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Falls in patients with neurodegenerative diseases (NDDs) have enormous detrimental consequences. A better understanding of the interplay between physical activity (PA) and fall risk might help to reduce fall frequency. We aimed to investigate the association between sensor-based PA and fall risk in NDDs, using 'falls per individual PA exposure time' as a novel measure. Eighty-eight subjects (n = 31 degenerative ataxia (DA), n = 14 Parkinson's disease (PD), n = 12 progressive supranuclear palsy (PSP) and 31 healthy controls) were included in this pilot study. PA was recorded in free-living environments with three-axial accelerometers (activPAL™) over 7 days. Falls were prospectively assessed over 12 months. Fall incidence was calculated by (i) absolute number of falls per person years (py) and (ii) falls per exposure to individual PA. Absolute fall incidence was high in all three NDDs, with differing levels (DA, 9 falls/py; PD, 14 falls/py; PSP, 29 falls/py). Providing a more fine-grained view on fall risk, correction for individual exposure to PA revealed that measures of low walking PA were associated with higher fall incidence in all three NDDs. Additionally, higher fall incidence was associated with more sit-to-stand transfers in PD and longer walking bouts in PSP. Our results suggest that low walking PA is a risk factor for falls in DA, PD and PSP, indicating the potential benefit of increasing individual PA in these NDDs to reduce fall risk. Moreover, they show that correction for individual exposure to PA yields a more differentiated view on fall risk within and across NDDs.

Background A proportion of idiopathic Parkinson's disease patients (PDidiopathic) with dementia show altered CSF profiles of amyloid β (Aβ) and Tau. PD patients with Glucocerebrosidase (GBA) mutations (PDGBA) present with even more cognitive decline than seen in PDidiopathic. Objective The objective of this study was to evaluate whether CSF profiles of Aβ and tau are associated with the prominent cognitive impairment in PDGBA. Methods CSF levels of Aβ1-42, t-Tau, p-Tau, and total alpha-synuclein were assessed in 479 participants (50 PDGBA, 308 PDidiopathic, 121 healthy controls). Results Older age was associated with cognitive impairment in PDGBA and PDidiopathic. Despite prominent cognitive impairment, PDGBA showed similar CSF levels of Aβ1-42, t-Tau, and p-Tau as seen in healthy controls. In contrast, lower levels of Aβ1-42 and higher levels of t-Tau and p-Tau were associated with worse cognitive performance in PDidiopathic. Conclusions The prominent cognitive impairment in PDGBA seems not primarily associated with Aβ and Tau profiles in CSF. © 2017 International Parkinson and Movement Disorder Society

We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor.

BACKGROUND Prevalence and time of occurrence of prodromal symptoms of Parkinson's disease (PD) in relation to the onset of classical motor manifestation varies between patients. Possible modifying factors might be different genetic architectures predisposing to varying burden of manifestations. OBJECTIVES To characterize the prodromal phase in PD patients with heterozygous mutations in the GBA gene compared to PD patients without GBA mutation. METHODS In a retrospective design, 151 participants [47 PD patients carrying a GBA mutation (PDGBA ), 52 idiopathic PD patients (PDidiopathic ), 52 healthy elderly (CON)] underwent a validated structured interview designed to assess prevalence and time of occurrence of prodromal symptoms. RESULTS PDGBA showed a higher prevalence of prodromal symptoms and almost simultaneous occurrence of non-motor and early motor symptoms shortly before PD diagnosis whereas PDidiopathic reported a longer prodromal phase starting with non-motor symptoms. CONCLUSION The short and severe prodromal phase in PDGBA might call for shorter assessment intervals in yet premanifest GBA mutation carriers.

