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Increasing evidence suggests persistent cognitive dysfunction after COVID-19. In this cross-sectional study, frontal lobe function was assessed 12 months after the acute phase of the disease, using tailored eye tracking assessments. Individuals who recovered from COVID-19 made significantly more errors in all eye tracking tasks compared to age/sex-matched healthy controls. Furthermore, patients who were treated as inpatients performed worse compared to outpatients and controls. Our results show impaired inhibitory cortical control in individuals who recovered from COVID-19. The association between disease severity and its sequelae may contribute to a better understanding of post-COVID-19 cognitive function.

Neurological sequelae from coronavirus disease 2019 (COVID-19) may persist after recovery from acute infection. Here, the aim was to describe the natural history of neurological manifestations over 1 year after COVID-19.A prospective, multicentre, longitudinal cohort study in COVID-19 survivors was performed. At a 3-month and 1-year follow-up, patients were assessed for neurological impairments by a neurological examination and a standardized test battery including the assessment of hyposmia (16-item Sniffin' Sticks test), cognitive deficits (Montreal Cognitive Assessment26) and mental health (Hospital Anxiety and Depression Scale and Post-traumatic Stress Disorder Checklist 5).Eighty-one patients were evaluated 1 year after COVID-19, out of which 76 (94%) patients completed a 3-month and 1-year follow-up. Patients were 54 (47-64) years old and 59% were male. New and persistent neurological disorders were found in 15% (3 months) and 12% (10/81; 1 year). Symptoms at 1-year follow-up were reported by 48/81 (59%) patients, including fatigue (38%), concentration difficulties (25%), forgetfulness (25%), sleep disturbances (22%), myalgia (17%), limb weakness (17%), headache (16%), impaired sensation (16%) and hyposmia (15%). Neurological examination revealed findings in 52/81 (64%) patients without improvement over time (3 months, 61%, p = 0.230) including objective hyposmia (Sniffin' Sticks test13; 51%). Cognitive deficits were apparent in 18%, whereas signs of depression, anxiety and post-traumatic stress disorders were found in 6%, 29% and 10% respectively 1 year after infection. These mental and cognitive disorders had not improved after the 3-month follow-up (all p 0.05).Our data indicate that a significant patient number still suffer from neurological sequelae including neuropsychiatric symptoms 1 year after COVID-19 calling for interdisciplinary management of these patients.

Background: Early identification of Parkinson’s disease (PD) patients at risk for becoming functionally dependent is important for patient counseling. Several models describing the relationship between predictors and outcome have been reported, however, most of these require computer software for practical use. Objective: Here we report the development of a risk nomogram allowing an approximate graphical computation of the risk of becoming functionally dependent in early PD. Methods: We analyzed data form the Parkinson’s Progression Markers Initiative cohort of newly diagnosed PD patients from baseline through the first 5 years of follow-up. Functional dependence was defined as a score

Purpose To assess patient characteristics associated with health-related quality of life (HR-QoL) and its mental and physical subcategories 3 months after diagnosis with COVID-19. Methods In this prospective multicentre cohort study, HR-QoL was assessed in 90 patients using the SF-36 questionnaire (36-item Short Form Health Survey), which consists of 8 health domains that can be divided into a mental and physical health component. Mental health symptoms including anxiety, depression, and post-traumatic stress disorders were evaluated using the Hospital Anxiety and Depression Scale (HADS) and Post-traumatic Stress Disorder Checklist-5 (PCL-5) 3 months after COVID-19. Using descriptive statistics and multivariable regression analysis, we identified factors associated with impaired HR-QoL 3 months after COVID-19 diagnosis. Results Patients were 55 years of age (IQR, 49–63; 39% women) and were classified as severe (23%), moderate (57%), or mild (20%) according to acute disease severity. HR-QoL was impaired in 28/90 patients (31%). Younger age [per year, adjOR (95%CI) 0.94 (0.88–1.00), p = 0.049], longer hospitalization [per day, adjOR (95%CI) 1.07 (1.01–1.13), p = 0.015], impaired sleep [adjOR (95%CI) 5.54 (1.2–25.61), p = 0.028], and anxiety [adjOR (95%CI) 15.67 (3.03–80.99), p = 0.001) were independently associated with impaired HR-QoL. Twenty-nine percent (n = 26) scored below the normal range on the mental health component of the SF-36 and independent associations emerged for anxiety, depression, and self-reported numbness. Impairments in the physical health component of the SF-36 were reported by 12 (13%) patients and linked to hypogeusia and fatigue. Conclusion Every third patient reported a reduction in HR-QoL 3 months after COVID-19 diagnosis and impairments were more prominent in mental than physical well-being.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment option for Parkinson's disease (PD). Recent work has shown that using low- and high-frequency DBS can have a different effect on axial and distal limb functions suggesting that the frequency might affect pathways differently. The STN is also a critical node in the oculomotor and associative networks, which can lead to collateral visual and cognitive side effects. The role of frequency of stimulation on these networks remains unknown. The objective of this study was to investigate the effects of low- vs. high-frequency STN-DBS on eye movements and executive control. Twenty-one STN-DBS PD patients with 130Hz vs. 80Hz stimulation were compared with a healthy control group (n=16). All participants were tested twice in a double-blind manner. We examined prosaccades (latency and gain) and antisaccades (latency of the correct antisaccades, latency of the incorrect antisaccades, error rate and gain of the correct antisaccades). Non-oculomotor executive functions were tested with the Stroop task. The motor condition was assessed using Unified Parkinson’s Disease Rating Scale part III. The antisaccadic error rate was higher in patients (p=0.0113), and it was higher in patients on 80Hz compared to 130Hz (p=0.001). The differences between patients and controls and between different frequency of stimulation for all other eye-movements or cognitive measures were statistically non-significant. We show that 80Hz STN-DBS in PD reduces the ability to maintain stable fixation but does not alter inhibition, resulting in a higher antisaccade error rate due to less efficient fixation, without altering the motor state of the patients. This is also clinically important because it means that lowering the stimulation frequency from 130Hz to 80Hz can alter eye movement performance without affecting motor symptoms. This provides a wider range of stimulation parameters that can reduce specific DBS-related side effects without affecting motor outcomes.

