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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.

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 (

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'.

OBJECTIVE We aimed to identify prodromal Parkinson's disease (PD) and its predictive accuracy for incident PD in an unselected elderly population and to estimate the relevance of this approach for future neuroprotection trials. METHODS We applied the recently published Movement Disorders Society (MDS) research criteria for prodromal PD to participants of the prospective population-based Bruneck Study of the 2005 assessment (n = 574, ages 55-94 years). Cases of incident PD were identified at 3-year, 5-year, and 10-year follow-up visits. We calculated predictive accuracies of baseline prodromal PD status for incident cases, and, based on them, estimated sample sizes for neuroprotection trials with conversion to PD as the primary outcome. RESULTS Baseline status of probable prodromal PD (n = 12) had a specificity in predicting incident PD of 98.8% (95% confidence interval, 97.3%-99.5%), a sensitivity of 66.7% (29.6%-90.8%), and a positive predictive value of 40.0% (16.7%-68.8%) over 3 years. Specificity remained stable with increasing follow-up time, sensitivity decreased to 54.6% (28.0%-78.8%) over 5 years and to 35.0% (18.0%-56.8%) over 10 years, whereas positive predictive value rose to 60.0% (31.2%-83.3%) and 77.8% (44.3%-94.7%), respectively. Sample size estimates at 80% power in an intention-to-treat approach ranged from 108 to 540 patients with probable prodromal PD depending on trial duration (3-5 years) and effect size of the agent (30%-50%). CONCLUSIONS Our findings show that the MDS criteria for prodromal PD yield moderate to high predictive power for incident PD in a community-based setting and may thus be helpful to define target populations of future neuroprotection trials. © 2018 International Parkinson and Movement Disorder Society.

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 effective treatment for Parkinson's disease (PD), but can have side effects caused by stimulus spread to structures outside the target volume such as the pyramidal tract. Objectives To assess the relevance of pyramidal tract activation with STN-DBS in PD. Methods In a multimodal, blinded study in 20 STN-DBS patients, we measured stimulation thresholds for evoking electromyographic activity in orbicularis oris and first dorsal interosseous muscles at each of 150 electrode sites. We also modeled the electric field spread and calculated its overlap with the estimated anatomical location of corticospinal and corticobulbar tracts from primary motor cortex using 3 Tesla MRI probabilistic tractography. Results Mean resting motor thresholds were significantly lower for the contralateral orbicularis oris (3.5 ± 1.0 mA) compared with ipsilaterally (4.1 ± 1.1 mA) and with the contralateral first dorsal interosseous (4.0 ± 1.2 mA). The modeled volumes of corticobulbar and corticospinal tract activated correlated inversely with the resting motor threshold of the contralateral orbicularis oris and first dorsal interosseous, respectively. Active motor thresholds were significantly lower compared with resting motor thresholds by around 30% to 35% and correlated with the clinically used stimulation amplitude. Backward multiple regression in 12 individuals with a “lateral-type” speech showed that stimulation amplitude, levodopa equivalent dose reduction postsurgery, preoperative speech intelligibility, and first dorsal interosseous resting motor thresholds explained 79.9% of the variance in postoperative speech intelligibility. Conclusions Direct pyramidal tract activation can occur at stimulation thresholds that are within the range used in clinical routine. This spread of current compromises increase in stimulation strengths and is related to the development of side effects such as speech disturbances with chronic stimulation. © 2017 International Parkinson and Movement Disorder Society

Background Dorsolateral nigral hyperintensity on iron-sensitive magnetic resonance imaging (MRI) sequences seems to be a typical finding in Parkinson's disease (PD), but most studies have involved small samples and have had heterogeneous control populations. Objectives The objective of this study was to perform a meta-analysis on dorsolateral nigral hyperintensity as an imaging marker for PD. Methods The methods included a systematic literature search and a hierarchical summary receiver operating characteristics curve approach. Results Of the 16 identified studies, 10 were suitable for analysis, including 364 PD and 231 control cases. The meta-analysis showed an overall sensitivity and specificity of the absence of dorsolateral nigral hyperintensity for PD versus controls of 97.7% and 94.6% (3 and 7 Tesla) and of 94.6% and 94.4% (3 Tesla only). Descriptive analysis among the 4 studies including patients with non-PD parkinsonism showed that dorsolateral nigral hyperintensity was absent in 89.4% of cases with atypical parkinsonian disorders (n = 74), but only in 21.7% of cases with non-neurodegenerative parkinsonism (n = 69). Moreover, in 2 of these studies, the absence of dorsolateral nigral hyperintensity predicted ipsilateral dopamine-transporter deficiency with 87.5% sensitivity and 83.6% specificity. Conclusions Visual assessment of dorsolateral nigral hyperintensity on iron-sensitive MRI sequences provides excellent diagnostic accuracy for PD versus controls. Moreover, its loss appears to be a marker of nigral pathology and holds the potential for the differentiation of neurodegenerative from non-neurodegenerative parkinsonian disorders. © 2017 International Parkinson and Movement Disorder Society