Background and Purpose: Reduced ambulatory activity is a major burden in neurodegenerative disease (NDD), leading to severe restrictions in social participation and further deterioration of motor capacities. However, objective evidence on walking behavior patterns and components underlying this impairment and its decline with disease progression is scarce for many NDDs. We aimed to unravel the detailed metrics underlying the reduced ambulatory activity in selected NDDs, and their relation to disease duration. We hypothesized that progressively reduced ambulatory activity is a feature shared across different NDDs, characterized by changes in both common and distinct components. Methods: Sixty-five subjects with NDD (n = 34 degenerative ataxia; n = 15 progressive supranuclear palsy, and n = 16 Parkinson's disease) and 38 healthy older adults (total n = 103) wore a three-axial accelerometer (activPAL3™) for 7 consecutive days. Detailed metrics of ambulatory activity were calculated. Results: The average daily walking duration was significantly decreased in all three NDDs, yet characterized by a differential pattern of changes in number and length of walking bouts and sit-to-stand transfers. Decline in walking duration progressed with increased disease duration in all three NDDs, yet at a differing rate. This decline was associated with progressive reductions in walking bout length and walking behavior pattern diversity in all three NDDs. Conclusions: These findings provide objective evidence that reduced ambulatory activity is a shared feature across different NDDs. Moreover, they reveal that several underlying walking behavior components change with increasing disease duration, yet at a differing rate in different NDDs. This indicates that metric analysis of ambulatory activity might provide ecologically relevant and disease-specific progression and outcome markers in several NDDs.

Background: Parkinson’s disease (PD) patients with GBA mutations show an earlier age at onset and more severe non-motor symptoms compared with PD patients without GBA mutations. Objective: This study was undertaken to evaluate progression of motor and non-motor symptoms in sporadic PD patients depending on the mutational GBA status. Methods: We used regression analysis to evaluate independent effects of the mutational GBA status, age at onset, age at examination, and disease duration on motor (Unified Parkinson’s Disease Rating Scale [UPDRS]-III, Hoehn and Yahr [H&Y] stage, Levodopa [L-dopa]-equivalent-dosage) and non-motor characteristics (cognition and mood). Disease progression was assessed prospectively over 3 years. Results: The GBA-associated PD patients compared with non-mutation PD patients, although younger and with an earlier age at onset, show (1) a more rapid disease progression of motor impairment and cognitive decline and (2) reduced survival rates. Conclusions: The mutational GBA status, rather than older age and age at onset, presents an important predictor for disease progression in this specific subgroup of PD patients. V C 2014 International Parkinson and

There is a rapidly growing interest in the quantitative assessment of Parkinson's disease (PD)-associated signs and disability using wearable technology. Both persons with PD and their clinicians see advantages in such developments. Specifically, quantitative assessments using wearable technology may allow for continuous, unobtrusive, objective, and ecologically valid data collection. Also, this approach may improve patient-doctor interaction, influence therapeutic decisions, and ultimately ameliorate patients' global health status. In addition, such measures have the potential to be used as outcome parameters in clinical trials, allowing for frequent assessments; eg, in the home setting. This review discusses promising wearable technology, addresses which parameters should be prioritized in such assessment strategies, and reports about studies that have already investigated daily life issues in PD using this new technology.

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

Objective: To elucidate possible mechanisms leading to neurodegeneration in patients with glucocerebrosidase ( GBA )–associated Parkinson disease (PD) using combined proton ( 1 H) and phosphorus ( 31 P) magnetic resonance spectroscopic imaging (MRSI) in vivo. Methods: 1 H and 1 H-decoupled 31 P MRSI was performed in 13 patients with PD with heterozygous GBA mutations (GBA-PD) and 19 age- and sex-matched healthy controls to investigate metabolite concentrations in the mesostriatal target regions of PD pathology. NAA as marker of neuronal integrity, choline and ethanolamine containing compounds as markers of membrane phospholipid metabolism, and energy metabolites (notably high-energy phosphates) were quantified. Results: Compared to controls, NAA was significantly reduced in the putamen ( p = 0.012) and in the midbrain of GBA-PD ( p = 0.05). The choline concentration obtained from 1 H MRSI was significantly decreased in the midbrain of GBA-PD ( p = 0.010). The phospholipid degradation product glycerophosphoethalonamine was increased in the putamen of GBA-PD ( p = 0.05). Changes of energy metabolism were not detected in any region of interest. Conclusion: The pattern of neurodegeneration in GBA -associated PD is more pronounced in the putamen than in the midbrain. Our MRSI findings suggest that the neurodegenerative process in GBA-PD is associated with alterations of membrane phospholipid metabolism which might be also involved in abnormal α-synuclein aggregation.