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.

Contains fulltext : 232804.pdf (Publisher’s version ) (Open Access) BACKGROUND: Interest has risen in identifying individuals at high risk of incident Parkinson's disease (PD) to facilitate inclusion in neuroprotective treatment trials. Current risk estimates of prodromal markers are based on aggregated data of an entire population, but this approach disregards differences in risk estimates by subgroups of a population. In this proof of concept, we determine subgroup-specific risk estimates of olfactory dysfunction for incident PD. METHODS: PubMed, EMBASE and Cochrane were searched for prospective studies investigating the association between olfactory dysfunction and incident PD. Random-effects meta-analysis, subgroup analyses and meta-regression were performed to investigate general and subgroup risk estimates. RESULTS: Individuals with odor identification dysfunction seemed to be at greater risk of incident PD compared to controls without olfactory dysfunction (OR = 4.18; 95%CI [2.47-7.07]). Risk estimates were higher in studies that included higher percentages of women (regression slope β = 0.053 increase in log odds ratio per 1% increase 1%, p = 0.0006), increased with mean study age (β = 0.21 per one year increase; p = 0.005) and in REM-sleep behavior disorder cohorts (β = 1.95; p = 0.03). Furthermore, the association between olfactory dysfunction and incident PD was most distinct in studies with shorter follow-up duration (ß = -0.56; p = 0.0047). CONCLUSION: The presence of olfactory dysfunction conveys a considerably elevated risk of incident PD, likely more in studies with a higher proportion of women, older individuals or short follow-up duration. Individual patient data are warranted to confirm these findings and to yield subgroup-specific risk estimates of other common markers to refine prodromal PD criteria.

Background The pathophysiology of cervical dystonia is still unclear. Recent evidence points toward a network disorder affecting several brain areas. The objective of this study was to assess the saccadic inhibition as a marker of corticostriatal function in cervical dystonia. Methods We recruited 31 cervical dystonia patients and 17 matched healthy controls. Subjects performed an overlap prosaccade, an antisaccade, and a countermanding task on an eye tracker to assess automatic visual response and response inhibition. Results Cervical dystonia patients made more premature saccades (P = 0.041) in the overlap prosaccade task and more directional errors in the antisaccade task (P = 0.011) and had a higher rate of failed inhibition in the countermanding task (P = 0.001). Conclusions The results suggest altered saccadic inhibition in cervical dystonia, possibly as a consequence of dysfunctional corticostriatal networks. Further studies are warranted to confirm whether these abnormalities are affected by the available therapies and whether this type of impairment is found in other focal dystonias. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background Gait impairment is a pivotal feature of parkinsonian syndromes and increased gait variability is associated with postural instability and a higher risk of falls. Objectives We compared gait variability at different walking velocities between and within groups of patients with Parkinson-variant multiple system atrophy, idiopathic Parkinson’s disease, and a control group of older adults. Methods Gait metrics were recorded in 11 multiple system atrophy, 12 Parkinson’s disease patients, and 18 controls using sensor-based gait analysis. Gait variability was analyzed for stride, swing and stance time, stride length and gait velocity. Values were compared between and within the groups at self-paced comfortable, fast and slow walking speed. Results Multiple system atrophy patients displayed higher gait variability except for stride time at all velocities compared with controls, while Parkinson’s patients did not. Compared with Parkinson’s disease, multiple system atrophy patients displayed higher variability of swing time, stride length and gait velocity at comfortable speed and at slow speed for swing and stance time, stride length and gait velocity (all P P = 0.014). Variability parameters significantly correlated with the postural instability/gait difficulty subscore in both disease groups. Conversely, significant correlations between variability parameters and MDS-UPDRS III score was observed only for multiple system atrophy patients. Conclusion This analysis suggests that gait variability parameters reflect the major axial impairment and postural instability displayed by multiple system atrophy patients compared with Parkinson’s disease patients and controls.