Objective To determine the diagnostic utility of olfactory testing in patients with neurodegenerative parkinsonism. Methods The Sniffin' Sticks test battery for assessment of odor identification, discrimination, and threshold was applied to patients with Parkinson's disease (PD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) as well as healthy controls (HC). Two different cohorts were analyzed: A PD/healthy control that included PD patients and HC as well as a PD/diseased control cohort for which patients PD, MSA and PSP were recruited. The former cohort was exploited to calculate cut-off values that discriminate PD patients from HC with a sensitivity (sensitivity-weighted cut-off) or specificity (specificity-weighted cut-off) exceeding 95%, respectively. The PD/diseased controls cohort was used to determine the diagnostic accuracy using these cut-off values in discriminating patients with neurodegenerative parkinsonism. Results PD patients (n = 67) performed significantly worse in olfactory testing than HC (n = 41) and patients with MSA (n = 23) or PSP (n = 23). There was no significant difference in olfactory function between MSA and PSP patients. Diagnostic performance of the identification subscore was similar to the sum score of the Sniffin’ Sticks test (AUC identification test 0.94, AUC sum score 0.96), while threshold and discrimination subscores were inferior. In patients with parkinsonism, the specificity-weighted cut-off predicted a diagnosis of PD with a sensitivity and specificity of 76.6 and 87.0%, respectively. The discriminative value of this cut-off in separating PD from MSA was 76.7% (sensitivity) and 95.7% (specificity). The corresponding, prevalence-adjusted positive predictive value of olfactory testing exceeded 95%. Conclusions Our data suggest that assessment of olfactory function, particularly odor identification, can be useful to discriminate PD from atypical parkinsonian disorders, particularly MSA patients.

Introduction Associations of substantia nigra (SN) hyperechogenicity on transcranial sonography, olfactory dysfunction, and mild parkinsonian signs (MPS) with incident Parkinson's disease (PD) have only been studied over limited periods of follow-up and their long-term predictive properties are unclear. We aimed to prospectively assess the risk for incident PD over 10 years in community-dwelling elderly individuals with these risk markers. Methods SN-hyperechogenicity, olfactory function, and MPS were assessed in the prospective population-based Bruneck Study (2005 in-person assessment; n = 574, aged 55–94 years). Cases of incident PD were identified at 5-year and 10-year follow-up visits. We estimated relative risks of baseline markers for incident cases. Results After excluding 35 cases with PD or secondary parkinsonism at baseline, a total of 20 cases of incident PD were identified from the remaining 539 participants (11 at 5 years and 9 at 10 years). Relative risks for incident PD over the 10-year follow-up period were 7.43 (2.71–20.39), 3.60 (1.48–8.78), and 5.52 (2.43–12.57) for baseline SN-hyperechogenicity, hyposmia, and mild parkinsonian signs, respectively. While risk of hyposmia for incident PD was similar for the two sequential 5-year periods studied, relative risks of SN-hyperechogenicity and MPS were higher for the first five years as compared to later. Conclusion Our findings extend the established risk relationship of SN-hyperechogenicity, hyposmia, and MPS with incident PD beyond 5 years of follow-up.

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.

Background Recently, the International Parkinson and Movement Disorder Society has defined research criteria for prodromal Parkinson's disease (PD), but to date their predictive value has not yet been tested in population-based cohorts. Methods We retrospectively applied these criteria to the longitudinal Bruneck Study cohort aged 55-94 years using recorded data on all included risk and prodromal markers that are quick and easily assessable. Results After excluding participants with idiopathic PD or secondary parkinsonism, prevalence of probable prodromal PD in the remaining 539 participants was 2.2% (95% confidence interval, 1.2%-3.9%). Of 488 participants followed up over 5 years, 11 developed incident PD. Sensitivity of “probable prodromal PD” status for incident PD was 54.6% (95% confidence interval, 28.0%-78.8%), specificity was 99.2% (97.8%-99.8%), positive predictive value was 60.0% (31.2%-83.3%), and negative predictive value was 99.0% (97.5%-99.6%). Conclusions Our findings suggest that the new research criteria for prodromal PD are a promising tool to identify cases of incident PD over 5 years, arguing for their usefulness in defining target populations for disease-prevention trials. © 2016 International Parkinson and Movement Disorder Society

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.