Background: Heterozygous mutations in the glucocer-ebrosidase gene lead to an increased risk for and tomore severe alpha-synuclein-associated pathology inParkinson’s disease. As both glucocerebrosidase andalpha-synuclein interact with fatty acids, we hypothe-sized that cerebrospinal fluid fatty acid levelsare altered in these Parkinson’s disease patients.Methods: Cerebrospinal fluid levels of 13 fatty acids in8 Parkinson’s disease patients with a heterozygousglucocerebrosidase mutation were compared withthose of 41 idiopathic Parkinson’s disease patients and ------------------------------------------------------------ Additional Supporting Information may be found in the online version ofthis article.Stefan P. Schmid and Erwin D. Schleicher contributed equally to thisarticle.*Correspondence to: Walter Maetzler, Department ofNeurodegeneration, University of Tuebingen, Germany, OtfriedMu¨ller-Strasse 27, 72076 Tuebingen, Germany; walter.maetzler@uni-tuebingen.deRelevant conflicts of interest/financial disclosures: Stefan Schmid issupported by a German National Genome Network Grant (NGFNplus01GS08134). Walter Maetzler is supported by a ForschungskollegGeriatrie Grant from the Robert Bosch Foundation, Stuttgart, Germany(Nr. 32.5.1141.0019.0).Full financial disclosures and author roles may be found in the onlineversion of this article.Received: 7 April 2011; Revised: 15 August 2011; Accepted: 25August 2011Published online 21 October 2011 in Wiley Online Library(wileyonlinelibrary.com). DOI: 10.1002/mds.23984SCHMID ET AL.

Objective: To evaluate whether there exists distinct characteristics in glucocerebrosidase ( GBA )–associated Parkinson disease (PD) with regard to motor and nonmotor symptoms as well as imaging characteristics assessed by transcranial sonography (TCS). Methods: Twenty patients with PD with heterozygous GBA mutations (N370S, L444P) (GBA-PD) in comparison to 20 patients with sporadic PD negative for GBA mutations (sPD) were included. We assessed motor impairment with the Unified Parkinson’s Disease Rating Scale–III. Nonmotor symptoms were evaluated using the Montreal Cognitive Assessment, Neuropsychiatric Inventory, revised form of the Beck Depression Inventory, Parkinson Disease Sleep Scale, Sniffin’ Sticks, and Unified Multiple System Atrophy Rating Scale items 9–12. TCS imaging was used to detect morphologic characteristics. Results: Patients with GBA-PD more often had a variety of nonmotor symptoms, namely dementia, neuropsychiatric disturbances, and autonomic dysfunction, and had more severe cases, than patients with sPD. They also demonstrated a higher prevalence of a reduced echogenicity of the brainstem raphe assessed by TCS. Conclusions: Especially nonmotor symptoms seem to be very common in GBA-PD. Further studies are needed to validate these observations in order to better understand the pathogenesis of GBA-PD and develop specific therapeutic concepts.

Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common being Alzheimer’s disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 PSP cases and 3,247 controls (Stage 1) followed up by a second stage where 1,051 cases and 3,560 controls were genotyped for Stage 1 SNPs that yielded P ≤ 10−3. We found significant novel signals (P < 5 × 10−8) associated with PSP risk at STX6, EIF2AK3, and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response, and for a myelin structural component., T.G. serves as an editorial board member of Movement Disorders and Parkinsonism and Related Disorders and is funded by Novartis Pharma, the Federal Ministry of Education and Research (BMBF) (NGFN-Plus and ERA-Net NEURON), the Helmholtz Association (HelMA, Helmholtz Alliance for Health in an Ageing Society) and the European Community (MeFoPa, Medndelian Forms of Parkinsonism). T.G. received speakers honoraria from Novartis, Merck-Serono, Schwarz Pharma, Boehringer Ingelheim and Valeant Pharma and royalties for his consulting activities from Cefalon Pharma and Merck-Serono. T.G. holds a patent concerning the LRRK2 gene and neurodegenerative disorders. J.H. is consulting for Merck Serono and Eisai. I.Litvan is the founder of the Litvan Neurological Research Foundation, whose mission is to increase awareness, determine the cause/s and search for a cure for neurodegenerative disorders presenting with either parkinsonian or dementia symptoms (501c3).