A robust body of evidence from randomized controlled trials has established the efficacy of deep brain stimulation (DBS) in reducing off time and dyskinesias in levodopa-treated patients with Parkinson's disease (PD). These effects go along with improvements in on period motor function, activities of daily living, and quality of life. In addition, subthalamic DBS is effective in controlling drug-refractory PD tremor. Here, we review the available data from long-term observational and controlled follow-up studies in DBS-treated patients to re-examine the persistence of motor and quality of life benefits and evaluate the effects on disease progression, major disability milestones, and survival. Although there is consistent evidence from observational follow-up studies in DBS-treated patients over 5-10 years and beyond showing sustained improvement of motor control, the long-term impact of DBS on overall progression of disability in PD is less clear. Whether DBS reduces or delays the development of later motor and non-motor disability milestones in comparison to best medical management strategies is difficult to answer by uncontrolled observational follow-up, but there are signals from controlled long-term observational studies suggesting that subthalamic DBS may delay some of the late-stage disability milestones including psychosis, falls, and institutionalization, and also slightly prolongs survival compared with matched medically managed patients. These observations could be attributable to the sustained improvements in motor function and reduction in medication-induced side effects, whereas there is no clinical evidence of direct effects of DBS on the underlying disease progression. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Dystonia is a debilitating disease with few treatment options. One effective option is deep brain stimulation (DBS) to the internal pallidum. While cervical and generalized forms of isolated dystonia have been targeted with a common approach to the posterior third of the nucleus, large-scale investigations regarding optimal stimulation sites and potential network effects have not been carried out. Here, we retrospectively studied clinical results following DBS for cervical and generalized dystonia in a multicenter cohort of 80 patients. We model DBS electrode placement based on pre- and postoperative imaging and introduce an approach to map optimal stimulation sites to anatomical space. Second, we investigate which tracts account for optimal clinical improvements, when modulated. Third, we investigate distributed stimulation effects on a whole-brain functional connectome level. Our results show marked differences of optimal stimulation sites that map to the somatotopic structure of the internal pallidum. While modulation of the striatopallidofugal axis of the basal ganglia accounted for optimal treatment of cervical dystonia, modulation of pallidothalamic bundles did so in generalized dystonia. Finally, we show a common multisynaptic network substrate for both phenotypes in the form of connectivity to the cerebellum and somatomotor cortex. Our results suggest a brief divergence of optimal stimulation networks for cervical vs. generalized dystonia within the pallidothalamic loop that merge again on a thalamo-cortical level and share a common whole-brain network.

Background The long-term impact of deep brain stimulation (DBS) on Parkinson's disease (PD) is difficult to assess and has not yet been rigorously evaluated in comparison to its natural history. Objective Comparison of key disability milestones (recurrent falls, psychosis, dementia, and institutionalization) and death in patients with PD with versus without DBS. Methods We collected retrospective information from clinical notes of patients with PD at our center that were implanted with subthalamic DBS >8 years ago (1999-2010) and a control group of PD patients without DBS similar in age at onset, age at baseline, sex distribution, and number of comorbidities at baseline (extracted from a registry study performed in 2004). Cox regression models were used to calculate hazard ratios, adjusted for potential baseline confounding variables (age, sex, disease duration, disease severity, and number of comorbidities). Results A total of 74 DBS-treated and 61 control patients with PD were included. For a median observational period of 14 years, patients treated with DBS were at lower risk of experiencing recurrent falls (hazard ratio = 0.57; 95% confidence interval, 0.37-0.90; P = 0.015) and psychosis (hazard ratio = 0.26; 95% confidence interval, 0.12-0.59; P = 0.001) compared with control patients. There was no significant difference in risk for dementia, institutionalization, or death. Disease progression as assessed by Hoehn and Yahr scores was not slower in DBS-treated patients. Conclusions Treatment with chronic subthalamic DBS was associated with lower risk for recurrent falls and psychotic symptoms, effects that may be mediated through improved motor symptom control and reduction in dopaminergic therapies, respectively. There was no evidence for DBS effects on underlying disease progression.

Background Identifying individuals at risk of developing Parkinson's disease (PD) is critical to define target populations for future neuroprotective trials. Objective The objective of this study was to apply the PREDICT‐PD algorithm of risk indicators for PD in a prospective community‐based study (the Bruneck study), representative of the general elderly population. Methods PREDICT‐PD risk scores were calculated based on risk factor assessments obtained at baseline (2005, n = 574 participants). Cases of incident PD were identified at 5‐year and 10‐year follow‐ups. Participants with PD or secondary parkinsonism at baseline were excluded (n = 35). We analyzed the association of log‐transformed risk scores with the presence of well‐established markers as surrogates for PD risk at baseline and with incident PD at follow‐up. Results A total of 20 participants with incident PD were identified during follow‐up (11 after 5 years and 9 after 10 years). Baseline PREDICT‐PD risk scores were associated with incident PD with odds ratios of 2.09 (95% confidence interval, 1.35–3.25; P = 0.001) after 5 years and of 1.95 (1.36–2.79; P