Background: Sarcopenia and frailty are found in up to one-third of the general elderly population. Both are associated with major adverse health outcomes such as nursing home placement, disability, decreased quality of life, and death. Data on the frequency of both syndromes in Parkinson’s disease (PD), however, are very limited. Objective: We aimed to screen for sarcopenia and frailty in PD patients and to assess potential associations of both geriatric syndromes with demographic and clinical parameters as well as quality of life. Methods: In this observational, cross-sectional study, we included 104 PD patients from a tertiary center and 330 non-PD controls from a population-based cohort aged > 65 years. All groups were screened for sarcopenia using the SARC-F score and for frailty using the Clinical Frailty Scale of the Canadian Study of Health and Aging (CSHA CFS). Prevalence rates of sarcopenia and frailty were also assessed in 18 PD patients from a population-based cohort aged > 65 years. Moreover, PD patients from the tertiary center were evaluated for motor and non-motor symptoms, quality of life, and dependency. Results: The prevalence of sarcopenia was 55.8% (95% CI: 46.2–64.9%) in PD patients from the tertiary center and 8.2% (5.7–11.7%; p < 0.001) in non-PD controls. Frailty was detected in 35.6% (27.0–45.2%) and 5.2% (3.2–8.1%; p < 0.001). Prevalence rates for sarcopenia and frailty were 33.3% (16.1–56.4%; p = 0.004) and 22.2% (8.5–45.8%; p = 0.017) in the community-based PD sample. Both sarcopenia and frailty were significantly associated with longer disease duration, higher motor impairment, higher Hoehn and Yahr stages, decreased quality of life, higher frequency of falls, a higher non-motor symptom burden, institutionalization, and higher care levels in PD patients from a tertiary center compared to not affected PD patients (all p < 0.05). Conclusions: Both frailty and sarcopenia are more common in PD patients than in the general community and are associated with a more adverse course of the disease. Future studies should look into underlying risk factors for the occurrence of sarcopenia and frailty in PD patients and into adequate management to prevent and mitigate them.

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.

Multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) are relentlessly progressive neurodegenerative diseases leading to severe disability and ultimately death within less than 10 y. Despite increasing efforts in basic and clinical research, effective therapies for these atypical parkinsonian disorders are lacking. Although earlier small clinical studies in MSA and PSP mainly focused on symptomatic treatment, advances in the understanding of the molecular underpinnings of these diseases and in the search for biomarkers have paved the way for the first large and well-designed clinical trials aiming at disease modification. Targets of intervention in these trials have included α-synuclein inclusion pathology in the case of MSA and tau-related mechanisms in PSP. Since 2013, four large randomized, placebo-controlled, double-blind disease-modification trials have been completed and published, using rasagiline (MSA), rifampicin (MSA), tideglusib (PSP), or davunetide (PSP). All of these failed to demonstrate signal efficacy with regard to the primary outcome measures. In addition, two randomized, placebo-controlled, double-blind trials have studied the efficacy of droxidopa in the symptomatic treatment of neurogenic orthostatic hypotension, including patients with MSA, with positive results in one trial. This review summarizes the design and the outcomes of these and other smaller trials published since 2013 and attempts to highlight priority areas of future therapeutic research in MSA and PSP. © 2015 International Parkinson and Movement Disorder Society

