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1.  The FARSEEING real-world fall repository: a large-scale collaborative database to collect and share sensor signals from real-world falls 
Background
Real-world fall events objectively measured by body-worn sensors can improve the understanding of fall events in older people. However, these events are rare and hence challenging to capture. Therefore, the FARSEEING (FAll Repository for the design of Smart and sElf-adaptive Environments prolonging Independent livinG) consortium and associated partners started to build up a meta-database of real-world falls.
Results
Between January 2012 and December 2015 more than 300 real-world fall events have been recorded. This is currently the largest collection of real-world fall data recorded with inertial sensors. A signal processing and fall verification procedure has been developed and applied to the data. Since the end of 2015, 208 verified real-world fall events are available for analyses. The fall events have been recorded within several studies, with different methods, and in different populations. All sensor signals include at least accelerometer measurements and 58 % additionally include gyroscope and magnetometer measurements. The collection of data is ongoing and open to further partners contributing with fall signals. The FARSEEING consortium also aims to share the collected real-world falls data with other researchers on request.
Conclusions
The FARSEEING meta-database will help to improve the understanding of falls and enable new approaches in fall risk assessment, fall prevention, and fall detection in both aging and disease.
Electronic supplementary material
The online version of this article (doi:10.1186/s11556-016-0168-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s11556-016-0168-9
PMCID: PMC5086409  PMID: 27807468
Falls; Database; Older adults; Body-worn sensors; Accelerometer
2.  Prospective longitudinal course of cognition in older subjects with mild parkinsonian signs 
Background
Mild parkinsonian signs (MPS) are common in older people and are associated with an increased risk of different neurodegenerative diseases. This study prospectively evaluates the longitudinal course of cognitive performance in older individuals with MPS.
Methods
From the TREND study, 480 individuals neurologically healthy at baseline, aged between 50 and 80 years, with complete follow-up data for three assessments within a mean of 43.8 months, were included in this analysis. Participants underwent a detailed cognitive test battery, evaluation of prodromal markers for neurodegenerative diseases and history of vascular diseases at each study visit. In addition, plasma levels of amyloid-beta (Aβ)1–40 and Aβ1–42 were evaluated longitudinally.
Results
In 52 (11 %) of the 480 participants, MPS could be detected at baseline. These individuals had cognitive deficits significantly more often compared with controls at each time point and their cognitive performance showed a steeper decline during follow-up. In addition, their levels of plasma Aβ1–42 were significantly lower than those of controls, and declined more rapidly over time.
Conclusions
This longitudinal study shows that MPS are associated with cognitive decline and decrease in plasma Aβ1–42, possibly indicating an ongoing neurodegenerative process.
Electronic supplementary material
The online version of this article (doi:10.1186/s13195-016-0209-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s13195-016-0209-7
PMCID: PMC5057460  PMID: 27724983
Amyloid-beta; Dementia; Prospective; Longitudinal; Cohort study
4.  In-vivo evidence that high mobility group box 1 exerts deleterious effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model and Parkinson's disease which can be attenuated by glycyrrhizin 
Neurobiology of Disease  2016;91:59-68.
High-mobility group box 1 (HMGB1) is a nuclear and cytosolic protein that is released during tissue damage from immune and non-immune cells — including microglia and neurons. HMGB1 can contribute to progression of numerous chronic inflammatory and autoimmune diseases which is mediated in part by interaction with the receptor for advanced glycation endproducts (RAGE). There is increasing evidence from in vitro studies that HMGB1 may link the two main pathophysiological components of Parkinson's disease (PD), i.e. progressive dopaminergic degeneration and chronic neuroinflammation which underlie the mechanistic basis of PD progression.
Analysis of tissue and biofluid samples from PD patients, showed increased HMGB1 levels in human postmortem substantia nigra specimens as well as in the cerebrospinal fluid and serum of PD patients. In a mouse model of PD induced by sub-acute administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), systemic administration of neutralizing antibodies to HMGB1 partly inhibited the dopaminergic cell death, and reduced the increase of RAGE and tumour necrosis factor-alpha. The small natural molecule glycyrrhizin, a component from liquorice root which can directly bind to HMGB1, both suppressed MPTP-induced HMGB1 and RAGE upregulation while reducing MPTP-induced dopaminergic cell death in a dose dependent manner.
These results provide first in vivo evidence that HMGB1 serves as a powerful bridge between progressive dopaminergic neurodegeneration and chronic neuroinflammation in a model of PD, suggesting that HMGB1 is a suitable target for neuroprotective trials in PD.
