including clinical/cognitive assessments and structural MRI (total visits, 393). Baseline cortical thickness and gray matter volumetry were compared between groups. In PD, gray matter changes over time were investigated and compared between groups. Results At baseline, compared with Parkinson's disease with stable normal cognition cases, Parkinson's disease with conversion to mild cognitive impairment patients showed cortical atrophy of the parietal and occipital lobes, similar to Parkinson's disease with stable mild cognitive impairment and Parkinson's disease with conversion to dementia patients. The latter groups (ie, patients with cognitive impairment from the study entry) showed additional involvement of the frontotemporal cortices. No baseline volumetric differences among groups were detected. The longitudinal analysis (group-by-time interaction) showed that, versus the other patient groups, Parkinson's disease with stable mild cognitive impairment and Parkinson's disease with conversion to dementia cases accumulated the least cortical damage, with Parkinson's disease with conversion to dementia showing unique progression of right thalamic and hippocampal volume loss; Parkinson's disease with conversion to mild cognitive impairment patients showing specific cortical thinning accumulation in the medial and superior frontal gyri, inferior temporal, precuneus, posterior cingulum, and supramarginal gyri bilaterally; and Parkinson's disease with stable normal cognition patients showing cortical thinning progression, mainly in the occipital and parietal regions bilaterally. Conclusions Cortical thinning progression is more prominent in the initial stages of PD cognitive decline. The involvement of frontotemporoparietal regions, the hippocampus, and the thalamus is associated with conversion to a more severe stage of cognitive impairment. In PD, gray matter alterations of critical brain regions may be an MRI signature for the identification of patients at risk of developing dementia. © 2020 International Parkinson and Movement Disorder Society.

Highlights • Cortical and subcortical atrophy is accelerated early after the onset of PD. • Brain atrophy in PD progressed with cognitive, non-motor and mood deficits. • Structural MRI may be useful for predicting disease progression in PD., Clinical manifestations and evolution are very heterogeneous among individuals with Parkinson’s disease (PD). The aims of this study were to investigate the pattern of progressive brain atrophy in PD according to disease stage and to elucidate to what extent cortical thinning and subcortical atrophy are related to clinical motor and non-motor evolution. 154 patients at different PD stages were assessed over time using motor, non-motor and structural MRI evaluations for a maximum of 4 years. Cluster analysis defined clinical subtypes. Cortical thinning and subcortical atrophy were assessed at baseline in patients relative to 60 healthy controls. Longitudinal trends of brain atrophy progression were compared between PD clusters. The contribution of brain atrophy in predicting motor, non-motor, cognitive and mood deterioration was explored. Two main PD clusters were defined: mild (N = 87) and moderate-to-severe (N = 67). Two mild subtypes were further identified: mild motor-predominant (N = 43) and mild-diffuse (N = 44), with the latter group being older and having more severe non-motor and cognitive symptoms. The initial pattern of brain atrophy was more severe in patients with moderate-to-severe PD. Over time, mild-diffuse PD patients had the greatest brain atrophy accumulation in the cortex and the left hippocampus, while less distributed atrophy progression was observed in moderate-to-severe and mild motor-predominant patients. Baseline and 1-year cortical thinning was associated with long-term progression of motor, cognitive, non-motor and mood symptoms. Cortical and subcortical atrophy is accelerated early after the onset of PD and becomes prominent in later stages of disease according to the development of cognitive, non-motor and mood dysfunctions. Structural MRI may be useful for monitoring and predicting disease progression in PD.

Purpose: Huntington's disease (HD) is an neurodegenerative genetic disorder with characteristic gait changes. HD also results in a range of cognitive impairments, such as difficulties to divide attention, or simultaneously monitoring two tasks. Aim: The impact of cognitive and/or motor tasks on HD gait has not been fully elucidated. The aim was to examine gait in HD patients while performing motor and/or cognitive dual-task walking. Methods: Gait was measured with and without performing concurrent cognitive and/or motor tasks. Sixteen HD patients and 24 healthy control (HC) subjects performed a self-paced basic walking task, a dual motor, a dual mental and a combined motor and mental task while walking. Results: Base walk gait parameters are significantly different between HD and HC groups. Same is true for motor, mental and combined tasks comparisons of HD and HC subjects. Gait velocity is also significantly reduced in HD compared to HC for all experimental conditions. Comparison of base walk and mental task performance showing differences in cycle time, stride length, double support time and CV of stride length, while base walk to motor task comparison is different only in stride length. No differences were found when motor and combined tasks were compared to mental task in HD patients. Conclusion: Gait pattern in HD patients while performing motor and/or cognitive dual tasks walking is remarkably preserved. Gait parameters are changed in order to reduce possible falls, and lack of differences of dual tasks gait parameters variability is attributed that patients minimizing risk of falling and preserving stability.