Background The prevalence of rapid eye movement sleep behavior disorder (RBD) and its association with markers of neurodegeneration in the general population are poorly defined. Methods We assessed the prevalence of probable RBD defined by two validated questionnaires, the RBD Screening Questionnaire (RBDSQ) and the Innsbruck RBD-Inventory (RBD-I), and studied its associations with clinical and imaging markers for neurodegeneration in the Bruneck Study cohort aged 60 y or older. Results Of the 456 participants without Parkinson's disease, 4.6% (RBDSQ; 95%CI, 3.0%-7.0%) and 7.7% (RBD-I; 95%CI, 5.6%-10.5%) had probable RBD. Probable RBD diagnosed with either of the questionnaires was associated with hyposmia (trend; P < 0.1), anxiety (P < 0.05), depression (P < 0.05), antidepressant use (P < 0.05), and self-reported non-motor symptoms (P < 0.01), specifically, dribbling saliva, memory problems, apathy, concentration problems, and anxiety. Conclusions Our findings may provide a basis for future studies intending to identify cohorts at risk for Lewy body diseases through screening of the general elderly population for RBD. © 2015 International Parkinson and Movement Disorder Society

Objective:To evaluate the presence of prodromal markers of Parkinson disease (PD) in patients with longstanding idiopathic REM sleep behavior disorder (IRBD), a small subgroup of individuals with IRBD with long-term follow-up thought not to be at risk of developing PD.Methods:Demographic, clinical, and neuroimaging markers of PD were evaluated in 20 patients with polysomnographic-confirmed longstanding IRBD and in 32 matched controls.Results:Patients were 16 men and 4 women with mean age of 72.9 ± 8.6 years and mean follow-up from IRBD diagnosis of 12.1 ± 2.6 years. Patients more often had objective smell loss (35% vs 3.4%, p = 0.003), constipation (50% vs 15.6%, p = 0.008), and mild parkinsonian signs (45% vs 18.8%, p = 0.042) than controls. Unified Parkinson's Disease Rating Scale motor score was higher in patients than in controls (5.6 ± 3.5 vs 2.0 ± 2.1, p < 0.0001). Dopamine transporter imaging showed decreased striatal uptake in 82.4% of the patients and transcranial sonography found substantia nigra hyperechogenicity in 35.3%. α-Synuclein aggregates were found in 3 of 6 patients who underwent colon or submandibular gland biopsies. All 20 patients showed clinical, neuroimaging, or histologic markers of PD. Probability of prodromal PD (according to recent Movement Disorders Society research criteria) was higher in patients than in controls (Conclusions:Prodromal PD markers are common in individuals with longstanding IRBD, suggesting that they are affected by an underlying neurodegenerative process. This observation may be useful for the design of disease-modifying trials to prevent PD onset in IRBD.

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

Item does not contain fulltext Differentiating Parkinson's disease (PD) from other types of neurodegenerative atypical parkinsonism (AP) can be challenging, especially in early disease stages. Routine brain magnetic resonance imaging (MRI) can show atrophy or signal changes in several parts of the brain with fairly high specificity for particular forms of AP, but the overall diagnostic value of routine brain MRI is limited. In recent years, various advanced MRI sequences have become available, including diffusion weighted imaging (DWI) and diffusion tensor imaging (DTI). Here, we review available literature on the value of diffusion MRI for identifying and quantifying different patterns of neurodegeneration in PD and AP, in relation to what is known of underlying histopathologic changes and clinical presentation of these diseases. Next, we evaluate the value of diffusion MRI to differentiate between PD and AP and the potential value of serial diffusion MRI to monitor disease progression. We conclude that diffusion MRI may quantify patterns of neurodegeneration which could be of additional value in clinical use. Future prospective clinical cohort studies are warranted to assess the added diagnostic value of diffusion MRI.

Parkinson's disease (PD) is classically defined by its cardinal motor features and current clinical diagnostic criteria require the presence of bradykinesia and at least one additional motor symptom out of tremor, rigidity or postural instability. However, converging evidence from clinical, neuropathological, imaging and genetic research suggests initiation of PD-specific pathology prior to appearance of classical motor signs. This is of particular relevance in relation to the development of disease-modifying or neuroprotective therapies which would require intervention at the earliest stages of disease. A key challenge in PD research, therefore, is to better characterize markers for the 'preclinical' stages of the illness. Development of PD criteria by combining such markers allowing for an early diagnosis and intervention could pave the way for the design and implementation of future disease modification trials.

SUMMARY The diagnosis of Parkinson’s disease (PD) is based on clinical grounds alone and requires the presence of bradykinesia and at least one further motor symptom out of tremor, rigidity or postural instability. Nevertheless, a variety of non-motor symptoms are an integral part of the clinical spectrum of the disease and may even be present before the first appearance of classical motor signs. The ultimate goal of any neuroprotective therapy will be to delay or prevent the onset of clinical disease. The current challenge is, therefore, to identify markers that would allow earlier diagnosis during the premotor stages of PD. The present review discusses potential markers of premotor PD including non-motor symptoms, neuroimaging, genetic susceptibility factors and molecular biomarkers. With the aid of such biomarkers, PD risk cohorts may eventually become sufficiently well defined to allow for ‘neuroprevention’ trials using rates of conversion to motor PD as a primary end point.