Objectives MR planimetry of brainstem structures can be helpful for the discrimination of Parkinsonian syndromes. It has been suggested that ageing might influence brainstem MR measurements assessed by MR planimetry, while effects of gender and total intracranial volume (TIV) have not been assessed so far. The aim of this study was to evaluate age, gender and TIV effects on brainstem MR planimetric measures. Methods Brainstem MR planimetric measures of diameters (midbrain, pons, middle and superior cerebellar peduncle) and areas (pons and midbrain), the derived ratios, and the magnetic resonance Parkinsonism index (MRPI) were assessed on 1.5-T MR images in a large cohort of 97 healthy controls and analysed for the influence of age, gender and TIV with univariate and multivariate linear models. Results Neither gender nor age effects on planimetric measurements were observed in the population relevant for the differential diagnosis of neurodegenerative Parkinsonism, aged 50 to 80 years, except for single area-derived measurements, with gender effects on pontine area (p = 0.013) and age effects on midbrain area (p = 0.037). Results were similar upon inclusion of the TIV in the analyses. Conclusions There is no need to correct for age, gender or TIV when using brainstem-derived MR planimetric measurements in the differential diagnosis of neurodegenerative Parkinsonism. Key Points • There were no gender effects on single or combined imaging measurements of the brainstem in the population aged 50 to 80 years, the age range relevant for the differential diagnosis of neurodegenerative Parkinsonism (except for pontine area). • There were no age effects on single or combined imaging measurements of the brainstem in the population aged 50 to 80 years, the age range relevant for the differential diagnosis of neurodegenerative Parkinsonism (except for midbrain area). • There is no need for age- or gender-specific cut-offs for the relevant age group.

Dystonia is a debilitating disease with few conservative treatment options but many types of isolated dystonia can be effectively treated using deep brain stimulation (DBS) to the internal pallidum.While cervical and generalized forms of isolated dystonia have been targeted with a common approach to the posterior third of the nucleus, large-scale investigations between optimal stimulation sites and potential network effects in the two types of dystonia have not been carried out.Here, we retrospectively investigate clinical results following DBS for cervical and generalized dystonia in a multi-center cohort of 80 patients. We model DBS electrode placement based on pre- and postoperative imaging and introduce a novel approach to map optimal stimulation sites to anatomical space. Second, we analyse stimulation in context of a detailed pathway model of the subcortex to investigate the modulation of which tracts accounts for optimal clinical improvements. Third, we investigate stimulation in context of a broad-lense whole-brain functional connectome to illustrate potential multisynaptic network effects. Finally, we construct a joint model using local, tract- and network-based effects to explain variance in clinical outcomes in cervical and generalized dystonia.Our results show marked differences in optimal stimulation sites that map to the somatotopic structure of the internal pallidum. We further highlight that modulation of the pallidofugal main axis of the basal ganglia may be optimal for treatment of cervical dystonia, while pallidothalamic bundles account for effects in generalized dystonia. Finally, we show a common multisynaptic network substrate for both phenotypes in form of connectivity to cerebellum and somatomotor cortex.Our results suggest a multi-level model that could account for effectivity of treatment in cervical and generalized dystonia and could potentially help guide DBS programming and surgery, in the future.

Deep brain stimulation of the internal globus pallidus is a highly effective and established therapy for primary generalized and cervical dystonia, but therapeutic success is compromised by a non-responder rate of up to 25%, even in carefully-selected groups. Variability in electrode placement and inappropriate stimulation settings may account for a large proportion of this outcome variability. Here, we present probabilistic mapping data on a large cohort of patients collected from several European centres to resolve the optimal stimulation volume within the pallidal region. A total of 105 dystonia patients with pallidal deep brain stimulation were enrolled and 87 datasets (43 with cervical dystonia and 44 with generalized dystonia) were included into the subsequent 'normative brain' analysis. The average improvement of dystonia motor score was 50.5 ± 30.9% in cervical and 58.2 ± 48.8% in generalized dystonia, while 19.5% of patients did not respond to treatment (

Background and purpose To assess neurological manifestations and health‐related quality of life (QoL) 3 months after COVID‐19. Methods In this prospective, multicenter, observational cohort study we systematically evaluated neurological signs and diseases by detailed neurological examination and a predefined test battery assessing smelling disorders (16‐item Sniffin Sticks test), cognitive deficits (Montreal Cognitive Assessment), QoL (36‐item Short Form), and mental health (Hospital Anxiety and Depression Scale, Posttraumatic Stress Disorder Checklist–5) 3 months after disease onset. Results Of 135 consecutive COVID‐19 patients, 31 (23%) required intensive care unit (ICU) care (severe), 72 (53%) were admitted to the regular ward (moderate), and 32 (24%) underwent outpatient care (mild) during acute disease. At the 3‐month follow‐up, 20 patients (15%) presented with one or more neurological syndromes that were not evident before COVID‐19. These included polyneuro/myopathy (n = 17, 13%) with one patient presenting with Guillain‐Barré syndrome, mild encephalopathy (n = 2, 2%), parkinsonism (n = 1, 1%), orthostatic hypotension (n = 1, 1%), and ischemic stroke (n = 1, 1%). Objective testing revealed hyposmia/anosmia in 57/127 (45%) patients at the 3‐month follow‐up. Self‐reported hyposmia/anosmia was lower (17%) at 3 months, however, improved when compared to the acute disease phase (44%; p, Three months after COVID‐19, 20/135 patients (15%) presented with one or more neurological syndromes that were not evident before disease onset. Objective testing revealed hyposmia/anosmia in 45% of patients at the 3‐month follow‐up in comparison to 17% who reported hyposmia/anosmia. Cognitive deficits were apparent in 23%, quality of life was impaired in 31%, depression was found in 11%, anxiety in 25% and posttraumatic stress disorders in 11%.