Highlights
•HMGB1 is up-regulated in Parkinson's disease.•HMGB1 is translocalized into the cytoplasm after MPTP.•Inhibition of HMGB1 protects against MPTP-toxicity.•Translocalization of HMGB1 is reduced after inhibition a neutralizing antibody or glycyrrhizin.
doi:10.1016/j.nbd.2016.02.018
PMCID: PMC4867789  PMID: 26921471
COX, cyclooxygenase; CSF, Cerebrospinal fluid; DOPAC, 3,4-Dihydroxyphenylacetic acid; GFAP, glial fibrillary acidic protein; H&Y, Hoehn & Yahr; HMGB1, high-mobility group box 1; HVA, homovanillic acid; MPP+,  1-methyl-4-phenylpyridinium; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; OD, optical density; PD, Parkinson's disease; RAGE, receptor for advanced glycation endproducts; SNpc, substantia nigra pars compacta; TH, tyrosine-hydroxylase; TNF-α, tumour necrosis factor-alpha; Wt, wild type; Parkinson's disease; MPTP; High-mobility group box 1; receptor for advanced glycation endproducts
5.  Inflammatory profile in LRRK2-associated prodromal and clinical PD 
Background
There is evidence for a relevant role of inflammation in the pathogenesis of Parkinson’s disease (PD). Mutations in the LRRK2 gene represent the most frequent genetic cause for autosomal dominant PD. LRRK2 is highly expressed in macrophages and microglia suggesting an involvement in inflammatory pathways. The objectives are to test (1) whether idiopathic PD and LRRK2-associated PD share common inflammatory pathways or present distinct profiles and (2) whether non-manifesting LRRK2 mutation carriers present with similar aspects of inflammatory profiles as seen in PD-affected patients.
Methods
We assessed serum profiles of 23 immune-associated markers and the brain-derived neurotrophic factor in 534 individuals from the MJFF LRRK2 consortium.
Results
A large proportion of inflammatory markers were gender-dependent. Both PD-affected cohorts showed increased levels of the pro-inflammatory marker fatty-acid-binding protein. Additionally, idiopathic PD but not LRRK2-associated PD patients showed increased levels of the pro-inflammatory marker interleukin-12-p40 as well as the anti-inflammatory species interleukin-10, brain-derived neurotrophic factor, and stem cell factor. Non-manifesting LRRK2 mutation carriers including those with prodromal characteristics of PD presented with control-like inflammatory profiles.
Conclusions
Concomitant inflammation seems to be associated with idiopathic and LRRK2-associated PD. Identifying PD patients in whom inflammatory processes play a major role in their pathophysiology might offer a new therapeutic window at least for a subgroup of patients. Since non-manifesting LRRK2 mutation carriers with symptoms of the prodromal phase of PD did not show inflammatory profiles, activation of the immune system seems not an early event in the disease cascade.
Electronic supplementary material
The online version of this article (doi:10.1186/s12974-016-0588-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12974-016-0588-5
PMCID: PMC4879729  PMID: 27220776
Parkinson; LRRK2; Immune; Inflammation
6.  Validation of conversion between mini–mental state examination and montreal cognitive assessment 
Movement Disorders  2016;31(4):593-596.
ABSTRACT
Introduction
Harmonizing data across cohorts is important for validating findings or combining data in meta‐analyses. We replicate and validate a previous conversion of MoCA to MMSE in PD.
Methods
We used five studies with 1,161 PD individuals and 2,091 observations measured with both the MoCA and MMSE. We compared a previously published conversion table using equipercentile equating with log‐linear smoothing to our internally derived scores.
Results
Both conversions found good agreement within and across the studies when comparing true and converted MMSE (mean difference: 0.05; standard deviation: 1.84; median difference: 0; interquartile range: –1 to 1, using internal conversion).
Conclusions
These results show that one can get a reliable and valid conversion between two commonly used measures of cognition in PD studies. These approaches need to be applied to other scales and domains to enable large‐scale collaborative analyses across multiple PD cohorts. © 2016 International Parkinson and Movement Disorder Society
doi:10.1002/mds.26498
PMCID: PMC4864892  PMID: 26861697
Parkinson's disease; Mini–Mental State Examination; Montreal Cognitive Assessment; equating
7.  Intra-Rater, Inter-Rater and Test-Retest Reliability of an Instrumented Timed Up and Go (iTUG) Test in Patients with Parkinson’s Disease 
PLoS ONE  2016;11(3):e0151881.
Background
The “Timed Up and Go” (TUG) is a widely used measure of physical functioning in older people and in neurological populations, including Parkinson’s Disease. When using an inertial sensor measurement system (instrumented TUG [iTUG]), the individual components of the iTUG and the trunk kinematics can be measured separately, which may provide relevant additional information.
Objective
The aim of this study was to determine intra-rater, inter-rater and test-retest reliability of the iTUG in patients with Parkinson’s Disease.
Methods
Twenty eight PD patients, aged 50 years or older, were included. For the iTUG the DynaPort Hybrid (McRoberts, The Hague, The Netherlands) was worn at the lower back. The device measured acceleration and angular velocity in three directions at a rate of 100 samples/s. Patients performed the iTUG five times on two consecutive days. Repeated measurements by the same rater on the same day were used to calculate intra-rater reliability. Repeated measurements by different raters on the same day were used to calculate intra-rater and inter-rater reliability. Repeated measurements by the same rater on different days were used to calculate test-retest reliability.