Background and purpose To date the role of GBA mutations beyond α-synucleinopathies in the parkinsonism−dementia spectrum is still unclear. The aim of the study was to screen for GBA mutations in progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), primary progressive aphasia (PPA) and the behavioural variant of frontotemporal dementia (bvFTD). Methods In all, 303 patients with a clinical diagnosis of PSP (n = 157), CBS (n = 39), PPA (n = 35) and bvFTD (n = 72) and 587 neurologically healthy controls were screened for the most common GBA mutations. Results GBA mutations were detected in one healthy control and four patients with a clinical diagnosis of PSP (n = 1), probable CBS (n = 2) and PPA (n = 1, with concomitant C9orf72 expansion). Overall the prevalence of GBA mutations was low in non-α-synucleinopathies but significantly higher in the CBS subgroup compared to controls. Conclusion Although numbers are small, our findings indicate that the clinical phenotype of GBA-associated neurodegenerative disease is more heterogeneous than previously assumed, including phenotypes not usually associated with underlying α-synucleinopathies. This may be of relevance, once causal therapeutic strategies for GBA-associated neurodegenerative disease are developed.

There is evidence that nigrostriatal pathology may at least partly underlie mild Parkinsonian signs. We evaluated whether an increase in the Unified Parkinson's Disease Rating Scale part III (UPDRS-III) could be predicted by the presence of risk and prodromal markers for neurodegenerative diseases in elderly individuals without those diseases. Therefore, we analyzed the UPDRS-III score and various risk and prodromal markers known to antecede neurodegenerative diseases in a population-based cohort comprising 807 individuals free of neurodegenerative diseases at baseline. After 5 years, eight persons (1.0 %) were diagnosed with Parkinson's Disease (PD). Of those, seven (87.5 %) had motor worsening ≥3 points on the UPDRS-III from baseline to follow-up, one had two points increase. Of the 788 people without PD, 568 (72.1 %) showed no increase in the UPDRS-III scale, 220 (27.9 %) had ≥1 point increase and out of these 104 (13.2 %) had an increase of ≥3 points in the UPDRS-III score after 5 years. We identified an age >60 years (relative risk, RR = 1.7; confidence interval, CI 1.3-2.1) and the occurrence of ≥2 risk factors (RR = 1.5; CI 1.2-1.9) as possible predictors of motor progression. After 5 years, individuals with an increase in the UPDRS-III score had more often a one-sided reduced arm swing (p < 0.001) and identified less odors in the Sniffin' sticks test (p < 0.041) than persons with stable motor performance. Our data support the assumption that progression of Parkinsonian signs assessed by the UPDRS-III parallels the development of prodromal markers for neurodegenerative diseases in the elderly population.

With a prevalence of about 5/100.000, progressive supranuclear palsy is one of the most frequent tauopathies. Clinically, PSP is characterized by early occurrence of severe postural instability and consecutive falls, supranuclear gaze palsy, axial rigidity, dysphagia, and levodopa unresponsiveness. Approximately half of patients develop cognitive symptoms, mostly executive dysfunction and neurobehavioral signs like apathy and disinhibition. These symptoms are associated with degeneration of cholinergic circuits. Cognitive changes are more severe than in Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy, and corticobasal degeneration. Neuropsychological tests and imaging methods can be helpful diagnostic tools. Cholinesterase inhibitors and even levodopa can improve cognitive symptoms. New disease-modifying therapies targeting dysfunctional tau or mitochondrial dysfunction are promising.

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.