To date, despite numerous clinical trials, no intervention has been demonstrated to modify the progression of Parkinson's disease (PD). However, over the past decades encouraging progress has been made towards a better understanding of molecular pathways relevant for the neurodegenerative process in PD. This is also based on new insights into the genetic architecture of the disease, revealing multiple novel targets for potentially disease-modifying interventions. Important achievements have also been made in the field of risk markers and combinations thereof, in the form of risk algorithms, will hopefully soon provide the possibility to identify affected individuals at yet prediagnostic or prodromal stages of the illness. Such phases of the disease would provide an ideal window for neuroprotection trials. Taken together, these developments offer hope that a breakthrough towards modifying the course of PD might be reached. In this article we summarize various approaches currently pursued in this quest. This article is part of the special issue entitled 'The Quest for Disease-Modifying Therapies for Neurodegenerative Disorders'.

Motor symptoms are a major feature of Huntington's disease (HD). The International Parkinson and Movement Disorder Society (MDS) commissioned the assessment of the clinimetric properties of motor rating scales in HD to make recommendations regarding their use, following previously established standardized criteria. After a systematic literature search, a total of 6 rating scales assessing motor symptoms and signs in HD were included for review. Performance testing (reviewed elsewhere) and quantitative motor rating methods were excluded. Only the Unified Huntington's Disease Rating Scale-Total Motor Score (UHDRS-TMS) was classified as "recommended" for assessing the severity of motor signs in HD. The following scales were classified as "suggested": Abnormal Involuntary Movement Scale, the UHDRS-TMS4, the Quantified Neurological Examination, and the Marsden and Quinn Chorea Severity Scale. The committee also concluded that further assessment of existing rating scales, including the UHDRS-TMS, is necessary to determine sensitivity to change and to screening for the presence of motor signs specific to HD. There is also a need to develop a motor rating scale to be used in positive gene carriers with subtle but not definite motor signs.

BACKGROUND: Subthalamic deep brain stimulation (STN-DBS) is an established treatment for late stage Parkinson's disease (PD). Speech intelligibility (SI) and verbal fluency (VF) have been shown to deteriorate following chronic STN-DBS. It has been suggested that speech might respond favourably to low frequency stimulation (LFS). OBJECTIVE: We examined how speech intelligibility, perceptual speech characteristics, phonemic and semantic VF and processes underlying it (clustering and switching) respond to LFS of 60 and 80 Hz in comparison to high frequency stimulation (HFS) (110, 130 and 200 Hz). METHODS: In this double-blind study, 15 STN-DBS PD patients (mean age 65, SD = 5.8, 14 right handed, three females), were assessed at five stimulation frequencies: 60 Hz, 80 Hz, 110 Hz, 130 Hz and 200 Hz. In addition to the clinical neurological assessment of speech, VF and SI were assessed. RESULTS: Speech intelligibility and in particular articulation, respiration, phonation and prosody improved with LFS (all p < 0.05). Phonemic VF switching improved with LFS (p = 0.005) but this did not translate to an improved phonemic VF score. A trend for improved semantic VF was found. A negative correlation was found between perceptual characteristics of speech and duration of chronic stimulation (all p < 0.05). CONCLUSIONS: These findings highlight the need for meticulous programming of frequency to maximise speech intelligibility in chronic STN-DBS. The findings further implicate stimulation frequency in changes to specific processes underlying VF, namely phonemic switching and demonstrate the potential to address such deficits through advanced adjustment of stimulation parameters.

Behavioral symptoms are an important feature of Huntington’s disease and contribute to impairment in quality of life. The Movement Disorder Society commissioned the assessment of the clinimetric properties of rating scales in Huntington’s disease in order to make recommendations regarding their use, following previously used standardized criteria. A systematic literature search was conducted to identify the scales used to assess behavioral symptoms in Huntington’s disease. For the purpose of this review, seven behavioral domains were deemed significant in Huntington’s disease: irritability, anxiety, depression, apathy, obsessive-compulsive behaviors, psychosis and suicidal ideation. We included a total of 27 behavioral rating scales, 19 of which were of a single behavioral domain, and the remaining 8 scales included multiple behavioral domains. Three rating scales were classified as “recommended” exclusively for screening purposes: the Irritability Scale for irritability, and the Beck Depression Inventory-II and the Hospital Anxiety and Depression Scale for depression. There were no “recommended” scales for other purposes such as diagnosis, severity or change in time or to treatment. The main challenges identified for assessment of behavioral symptoms in Huntington’s disease are the co-occurrence of multiple behavioural symptoms, the particular features of a behavioral symptom in Huntington’s disease, as well as the need to address stage- and disease-specific features, including cognitive impairment and lack of insight. The committee concluded that there is a need to further validate currently available behavioral rating scales in Huntington’s disease to address gaps in scale validation for specific behavioral domains and purpose of use.