Introduction Impulsive compulsive behaviors (ICBs) in Parkinson's disease (PD) are debilitating disorders of repetitive, excessive, and compulsive nature affecting up to one third of PD patients. Objectives are to address clinical, psychiatric, and cognitive characteristics of ICBs and to define risk factors in PD patients in the initial motor stage, followed up for 5 years. Methods We analyzed 106 consecutive PD outpatients at Hoehn and Yahr disease stage 1 and 125 healthy controls. The participants were assessed for the presence of any ICB using the current clinical criteria and underwent comprehensive clinical, psychiatric, and neuropsychological evaluations. The patients completed the same protocol at Years 1, 2, 3, and 5. Results ICBs were present in 21 (19.8%) PD patients and 13 (10.4%) healthy controls at baseline. Prevalence of ICBs increased to 29.2% at Year 5, significantly after Year 2. Multiple ICBs were present in 4,7% and 61.9% of PD-ICBs at the baseline and Year 5, respectively. ICBs resolved in 30% of cases (most often compulsive eating). Dopamine agonist treatment at the baseline carried five times higher risk of having or developing ICB(s) anytime during follow-up. We identified risk factors for compulsive eating (dopamine agonist treatment at baseline), hypersexuality (males), compulsive buying (depression and younger age), and punding (younger age and higher levodopa dose at baseline). Significant interaction of rate of motor progression and ICB diagnosis was shown. Conclusions PD patients showed increasing frequency of most ICBs during the 5-year follow-up. Specific risk factors were identified for different types of ICBs.

Background:Fear of falling in Parkinson's disease (PD) has been suggested as predictor of future falling. The purpose of this study was to compare fear of falling score after two years of follow-up with those observed at baseline and to assess factors associated with change in fear of falling over time.Methods:A total of 120 consecutive persons with PD were recruited and followed for two years. Fear of falling was assessed by using the 10-item Falls Efficacy Scale (FES). Occurrence of falling was registered during the first year of follow-up.Results:After two years, the average FES score statistically significantly changed (p = 0.003) from 30.5 to 37.5 out of 100 (increase of 22.9%). We observed that median scores of all FES items, except for “Preparing a meal, not requiring carrying of heavy or hot objects” and “Personal grooming,” significantly increased after two-year follow-up. After accounting for age, gender, PD duration, levodopa dosage, Hoehn and Yayhr stage, Unified Parkinson's Disease Rating Scale score three, depression, anxiety, and falling, we observed that sustaining greater number of falls in the first year of follow-up was associated with higher increase in FES score after two years (odds ratio 3.08, 95% confidence interval 1.30–4.87).Conclusion:After two years of follow-up, we observed a decrease in confidence at performing nearly all basic daily activities. Fall prevention programs should be prioritized in management of PD.

Objectives To describe circumstances of near-falls among persons with Parkinson's disease (PD), assess factors associated with near-falling and assess whether near-falls in the first 6 months are associated with falling in the latter 6 months over one year of follow-up. Materials and methods In the period August 2011-December 2012, 120 consecutive persons with PD, who denied having fallen in the past 6 months, were recruited at Clinical center of Serbia in Belgrade. Occurrence of falling and near-falls was followed for one year. Results A total of 31 persons with PD (25.8%) experienced near-falls, but did not fall. Of 42 fallers, 32 (76.2%) experienced near-falls. Tripping was the most common cause of near-falls among fallers, whereas postural instability was the most common in non-fallers. Regardless of falling experience, the most common manner to avoid fall was holding onto furniture or wall. After adjustment for multiple motor and non-motor PD features, more severe freezing of gait was associated with occurrence of near-falls over one year of follow-up (odds ratio [OR] = 1.08, 95% confidence interval [CI] 1.01–1.16; p = 0.043). Adjusted regression analysis did not show associations between near-falling in the first 6 months and falling in the latter 6 months of follow-up. Conclusion Near-falls commonly occur in persons with PD. More severe freezing of gait appears to predispose near-falling. Fall prevention programs focusing on balance maintenance when experiencing freezing of gait could potentially be useful in reduction of near-falls.