In a previous study, retinal nerve fiber layer thickness (RNFLT) loss was shown as part of the neurodegenerative process in multiple system atrophy (MSA). Here, we investigate in a larger cohort of MSA patients whether the RNFLT loss translates into respective visual field defects. Spectral domain optical coherence tomography was performed in 20 MSA patients (parkinsonian subtype = 12, cerebellar subtype = 8) to quantify peripapillary RNFLT. Visual field (90°) was analyzed by automated static perimetry to investigate retinal structure/function relationship. Eight data sets did not meet stringent quality criteria, and only 12 data sets were further analyzed. Compared to healthy controls, MSA patients demonstrated a significant reduction of RNFLT in the nasal sectors (p nasal-superior = 0.02, p nasal = 0.03, p nasal-inferior

Progressive supranuclear palsy (PSP) is the most common atypical parkinsonian syndrome comprising two main clinical subtypes: Richardson's syndrome (RS), characterized by prominent postural instability, supranuclear vertical gaze palsy and frontal dysfunction ; and PSP-parkinsonism (PSP-P) which is characterized by an asymmetric onset, tremor and moderate initial therapeutic response to levodopa. The early clinical features of PSP-P are often difficult to discern from idiopathic Parkinson's disease (PD), and other atypical parkinsonian disorders, including multiple system atrophy (MSA) and corticobasal syndrome (CBS). In addition, rare PSP subtypes may be overlooked or misdiagnosed if there are atypical features present. The differentiation between atypical parkinsonian disorders and PD is important because the prognoses are different, and there are different responses to therapy. Structural and functional imaging, although currently of limited diagnostic value for individual use in early disease, may contribute valuable information in the differential diagnosis of PSP. A growing body of evidence shows the importance of CSF biomarkers in distinguishing between atypical parkinsonian disorders particularly early in their course when disease-modifying therapies are becoming available. However, specific diagnostic CSF biomarkers have yet to be identified. In the absence of reliable disease-specific markers, we provide an update of the recent literature on the assessment of clinical symptoms, pathology, neuroimaging and biofluid markers that might help to distinguish between these overlapping conditions early in the course of the disease.

Parkinson’s disease is characterized by a substantial cognitive heterogeneity, which is apparent in different profiles and levels of severity. To date, a distinct clinical profile for patients with a potential risk of developing dementia still has to be identified. We introduce a data-driven approach to detect different cognitive profiles and stages. Comprehensive neuropsychological data sets from a cohort of 121 Parkinson’s disease patients with and without dementia were explored by a factor analysis to characterize different cognitive domains. Based on the factor scores that represent individual performance in each domain, hierarchical cluster analyses determined whether subgroups of Parkinson’s disease patients show varying cognitive profiles. A six-factor solution accounting for 65.2% of total variance fitted best to our data and revealed high internal consistencies (Cronbach’s alpha coefficients>0.6). The cluster analyses suggested two independent patient clusters with different cognitive profiles. They differed only in severity of cognitive impairment and self-reported limitation of activities of daily living function but not in motor performance, disease duration, or dopaminergic medication. Based on a data-driven approach, divers cognitive profiles were identified, which separated early and more advanced stages of cognitive impairment in Parkinson’s disease without dementia. Importantly, these profiles were independent of motor progression.