Idiopathic rapid eye movement (REM) sleep behavior disorder (RBD) is a harbinger of synuclein-mediated neurodegenerative diseases. It is unknown if this also applies to isolated REM sleep without atonia (RWA). We performed a long-term follow-up investigation of subjects with isolated RWA.Participants were recruited from 50 subjects with isolated RWA who were identified at the sleep laboratory of the Department of Neurology at the Medical University of Innsbruck between 2003 and 2005. Eligible subjects underwent follow-up clinical examination, polysomnography, and assessment of neurodegenerative biomarkers (cognitive impairment, finger speed deficit, impaired color vision, olfactory dysfunction, orthostatic hypotension, and substantia nigra hyperechogenicity).After a mean of 8.6 ± 0.9 y, 1 of 14 participating subjects (7.3%) progressed to RBD. Ten of 14 RWA subjects (71.4%) were positive for at least one neurodegenerative biomarker. Substantia nigra hyperechogenicity and presence of mild cognitive impairment were both present in 4 of 14 subjects with isolated RWA. Electromyographic activity measures increased significantly from baseline to follow-up polysomnography ("any" mentalis and both anterior tibialis muscles: 32.5 ± 9.4 versus 52.2 ± 16.6%; p = 0.004).This study provides first evidence that isolated RWA is an early biomarker of synuclein-mediated neurodegeneration. These results will have to be replicated in larger studies with longer observational periods. If confirmed, these disease findings have implications for defining at-risk cohorts for Parkinson disease.

Introduction The aim of this study was to evaluate the consistency of “probable RBD” diagnosis with the RBD screening questionnaire (RBDSQ) assessed 2 years apart in a population-based study. Methods Probable RBD was assessed by RBDSQ in 2008 and in 2010 in the Bruneck Study Cohort, with participants aged ≥60 years. Results A total of 437 participants completed the RBDSQ in 2008 and 2010. There were 29 (6.6%) and 23 (5.3%) participants with probable RBD in 2008 and in 2010, respectively. Only eight (1.8%) screened positive on both occasions. RBDSQ values 2 years apart showed low correlation with each other (Spearman rank coefficient r = 0.348, P < 0.001) and low agreement (intraclass correlation coefficient 0.388, P < 0.001). Conclusions We found low agreement between the two assessments. Possible explanations are the fluctuation of untreated RBD expression and the poor utility of the RBDSQ to detect RBD in the general population. Until further PSG validation of the RBDSQ in population-based studies, investigators must be aware of the inherent uncertainty of questionnaire-based RBD diagnosis.

Pallidal deep brain stimulation is an established treatment in patients with dystonia. However, evidence from case series or uncontrolled studies suggests that it may lead in some patients to specific parkinsonian symptoms such as freezing of gait, micrographia, and bradykinesia. We investigated parkinsonian signs using the Movement Disorder Society Unified Parkinson's Disease Rating Scale motor score by means of observer-blinded video ratings in a group of 29 patients treated with pallidal stimulation and a non-surgical control group of 22 patients, both with predominant cervical dystonia. Additional assessments included MRI-based models of volume of neural tissue activated to investigate areas of stimulation related to dystonic symptom control and those likely to induce parkinsonian signs as well as an EMG analysis to investigate functional vicinity of stimulation fields to the pyramidal tract. Compared with controls, stimulated patients had significantly higher motor scores (median, 25th-75th percentile: 14.0, 8.0-19.5 versus 3.0, 2.0-8.0; P < 0.0001), as well as bradykinesia (8.0, 6.0-14.0 versus 2.0, 0.0-3.0; P < 0.0001) and axial motor subscores (2.0, 1.0-4.0 versus 0.0, 0.0-1.0; P = 0.0002), while rigidity and tremor subscores were not different between groups. Parkinsonian signs were partially reversible upon switching stimulation off for a median of 90 min in a subset of 19 patients tolerating this condition. Furthermore, the stimulation group reported more features of freezing of gait on a questionnaire basis. Quality of life was better in stimulated patients compared with control patients, but parkinsonian signs were negatively associated with quality of life. In the descriptive imaging analysis maximum efficacy for dystonia improvement projected to the posteroventrolateral internal pallidum with overlapping clusters driving severity of bradykinesia and axial motor symptoms. The severities of parkinsonian signs were not correlated with functional vicinity to the pyramidal tract as assessed by EMG. In conclusion, parkinsonian signs, particularly bradykinesia and axial motor signs, due to pallidal stimulation in dystonic patients are frequent and negatively impact on motor functioning and quality of life. Therefore, patients with pallidal stimulation should be monitored closely for such signs both in clinical routine and future clinical trials. Spread of current outside the internal pallidum is an unlikely explanation for this phenomenon, which seems to be caused by stimulation of neural elements within the stimulation target volume.