Background SN hyperechogenicity (SN+), determined by transcranial sonography, has been proposed as a risk factor for Parkinson's disease (PD). Recently, we reported a 17.4-fold increased risk for PD in individuals with SN+ older than 50 years within 3 years. Methods This is the second follow-up of a prospective, longitudinal, three-center observational study after 5 years. Of the initial 1,847 at baseline PD-free participants 50 years or older, 1,271 underwent the 5-year reassessment. Results Within 5 years, 21 individuals developed incident PD. Participants with SN+ at baseline had a more than 20.6 times increased risk to develop PD in this time span than those without this echo feature. Conclusion We thus confirm our finding of the 3-year follow-up examination in a longer observation time and higher number of individuals with incident PD and suggest SN+ as an important risk marker for PD. © 2012 Movement Disorder Society

Parkinson's disease (PD) is known as a chronic neurodegenerative disorder with a relentlessly progressive course of illness. Although in recent decades there have been many advances in symptomatic therapy, there is still no established therapy that will halt or slow progression in a clinically meaningful way. So far, disease-modification trials have focused on indices of progression of cardinal motor features such as bradykinesia, rigidity and tremor as captured by the Unified Parkinson's Disease Rating Scale, and the emerging need for effective symptomatic dopaminergic therapy. Progression of global disability in PD, however, is driven by additional factors beyond progressive nigrostriatal denervation, leading to increasing severity of cardinal motor features. Progressive pathology in extranigral sites inevitably leads to poorly L-dopa-responsive motor symptoms such as postural instability, freezing and falls, or non-motor symptoms. Furthermore, treatment-induced motor complications also contribute to PD disability. Progression of PD is multidimensional with superimposed age-related co-morbidities. Hence there is no consensus on how to best implement more clinically meaningful end-points for disease progression trials that would reflect these complex interactions impacting on the evolution of global disability in PD. There is an urgent need for biomarkers identifying preclinical stages of illness and describing disease progression--thus faithfully reflecting early and advancing neurodegeneration--that could be used in short-term clinical trials testing putative disease-modifying agents.

Objective: The aim of the present study was to determine the predictive value of olfactory dysfunction for the early development of a synuclein-mediated neurodegenerative disease in subjects with idiopathic REM sleep behavior disorder (iRBD) over an observational period of 5 years. Methods: Thirty-four patients with polysomnography-confirmed iRBD underwent olfactory testing using the entire Sniffin9 Sticks test assessing odor identification, odor discrimination, and olfactory threshold. Patients with iRBD were prospectively followed up over a period of 4.9 ± 0.3 years (mean ± SD). The diagnosis of neurodegenerative diseases was based on current clinical diagnostic criteria. Results: After 2.4 ± 1.7 years (mean ± SD), 9 patients (26.5%) with iRBD developed a Lewy body disease (6 Parkinson disease and 3 dementia with Lewy bodies). The entire Sniffin9 Sticks test and the identification subtest had the same overall diagnostic accuracy of 82.4% (95% confidence interval: 66.1%–92.0%) in predicting conversion. The relative risk for a Lewy body disease in the lowest tertile of olfactory function was 7.3 (95% confidence interval: 1.8–29.6) compared with the top 2 tertiles. Conclusions: Assessment of olfactory function, particularly odor identification, may help to predict the development of a Lewy body disease in patients with iRBD over a relatively short time period and thus to identify patients suitable for future disease modification trials.

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.

Identification of risk factors and prodromal markers for Parkinson's disease (PD) and the understanding of the point in time of first occurrence is essential for the early detection of incident PD. In this three-center longitudinal, observational study, we evaluated the specific risk for PD associated with single or combinations of risk factors and prodromal markers. In addition, we evaluated which risk factors and prodromal markers emerge at which time before the diagnosis of PD. Of the 1,847 at-baseline PD-free individuals ≥ 50 years, 1,260 underwent the 5-year follow-up assessment. There were 21 cases of incident PD during the study period. Enlarged hyperechogenic substantia nigra was the most frequent baseline sign in individuals developing PD after 3 years (80.0 %) and 5 years (85.7 %) compared to healthy controls (17.5 %) followed by the occurrence of mild parkinsonian signs and hyposmia. Evaluation of the signs at the first follow-up assessment showed that individuals developing PD after two additional years showed the same pattern of signs as individuals who developed PD 3 years after baseline assessment.