Symptoms of Parkinson's disease (PD) progress over time causing significant disability. Yet, change in disability over shorter time periods has not been entirely understood. The purpose of this study was to assess the Self-Assessment Disability Scale (SADS) in persons with Parkinson's disease (PD) after 2 years of follow-up and compare it with the score observed at baseline. Additionally, we aimed at evaluating association of motor and non-motor PD features at baseline with a higher disability after 2 years of follow-up. A total of 120 consecutive persons with PD, who denied falling in the past 6 months, were initially recruited. After 2 years of follow-up, 88 (73.3%) persons with PD were evaluated for SADS. The total disability (SADS) score did not change after follow-up (p = 0.529). We observed increase in difficulty at "Getting out of bed" (p = 0.006), "Getting up out of armchair" (p = 0.013), "Walking about house/flat" (p = 0.003), "Walking outside" (p = 0.010), and "Traveling by public transport" (p = 0.014). After adjusting for several potential confounding factors, falls in the past year (β = 8.32, 95% confidence interval (CI) 1.04-15.59) and higher Unified Parkinson's Disease Rating Scale part 3 at baseline (β = 0.26, 95%CI 0.01-0.51) remained associated with higher PD-related disability. This finding suggests that accumulation of overall PD-related disability tends to occur over a longer time span. Further studies are needed to gradually assess long-term evolution of disability in PD.

Objective:To assess whether a functional dysregulation of the habenula and amygdala, as modulators of the reward brain circuit, contributes to Parkinson disease (PD) punding.Methods:Structural and resting-state functional MRI were obtained from 22 patients with PD punding, 30 patients with PD without any impulsive-compulsive behavior (ICB) matched for disease stage and duration, motor impairment, and cognitive status, and 30 healthy controls. Resting-state functional connectivity of the habenula and amygdala bilaterally was assessed using a seed-based approach. Habenula and amygdala volumes and cortical thickness measures were obtained.Results:Compared to both healthy controls and PD cases without any ICB (PD–no ICB), PD-punding patients showed higher functional connectivity of habenula and amygdala with thalamus and striatum bilaterally, and lower connectivity between bilateral habenula and left frontal and precentral cortices. In PD-punding relative to PD–no ICB patients, a lower functional connectivity between right amygdala and hippocampus was also observed. Habenula and amygdala volumes were not different among groups. PD-punding patients showed a cortical thinning of the left superior frontal and precentral gyri and right middle temporal gyrus and isthmus cingulate compared to healthy controls, and of the right inferior frontal gyrus compared to both controls and PD–no ICB patients.Conclusions:A breakdown of the connectivity among the crucial nodes of the reward circuit (i.e., habenula, amygdala, basal ganglia, frontal cortex) might be a contributory factor to punding in PD. This study provides potential instruments to detect and monitor punding in patients with PD.

Multiple system atrophy (MSA) is a sporadic, adult-onset, relentlessly progressive neurodegenerative disorder, clinically characterized by various combinations of autonomic failure, parkinsonism and ataxia. The neuropathological hallmark of MSA are glial cytoplasmic inclusions consisting of misfolded α-synuclein. Selective atrophy and neuronal loss in striatonigral and olivopontocerebellar systems underlie the division into two main motor phenotypes of MSA-parkinsonian type and MSA-cerebellar type. Isolated autonomic failure and REM sleep behavior disorder are common premotor features of MSA. Beyond the core clinical symptoms, MSA manifests with a number of non-motor and motor features. Red flags highly specific for MSA may provide clues for a correct diagnosis, but in general the diagnostic accuracy of the second consensus criteria is suboptimal, particularly in early disease stages. In this chapter, the authors discuss the historical milestones, etiopathogenesis, neuropathological findings, clinical features, red flags, differential diagnosis, diagnostic criteria, imaging and other biomarkers, current treatment, unmet needs and future treatments for MSA.

© 2019 International Parkinson and Movement Disorder Society, Multiple system atrophy (MSA) is an adult-onset progressive neurodegenerative disorder that manifests clinically with autonomic failure, parkinsonism, and ataxia in any combination. Oligodendroglial cytoplasmatic inclusions consisting of misfolded α-synuclein are a pathological hallmark of disease. The clinical diagnosis of MSA is typically delayed as a result of incomplete or nonspecific manifestations during early disease stages. Quinn first published diagnostic criteria for MSA in 1989. Since then, the first consensus criteria in 1998 and their revision in 2008 have been widely accepted as diagnostic guidelines for MSA.