Mutations in the mitochondrial DNA polymerase gamma (POLG) cause a highly pleomorphic disease spectrum, and reports about their frequencies in ataxia populations yield equivocal results. This leads to uncertainties about the role of POLG genetics in the workup of patients with unexplained ataxia. A comprehensive characterization of POLG-associated ataxia (POLG-A) will help guide genetic diagnostics and advance our understanding of the disease processes underlying POLG-A. Thirteen patients with POLG-A were assessed by standardized clinical investigation, nerve conduction studies, motor-evoked potentials, magnetic resonance imaging (MRI) and transcranial sonography (TCS). The findings were compared with 13 matched patients with Friedreich's ataxia (FA). In addition to the well-known POLG-associated features of chronic external ophthalmoplegia (100 %), areflexia to the lower extremity (100 %), impaired vibration sense (100 %), bilateral ptosis (69 %) and epilepsy (38 %), also hyperkinetic movement disorders were frequent in POLG-A patients, including chorea (31 %), dystonia (31 %) and myoclonus (23 %). Similar to FA, polyneuropathy was of sensory axonal type (100 %). In contrast to FA, none of the POLG-A patients showed impaired central motor conduction. TCS demonstrated less enlargement of the fourth ventricle and more diffuse cerebellar hyperechogenicity in POLG-A. Corresponding to TCS, MRI revealed no or only mild cerebellar atrophy in most POLG-A patients (85 %). POLG ataxia presents with the clinical characteristics of both afferent and cerebellar ataxia. Cerebellar alterations diffusely involve various parts of the cerebellum, yet cerebellar atrophy is generally mild. POLG-A presents with a high load of distinct non-ataxia features, namely, sensory neuropathy, external ophthalmoplegia, ptosis, epilepsy and/or hyperkinetic movement disorders. Involvement of the corticospinal tract, however, is rare.

Background We hypothesized that postural instability and cognitive decline in patients with Richardson’s syndrome could be a consequence of reduced thalamic and frontal metabolism. Severe Parkinsonian signs in patients with progressive supranuclear palsy-parkinsonism may be reflected by alterations in putaminal metabolism. Methods Eleven patients with Richardson’s syndrome, 8 patients with progressive supranuclear palsy-parkinsonism, 12 with Parkinson’s disease, and 10 controls underwent clinical assessment and fluorodeoxyglucose positron emission tomography (PET). Results Richardson’s syndrome patients showed pronounced thalamic hypometabolism, and patients with progressive supranuclear palsy-parkinsonism pronounced putaminal hypometabolism, compared to all other investigated groups. The putamen/thalamus uptake ratio differentiated progressive supranuclear palsy-parkinsonism from Richardson’s syndrome (area under the curve 5 0.86) and from Parkinson’s disease (area under the curve 5 0.80) with acceptable accuracy. Frontal hypometabolism was predominantly found in Richardson’s syndrome patients. Conclusions Richardson’s syndrome, progressive supranuclear palsy-parkinsonism and Parkinson’s disease showed different metabolic patterns in fluorodeoxyglucose PET.

Dear Sirs,Heterozygous mutations in the gene encoding the lyso-somal enzyme beta-glucocerebrosidase (GBA) are associ-ated with an increased susceptibility to Parkinson’s disease(PD) and dementia with Lewy body disease [1, 2] and somecases with phenotypes similar to multiple system atrophywere reported [3]. GBA mutation carriers generally presentwith an earlier age at onset and particularly severe motor[2, 5] and non-motor [6] genotype-phenotype relationsprobably reflecting the more pronounced neocortical Lewybody-type pathology in GBA-associated PD [4]. Therefore,these were predicted to show an unfavorable therapeuticoutcome from Deep-brain stimulation of the subthalamicnucleus (STN-DBS). Here, we provide the first quantitativedata on the therapeutic outcomes of GBA-associated PD inresponse to

The retina can be regarded as a ‘‘window to the central nervous system’’ that might provide new insights into the multisystemic character of neurodegenerative diseases. 1 Retinal nerve fibers (RNFs) can in particular be studied with optical coherence tomography (OCT), which allows fast, noninvasive imaging of retinal tissue with resolution reaching that of low-power histological sections. 2 Latest generation OCT devices are able to substantially reduce test–retest variability by real time eye tracking and to automatically segment and quantify the RNF layer, providing immediate data on the distribution and structural integrity of RNF tissue. We investigated whether multiple system atrophy (MSA) is associated with decreased RNF layer thickness (RNFLT) and if so, whether such an effect correlates with indices of disease severity or disease duration.