The ventral intermediate nucleus (VIM) of the thalamus is an established surgical target for stereotactic ablation and deep brain stimulation (DBS) in the treatment of tremor in Parkinson's disease (PD) and essential tremor (ET). It is centrally placed on a cerebello-thalamo-cortical network connecting the primary motor cortex, to the dentate nucleus of the contralateral cerebellum through the dentato-rubro-thalamic tract (DRT). The VIM is not readily visible on conventional MR imaging, so identifying the surgical target traditionally involved indirect targeting that relies on atlas-defined coordinates. Unfortunately, this approach does not fully account for individual variability and requires surgery to be performed with the patient awake to allow for intraoperative targeting confirmation. The aim of this study is to identify the VIM and the DRT using probabilistic tractography in patients that will undergo thalamic DBS for tremor. Four male patients with tremor dominant PD and five patients (three female) with ET underwent high angular resolution diffusion imaging (HARDI) (128 diffusion directions, 1.5 mm isotropic voxels and b value = 1500) preoperatively. Patients received VIM-DBS using an MR image guided and MR image verified approach with indirect targeting. Postoperatively, using parallel Graphical Processing Unit (GPU) processing, thalamic areas with the highest diffusion connectivity to the primary motor area (M1), supplementary motor area (SMA), primary sensory area (S1) and contralateral dentate nucleus were identified. Additionally, volume of tissue activation (VTA) corresponding to active DBS contacts were modelled. Response to treatment was defined as 40% reduction in the total Fahn-Tolosa-Martin Tremor Rating Score (FTMTRS) with DBS-ON, one year from surgery. Three out of nine patients had a suboptimal, long-term response to treatment. The segmented thalamic areas corresponded well to anatomically known counterparts in the ventrolateral (VL) and ventroposterior (VP) thalamus. The dentate-thalamic area, lay within the M1-thalamic area in a ventral and lateral location. Streamlines corresponding to the DRT connected M1 to the contralateral dentate nucleus via the dentate-thalamic area, clearly crossing the midline in the mesencephalon. Good response was seen when the active contact VTA was in the thalamic area with highest connectivity to the contralateral dentate nucleus. Non-responders had active contact VTAs outside the dentate-thalamic area. We conclude that probabilistic tractography techniques can be used to segment the VL and VP thalamus based on cortical and cerebellar connectivity. The thalamic area, best representing the VIM, is connected to the contralateral dentate cerebellar nucleus. Connectivity based segmentation of the VIM can be achieved in individual patients in a clinically feasible timescale, using HARDI and high performance computing with parallel GPU processing. This same technique can map out the DRT tract with clear mesencephalic crossing., Highlights • The thalamic target for surgery for tremor is not readily visible on conventional MRI. • Probabilistic tractography is used to segment the thalamus based on connectivity. • The best target area is connected to the contralateral dentate cerebellar nucleus. • GPU processing is used to segment the thalamus in a clinically feasible timescale. • This technique can map out the DRT tract with clear mesencephalic crossing.

IntroductionPallidal deep brain stimulation (GPi-DBS) is an effective therapy for isolated dystonia, but 10–20% of patients show improvement below 25–30%. We here investigated causes of insufficient response to GPi-DBS in isolated dystonia in a cross-sectional study.MethodsPatients with isolated dystonia at time of surgery, and

We read with interest the article by Buchman et al.,1 which reported that depressive symptoms, neuroticism, urinary incontinence, sleep complaints, and chronic health conditions were associated with incident parkinsonism (48.2% over 5 years) in the elderly. We previously reported on incidence and risk factors of mild parkinsonian signs, a similar concept to possible parkinsonism,1 in the cohort of the prospective population-based Bruneck Study of 2005.2 We now present an analysis of risk factors for parkinsonism according to the definition used by Buchman et al. in this population. Of 393 participants without parkinsonism at baseline undergoing 5-year follow-up, a markedly lower proportion of 16.0% (95% confidence interval [CI] 12.7%–20.0%) developed incident parkinsonism (excluding participants developing secondary parkinsonism). A logistic regression analysis adjusted for age and sex revealed that, out of single markers for prodromal Parkinson disease as defined per movement disorder society research criteria,3 assessed in the Bruneck study,4 substantia nigra hyperechogenicity on transcranial sonography (odds ratio 1.99; 95% CI 1.10–3.62, p = 0.024), probable REM sleep behavior disorder (6.88; 95% CI 1.10–43.10, p = 0.039), olfactory loss (1.96; 95% CI 1.01–3.81, p = 0.047), urinary dysfunction (5.15; 95% CI 1.65–16.14, p = 0.005), and depression/anxiety (2.85; 95% CI 1.28–6.36, p = 0.011) were significantly associated with incident parkinsonism, thus confirming and expanding the findings of Buchman et al.