Objective The goal of this study was to analyze how depression associated with Parkinson’s disease (PD) affected gait variability in these patients using a dual-task paradigm. Additionally, the dependency of the executive functions and the impact of depression on gait variability were analyzed. Patients and Methods Three subject groups were included: patients with PD, but no depression (PD-NonDep; 14 patients), patients with both PD and depression (PD-Dep; 16 patients) and healthy controls (HC; 15 subjects). Gait was recorded using the wireless sensors. The participants walked under four conditions: single-task, motor dual- task, cognitive dual-task, and combined dual-task. Variability of stride length, stride duration, and swing time was calculated and analyzed using the statistical methods. Results Variability of stride duration and stride length were not significantly different between PD-Dep and PD-NonDep patients. The linear mixed model showed that swing time variability was statistically significantly higher in PD-Dep patients compared to controls (p = 0.001). Hamilton Disease Rating Scale scores were significantly correlated with the swing time variability (p = 0.01). Variability of all three parameters of gait was significantly higher while performing combined or cognitive task and this effect was more pronounced in PD-Dep group of patients. Conclusions Depression in PD was associated with swing time variability, and this effect was more prominent while performing a dual-task. Significance Diagnosing and treating depression might be important for gait improvement and fall reduction in PD patients.

The aims of this study were to compare clinical and fall characteristics of single and recurrent falls among persons with PD and to evaluate factors associated with recurrent falls. A total of 120 consecutive persons with PD, who denied having fallen in the past 6 months, were recruited. Occurrence of falling was registered during one year. Each person was given a "fall diary" with the aim at writing characteristics of the fall and contacted by telephone each month. Over one year of follow-up 42 persons with PD (35.0%) reported falling. Of 42 persons, 19 (45.2%) went on to become single and 23 (54.8%) went on to become recurrent fallers. Indoor falls were more common among single fallers, whilst outdoor falls were more common among recurrent fallers (p=0.017). Slipping and freezing of gait was more common among single fallers (p=0.035 and p=0.024, respectively). Lower extremity weakness was more frequent among recurrent fallers (p=0.023). The most common injury both among single and recurrent fallers was the soft-tissue contusion. The only factor associated with recurrent falling among persons with PD, who did not fall in past 6 months before the start of follow-up, was worse motor performance as measured by the UPDRS III score (odds ratio [OR]=1.06, 95% confidence interval [CI] 1.01-1.11, p=0.022). These results could be used in selection of persons with PD to enroll in fall prevention programs.

Levodopa-induced dyskinesias (LID) appears in more than 50% of Parkinson's disease patients after 5 years of treatment and clinicians always have to ensure that there is a balance between the beneficial effect of the treatment and the potential complications.In this review, the authors discuss the treatment of LID. Treatment can be divided into strategies for preventing their occurrence, modification of dopaminergic therapy, and providing more continuous dopaminergic stimulation as well as the use of nondopaminergic drugs.Amantadine is currently considered the most effective drug for the treatment of LID. Several compounds developed to target adenosine, adrenergic, glutamatergic, and serotonergic receptors have shown to significantly decrease dyskinesias in animal models. However, despite promising preclinical results, translation to clinical practice remains challenging and majority of these compounds failed to decrease LID in randomized controlled trials with moderate-to-advanced parkinsonian patients. Despite promising results with nondopaminergic drugs, treatment of dyskinesias is still challenging and largely due to their side effects. Future research should focus on developing treatments that can provide continuous dopaminergic delivery throughout the day in a noninvasive manner. Studies on the impact of the early administration of long-acting formulations of levo-3,4-dihydroxy-phenylalanine on dyskinesias are also necessary.

Introduction It has been demonstrated that various domains of health-related quality of life (HRQoL) have predictive value in progression of disability and depression in a neurological setting. The aim of this study was to assess potential predictive value of domains of HRQoL in occurrence of falls among persons with Parkinson's disease (PD) over one year of follow-up. Methods The study comprised cross-sectional design at baseline and 1-year prospective cohort study. Those who denied having fallen in the past 6 months were followed for one year, while participants were asked to record falls prospectively in a falls diary for a year. A total of 300 consecutive PD outpatients without cognitive impairment were recruited from August 15, 2011 to December 15, 2012 in the outpatient Department of Movement Disorders, Institute of Neurology, Clinical Center of Serbia in Belgrade. The HRQoL was evaluated using the SF-36 questionnaire. Results All domains of the SF-36, except Role Emotional, were significantly lower among fallers. After controlling for potential confounding factors, the domain of Role Physical (p = 0.027), Physical Composite Score (p = 0.023) and the total SF-36 score (p = 0.029) were significant predictors of occurrence of falls within one year of follow-up. Conclusion Assessment of quality of life represents an additional tool to the established measures of clinical course of the disease and could provide further insight in complex distinction of risk factors for falling in PD.