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.

Background: The clinical diagnosis of Parkinson's disease (PD) is currently anchored in its cardinal motor symptoms. According to hospital-based studies, an enlarged echogenicity in the area of the substantia nigra (SN) assessed with transcranial sonography (TCS) may represent a useful biomarker in the diagnosis of PD. Objective: To evaluate SN hyperechogenicity as a marker for PD in the Bruneck Study cohort, which is representative of the general elderly community. Methods: The diagnostic accuracy of TCS in distinguishing clinically diagnosed PD from nonparkinsonian subjects was assessed in 574 subjects from this cohort. Results: There was a good diagnostic accuracy of TCS in distinguishing PD subjects from nonparkinsonian subjects with an area under the curve value of 0.82. At a receiver-operating characteristic curve analysis-based cutoff value for SN hyperechogenicity of 0.18 cm2, TCS had a sensitivity of 88.2% (95% confidence interval, CI, 64.4-98.0), a specificity of 77.0% (95% CI 72.8-80.6), a positive predictive value of 12.7% (95% CI 7.8-20.0) and a negative predictive value of 99.4% (95% CI 97.8-100.0) for subjects with clinically definite PD at baseline. When analyzing the same population after 5 years with regard to the presence of known and newly diagnosed PD cases, baseline TCS yielded very similar diagnostic accuracy values. Conclusion: SN hyperechogenicity may represent a useful biomarker for PD not only in a hospital-based setting but also in the general community.

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.

Using magnetic resonance (MR) planimetry, both the midbrain-to-pontine area ratio (m/p-ratio) and the MR parkinsonism index (MRPI) have been shown to assist in the differential diagnosis of progressive supranuclear palsy (PSP) from Parkinson's disease (PD) and the Parkinson variant of multiple system atrophy (MSA-P). The aim of this study was to determine the diagnostic accuracy of the MRPI compared with the m/p-ratio in a large cohort of 123 patients with neurodegenerative parkinsonism including patients with PSP, PD, and MSA-P. Patients with PSP had significant higher MRPI values and significant smaller m/p-ratios compared with the other groups with overlapping individual values. Overall predictive accuracy was similar for the m/p-ratio (87.0%) and the MRPI (80.5%) with a predictive accuracy for PSP from MSA-P being significantly better for the MRPI (87.5%) compared with the m/p-ratio (75%) as well as a predictive accuracy for PSP from PD being significantly better for the m/p-ratio (87.6%) compared with the MRPI (77.3%). Both the m/p-ratio and the MRPI may assist the clinical differential diagnosis in neurodegenerative parkinsonism. © 2010 Movement Disorder Society

The differential diagnosis of parkinsonian syndromes is considered one of the most challenging in neurology, even for movement disorder specialists. Despite published consensus operational criteria for the diagnosis of Parkinson’s disease (PD) and the various atypical parkinsonian disorders (APDs) such as progressive supranuclear palsy, multiple system atrophy, and corticobasal syndrome, the clinical separation of APDs from PD carries a high rate of misdiagnosis. However, an early differentiation between APD and PD, each characterized by a largely different natural history, is crucial for determining the prognosis and choosing a treatment strategy. Despite limitations, the different modern magnetic resonance (MR) techniques have undoubtedly added to the differential diagnosis of neurodegenerative parkinsonism. Conventional MRI with visual assessment of T2- and T1-weighted imaging as well as various advanced MRI techniques offer objective measures and may therefore be useful tools in the diagnostic workup of PD and APDs. In clinical practice, conventional MRI is a well-established method for the exclusion of symptomatic parkinsonism due to other pathologies such as tumors, cerebral ischemia or inflammatory diseases. Furthermore, over the past two decades, advances in MR techniques have enabled to quantitatively illustrate abnormalities in the basal ganglia and infratentorial structures in APDs by methods such as magnetic resonance volumetry, diffusion-weighted imaging, magnetization transfer imaging and proton magnetic resonance spectroscopy. This article aims to review research findings on the value of MRI techniques in the differential diagnosis of neurodegenerative parkinsonian disorders.

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.