Signal abnormalities of the substantia nigra and the olfactory tract detected either by diffusion tensor imaging, including measurements of mean diffusivity, a parameter of brain tissue integrity, and fractional anisotropy, a parameter of neuronal fibre integrity, or transcranial sonography, were recently reported in the early stages of Parkinson's disease. In this study, changes in the nigral and olfactory diffusion tensor signal, as well as nigral echogenicity, were correlated with clinical scales of motor disability, odour function and putaminal dopamine storage capacity measured with 6-[(18)F] fluorolevodopa positron emission tomography in early and advanced stages of Parkinson's disease. Diffusion tensor imaging, transcranial sonography and positron emission tomography were performed on 16 patients with Parkinson's disease (mean disease duration 3.7 ± 3.7 years, Hoehn and Yahr stage 1 to 4) and 14 age-matched healthy control subjects. Odour function was measured by the standardized Sniffin' Sticks Test. Mean putaminal 6-[(18)F] fluorolevodopa influx constant, mean nigral echogenicity, mean diffusivity and fractional anisotropy values of the substantia nigra and the olfactory tract were identified by region of interest analysis. When compared with the healthy control group, the Parkinson's disease group showed significant signal changes in the caudate and putamen by 6-[(18)F] fluorolevodopa positron emission tomography, in the substantia nigra by transcranial sonography, mean diffusivity and fractional anisotropy (P < 0.001, P < 0.01, P < 0.05, respectively) and in the olfactory tract by mean diffusivity (P < 0.05). Regional mean diffusivity values of the substantia nigra and the olfactory tract correlated significantly with putaminal 6-[(18)F] fluorolevodopa uptake (r = -0.52, P < 0.05 and r = -0.71, P < 0.01). Significant correlations were also found between nigral mean diffusivity values and the Unified Parkinson's Disease Rating Scale motor score (r = -0.48, P < 0.01) and between mean putaminal 6-[(18)F] fluorolevodopa uptake and the total odour score (r = 0.58; P < 0.05) as well as the Unified Parkinson's Disease Rating Scale motor score (r = -0.53, P < 0.05). This study reports a significant association between increased mean diffusivity signal and decreased 6-[(18)F] fluorolevodopa uptake, indicating that microstructural degradation of the substantia nigra and the olfactory tract parallels progression of putaminal dopaminergic dysfunction in Parkinson's disease. Since increases in nigral mean diffusivity signal also correlated with motor dysfunction, diffusion tensor imaging may serve as a surrogate marker for disease progression in future studies of putative disease modifying therapies.

The differential diagnosis of Parkinsonian syndromes can be challenging, particularly in early disease stages, when overlapping clinical signs and symptoms may lead to erroneous classification. However, an early differentiation between Parkinson's disease (PD) and other diseases causing Parkinsonism is crucial for prognostic and therapeutic reasons and is essential for clinical research. In a recent study, Busse et al. investigated the diagnostic utility of a set of tests to improve diagnostic differentiation between PD, essential tremor and other Parkinsonian disorders. The authors studied a total of 632 patients divided into a retrospective (n = 517) and a prospective (n = 115) group. Diagnostic anchors were based on clinical criteria. Combining midbrain hyperechogenicity, hyposmia and motor asymmetry increased specificity and positive predictive value for diagnosis of PD up to 98% at the expense of sensitivity, whereas two features provided 91% sensitivity with 77% specificity. The results of this study further support the diagnostic utility of transcranial sonography in diagnosing PD.

Background Microarray technology may offer a new opportunity to gain insight into disease-specific global protein expression profiles. The present study was performed to apply a serum antibody microarray to screen for differentially regulated cytokines in Parkinson's disease (PD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). Results Serum samples were obtained from patients with clinical diagnoses of PD (n = 117), MSA (n = 31) and PSP/CBS (n = 38) and 99 controls. Cytokine profiles of sera from patients and controls were analyzed with a semiquantitative human antibody array for 174 cytokines and the expression of 12 cytokines was found to be significantly altered. In a next step, results from the microarray experiment were individually validated by different immunoassays. Immunoassay validation confirmed a significant increase of median PDGF-BB levels in patients with PSP/CBS, MSA and PD and a decrease of median prolactin levels in PD. However, neither PDGF-BB nor prolactin were specific biomarkers to discriminate PSP/CBS, MSA, PD and controls. Conclusions In our unbiased cytokine array based screening approach and validation by a different immunoassay only two of 174 cytokines were significantly altered between patients and controls.

Contains fulltext : 183583.PDF (Publisher’s version ) (Open Access) BACKGROUND: Although gait disorders are common in the elderly, the prevalence and overall burden of these disorders in the general community is not well defined. METHODS: In a cross-sectional investigation of the population-based Bruneck Study cohort, 488 community-residing elderly aged 60-97 years underwent a thorough neurological assessment including a standardized gait evaluation. Gait disorders were classified according to an accepted scheme and their associations to falls, neuropsychological measures, and quality of life were explored. RESULTS: Overall, 32.2% (95% confidence interval [CI] 28.2%-36.4%) of participants presented with impaired gait. Prevalence increased with age (p

Objective To evaluate whether enlarged substantia nigra hyperechogenicity (SN+) is associated with an increased risk for Parkinson disease (PD) in a healthy elderly population. Design Longitudinal 3-center observational study with 37 months of prospective follow-up. Setting Individuals 50 years or older without evidence of PD or any other neurodegenerative disease. Participants Of 1847 participants who underwent a full medical history, neurological assessment, and transcranial sonography at baseline, 1535 could undergo reassessment. Main Outcome Measure Incidence of new-onset PD in relation to baseline transcranial sonography status. Results There were 11 cases of incident PD during the follow-up period. In participants with SN+ at baseline, the relative risk for incident PD was 17.37 (95% confidence interval, 3.71-81.34) times higher compared with normoechogenic participants. Conclusions In this prospective study, we demonstrate for the first time a highly increased risk for PD in elderly individuals with SN+. Transcranial sonography of the midbrain may therefore be a promising primary screening procedure to define a risk population for imminent PD.