Background: Motor symptoms in Parkinson's disease (PD) are typically asymmetrical. Early stage of PD is characterised with a predominantly unilateral appearance of tremor, rigidity and bradykinesia, with or without axial involvement. Also, studies have demonstrated gait asymmetry in de novo drug naive PD patients. Aim of this study was to investigate gait pattern, gait symmetry and gait variability in early phases of PD. Methods: The gait was measured in 40 de novo, drug naive PD patients and 43 healthy control subjects (HC) while performing a simple walking task. Calculated parameters were cycle time (CT), stride length (SL) and swing time (ST), and their coefficients of variation (CV). Results: Considering gait parameters, PD patients and HC differed in terms of all parameters, except for the CV of CT. Analysis of gait symmetry, comparison between the gait patterns of the left and the right leg in PD patients revealed no difference for any of the assessed parameters. The majority of the gait parameters did not differ between left and right legs of HC. Conclusions: It can be concluded that even gait was already altered in de novo drug naive PD patients, gait symmetry remained preserved. The SL was the most prominent parameter of altered gait in initial stages of PD patients, while the ST heralded postural asymmetry.

Background: Mild cognitive impairment (MCI) in Parkinson's disease (PD) is common and confers a higher risk for developing dementia. Methods: In this cross-sectional study of MCI in PD conducted at a university hospital, a comprehensive neuropsychological battery covering five domains (attention/working memory, executive, verbal, and visual memory, language, and visuospatial) was administered to 111 nondemented PD patients in Hoehn and Yahr stage 1 and to 105 healthy matched control subjects (HC). MCI was diagnosed according to level 2 of the Movement Disorder Society Task Force criteria. Results: Criteria for MCI associated with PD (PD-MCI) were fulfilled by 24% of PD patients in the initial stage of the disease at the z cutoff scores of -1.5 SD in contrast to 7% of HC fulfilling criteria for MCI. Memory and visuospatial domains were the most commonly affected at -1.5 SD. PD-MCI patients mostly had a multiple-domain MCI subtype (78%). They presented a more severe bradykinesia and higher mood and apathy scores in comparison with cognitively normal PD patients. Basic motor scores predicted performance on some cognitive tests and specific cognitive-motor relationships emerged. Conclusions: MCI, predominantly of a multiple-domain subtype, was quite prevalent even in the initial stage of PD.

Background: Gait disturbances are an integral part of clinical manifestations of Parkinson's disease (PD), even in the initial stages of the disease. Our goal was to identify the set of spatio-temporal gait parameters that bear the highest relevance for characterizing de novo PD patients. Methods: Forty patients with de novo PD and forty healthy controls were recorded while walking over an electronic walkway in three different conditions: (1) base walking, (2) walking with an additional motor task, (3) walking with an additional mental task. Both groups were well balanced concerning age and gender. To select a smaller number of relevant parameters, affinity propagation clustering was applied on parameter pairwise correlation. The exemplars were then sorted by importance using the random forest algorithm. Classification accuracy of a support vector machine was tested using the selected parameters and compared to the accuracy of the model using a set of parameters derived from literature. Results: Final selection of parameters included: stride length and stride length coefficient of variation (CV), stride time and stride time CV, swing time and swing time CV, step time asymmetry, and heel-to-heel base support CV. Classification performed using these parameters showed higher overall accuracy (85%) than classification using the common parameter set containing: stride time, stride length, swing time and double support time, along with their CVs (78%). Conclusion: In early stages of PD, double support time and its CV appear to be weak indicators of the disease. We instead found step time asymmetry and support base CV to significantly contribute to classification accuracy.