Essential tremor (ET) and Parkinson's disease (PD) are the most common movement disorders and show clinical, genetic, and pathophysiological overlap. Single-nucleotide polymorphisms (SNPs) in the leucine-rich repeat (LRR) and immunoglobulin (Ig) domain-containing, Nogo receptor-interacting protein gene (LINGO1) are associated with ET. LINGO1 is overexpressed in the substantia nigra (SN) of PD patients and inhibition of LINGO1 confers neuroprotection in a rodent model of PD. In this study we test the hypothesis whether SNPs in the LINGO1 gene that are associated with ET are also associated with PD. Three large German case–control samples from Kiel, Lubeck, and Tubingen (total: 1,798 cases and 1,482 controls) were genotyped for the three LINGO1 SNPs associated with ET. Association was assessed using allele- and genotype-based tests in each of the three samples separately, in the combined sample, and in subsets of patients with early-onset PD (

We reviewed eight studies on transcranial sonography (TCS) as a tool for differentiating idiopathic Parkinson's disease (IPD) from atypical parkinsonian syndromes (APS) and included some first data on TCS findings in the subforms of PSP. Changes of specific structures on TCS like the substantia nigra (SIN), lenticular nucleus (LN), and the third ventricle are discussed as well as how they can contribute to differentiate between IPD, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), Lewy body disease (LBD), and corticobasal degeneration (CBD). We finish with an algorithm that may be used to employ TCS as a diagnostic instrument delineating IPD from the APS and discerning among the APS themselves. As TCS is at present the most promising tool for this particular diagnostic problem, this algorithm might be a suitable hypothesis to study in future research.

Essential tremor (ET) and Parkinson disease (PD) are clearly distinct disorders. However, there is considerable clinical and pathophysiological overlap.1 ET patients are at an approximately fourfold risk to develop PD compared to population controls. Both, ET and PD, have a genetic component. For PD numerous monogenic forms are known and genome-wide-association-studies (GWAS) in sporadic patients have uncovered a number of disease associated genetic variants. For ET only two GWAS studies have been performed up to date.2, 3 In one of them we discovered an association between variants in the major glutamate reuptake transporter of the brain (EAAT2 encoded by the SLC1A gene) and ET.3 The strongest association was found for the intronic single nucleotide polymorphism (SNP) rs3794087. To investigate whether SNPs in or around the SLC1A2 gene are also associated with PD we undertook a two-part study. The study was approved by the local ethics committees and written informed consent was obtained from all participants. Firstly, we investigated the association between our ET lead SNP rs3794087 and PD in three previously described large German PD case/control samples (1798 PD patients, 1482 controls, a detailed description of the samples can be found in reference 4). Genotyping was performed using a TaqMan® assay. Association was assessed using PLINK.5 We calculated Hardy-Weinberg equilibrium (HWE, p-exclusion 95% and the SNP was in HWE. No significant p-values were obtained for rs3794087, neither in the complete sample (p=0.775), nor in the subsamples from Kiel (p=0.623), Lubeck (p=0.998) or Tubingen (p=0.766)(Table 1). Secondly, we analysed all 45 SNPs in the region of the SLC1A gene typed in the first stage sample of a large GWAS performed for PD (1713 PD patients, 3978 controls, a detailed description of the samples can be found in reference 6). All SNPs were in HWE. Two SNPs (rs12294045, p=0.034; rs3847618, p=0.035) yielded nominally significant p-values. Both p-values do not withstand Bonferroni correction for multiple testing (Bonferroni corrected alpha-level p

Phosphorylated α-synuclein (PS-129), a protein implicated in the pathogenesis of Parkinson's disease (PD), was identified by mass spectrometry in human cerebrospinal fluid (CSF). A highly sensitive and specific assay was established and used to measure PS-129 together with total α-synuclein in the CSF of patients with PD, other parkinsonian disorders such as multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), and healthy individuals (a total of ~600 samples). PS-129 CSF concentrations correlated weakly with PD severity and, when combined with total α-synuclein concentrations in CSF, contributed to distinguishing PD from MSA and PSP. Further rigorous validation in independent cohorts of patients, especially those where samples have been collected longitudinally, will determine whether the concentration of PS-129 in CSF will be useful for diagnosing PD and for monitoring PD severity and progression.

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.