Objective To assess brain white matter tract alterations in patients with Parkinson's disease and punding (PD-punding) compared with controls and PD cases without any impulsive-compulsive behaviour. Methods Forty-nine PD patients (21 PD-punding and 28 PD with no impulsive-compulsive behaviours) and 28 controls were consecutively recruited. Clinical, cognitive and psychopathological evaluations were performed. Diffusion tensor MRI metrics of the main white matter tracts were assessed using a tractography approach. Results Compared with controls, both PD groups showed white matter microstructural alterations of the left pedunculopontine tract and splenium of the corpus callosum. PD-punding patients showed a further damage to the right pedunculopontine tract and uncinate fasciculus, genu of the corpus callosum, and left parahippocampal tract relative to controls. When adjusting for depression and/or apathy severity, a greater damage of the genu of the corpus callosum and the left pedunculopontine tract was found in PD-punding compared with patients with no impulsive-compulsive behaviours. Conclusions PD-punding is associated with a disconnection between midbrain, limbic and white matter tracts projecting to the frontal cortices. These alterations are at least partially independent of their psychopathological changes. Diffusion tensor MRI is a powerful tool for understanding the neural substrates underlying punding in PD.

Falls represent continuing, disabling and costly problem in Parkinson's disease (PD). The study was carried out at the Neurology Clinic in Belgrade from August 2011 to December 2012. As many as 180 community dwelling persons with PD aged 22-83 years who sustained a fall in past 6 months were included. Characteristics of the most recent fall were obtained through detailed interviews. Inclusion criteria were: Mini Mental State Examination (MMSE)≥24, ability to walk independently for at least 10 m and ability to statically stand for at least 90 s. Exclusion criteria were: presence of other neurologic as well as psychiatric, visual, audio-vestibular and orthopedic impairments. Falls more frequently took place outside (57.2%) and in the morning (53.9%). As much as 38.9% of persons with PD sustained an injury. Soft-tissue contusion was the most common injury (71.8%) both after indoor and outdoor falls. Fractures accounted for 5% of all fall-related injuries. All the fractures were either arm, clavicle or rib fractures. Tripping was identified as risk factor for outdoor falls (OR=7.90; 95% confidence interval [95% CI] 3.21-19.39; p=0.001). In contrast, lower extremity weakness (OR=0.20; 95% CI 0.05-0.72; p=0.015) and internal sense of sudden loss of balance (OR=0.19; 95% CI 0.05-0.73; p=0.015) were risk factors for indoor falls. To accomplish long-term results, development of particular prevention programs for persons with PD who fall at home vs. outdoors is recommended.

Huntington disease (HD), the most common inherited cause of chorea, is an autosomal dominant disorder, caused by an expanded trinucleotide CAG repeat (>39) in the HTT gene on chromosome 4p16.3. Among patients diagnosed as HD solely on clinical grounds, a certain number was negative on genetic testing for HD. Therefore, HD-like disorders comprised a number of genetic causes of chorea, that may be indistinguishable from HD (e.g. HD phenocopy syndrome). Recent data suggested that the C9orf72 expansion may be the most common genetic cause of HD phenocopy presentations. In continuation with this observation, we analyzed a small cohort of 39 patients with HD phenocopy syndrome and detected the C9orf72 expansion in one female patient (2.6 %) with two-year lasting mild generalized chorea and severe oro-bucco-lingual dyskinesia, who complained on forgetfullness (neuropsychological testing revealed dysexecutive syndrome with preserved episodic memory and recognition), unexplainable fears and increased appetite. Our results confirmed a possible role of the C9orf72 expansion in the genetic background of HD phenocopy syndrome.

Alternation of walking pattern decreases quality of life and may result in falls and injuries. Freezing of gait (FOG) in Parkinson's disease (PD) patients occurs occasionally and intermittently, appearing in a random, inexplicable manner. In order to detect typical disturbances during walking, we designed an expert system for automatic classification of various gait patterns. The proposed method is based on processing of data obtained from an inertial sensor mounted on shank. The algorithm separates normal from abnormal gait using Pearson's correlation and describes each stride by duration, shank displacement, and spectral components. A rule-based data processing classifies strides as normal, short $({\hbox {short}}^{+})$ or very short $({\hbox {short}}^{-})$ strides, FOG with tremor $({\hbox {FOG}}^{+})$ or FOG with complete motor block $({\hbox {FOG}}^{-})$ . The algorithm also distinguishes between straight and turning strides. In 12 PD patients, ${\hbox {FOG}}^{+}$ and ${\hbox {FOG}}^{-}$ were identified correctly in 100% of strides, while normal strides were recognized in 95% of cases. ${\hbox {Short}}^{+}$ and ${\hbox {short}}^{-}$ strides were identified in about 84% and 78%. Turning strides were correctly identified in 88% of cases. The proposed method may be used as an expert system for detailed stride classification, providing warning for severe FOG episodes and near-fall situations.