Results
Nineteen ICC values (15%) were ≥ 0.9 which is considered as excellent reliability. Sixty four ICC values (49%) were ≥ 0.70 and < 0.90 which is considered as good reliability. Thirty one ICC values (24%) were ≥ 0.50 and < 0.70, indicating moderate reliability. Sixteen ICC values (12%) were ≥ 0.30 and < 0.50 indicating poor reliability. Two ICT values (2%) were < 0.30 indicating very poor reliability.
Conclusions
In conclusion, in patients with Parkinson’s disease the intra-rater, inter-rater, and test-retest reliability of the individual components of the instrumented TUG (iTUG) was excellent to good for total duration and for turning durations, and good to low for the sub durations and for the kinematics of the SiSt and StSi. The results of this fully automated analysis of instrumented TUG movements demonstrate that several reliable TUG parameters can be identified that provide a basis for a more precise, quantitative use of the TUG test, in clinical practice.
doi:10.1371/journal.pone.0151881
PMCID: PMC4801645  PMID: 26999051
8.  A systematic review of the characteristics and validity of monitoring technologies to assess Parkinson’s disease 
Background
There is growing interest in having objective assessment of health-related outcomes using technology-based devices that provide unbiased measurements which can be used in clinical practice and scientific research. Many studies have investigated the clinical manifestations of Parkinson’s disease using such devices. However, clinimetric properties and clinical validation vary among the different devices.
Methods
Given such heterogeneity, we sought to perform a systematic review in order to (i) list, (ii) compare and (iii) classify technological-based devices used to measure motor function in individuals with Parkinson's disease into three groups, namely wearable, non-wearable and hybrid devices. A systematic literature search of the PubMed database resulted in the inclusion of 168 studies. These studies were grouped based on the type of device used. For each device we reviewed availability, use, reliability, validity, and sensitivity to change. The devices were then classified as (i) ‘recommended’, (ii) ‘suggested’ or (iii) ‘listed’ based on the following criteria: (1) used in the assessment of Parkinson’s disease (yes/no), (2) used in published studies by people other than the developers (yes/no), and (3) successful clinimetric testing (yes/no).
Results
Seventy-three devices were identified, 22 were wearable, 38 were non-wearable, and 13 were hybrid devices. In accordance with our classification method, 9 devices were ‘recommended’, 34 devices were ‘suggested’, and 30 devices were classified as ‘listed’. Within the wearable devices group, the Mobility Lab sensors from Ambulatory Parkinson’s Disease Monitoring (APDM), Physilog®, StepWatch 3, TriTrac RT3 Triaxial accelerometer, McRoberts DynaPort, and Axivity (AX3) were classified as ‘recommended’. Within the non-wearable devices group, the Nintendo Wii Balance Board and GAITRite® gait analysis system were classified as ‘recommended’. Within the hybrid devices group only the Kinesia® system was classified as ‘recommended’.
Electronic supplementary material
The online version of this article (doi:10.1186/s12984-016-0136-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12984-016-0136-7
PMCID: PMC4788909  PMID: 26969628
Outcomes; Parkinson’s disease; Quantitative assessment; Wearable devices; Monitoring technologies
9.  Insulin-Like Growth Factor 1 (IGF-1) in Parkinson's Disease: Potential as Trait-, Progression- and Prediction Marker and Confounding Factors 
PLoS ONE  2016;11(3):e0150552.
Introduction
Biomarkers indicating trait, progression and prediction of pathology and symptoms in Parkinson's disease (PD) often lack specificity or reliability. Investigating biomarker variance between individuals and over time and the effect of confounding factors is essential for the evaluation of biomarkers in PD, such as insulin-like growth factor 1 (IGF-1).
Materials and Methods
IGF-1 serum levels were investigated in up to 8 biannual visits in 37 PD patients and 22 healthy controls (HC) in the longitudinal MODEP study. IGF-1 baseline levels and annual changes in IGF-1 were compared between PD patients and HC while accounting for baseline disease duration (19 early stage: ≤3.5 years; 18 moderate stage: >4 years), age, sex, body mass index (BMI) and common medical factors putatively modulating IGF-1. In addition, associations of baseline IGF-1 with annual changes of motor, cognitive and depressive symptoms and medication dose were investigated.
Results
PD patients in moderate (130±26 ng/mL; p = .004), but not early stages (115±19, p>.1), showed significantly increased baseline IGF-1 levels compared with HC (106±24 ng/mL; p = .017). Age had a significant negative correlation with IGF-1 levels in HC (r = -.47, p = .028) and no correlation in PD patients (r = -.06, p>.1). BMI was negatively correlated in the overall group (r = -.28, p = .034). The annual changes in IGF-1 did not differ significantly between groups and were not correlated with disease duration. Baseline IGF-1 levels were not associated with annual changes of clinical parameters.
Discussion
Elevated IGF-1 in serum might differentiate between patients in moderate PD stages and HC. However, the value of serum IGF-1 as a trait-, progression- and prediction marker in PD is limited as IGF-1 showed large inter- and intraindividual variability and may be modulated by several confounders.
doi:10.1371/journal.pone.0150552
PMCID: PMC4788352  PMID: 26967642
10.  GDF15/MIC1 and MMP9 Cerebrospinal Fluid Levels in Parkinson’s Disease and Lewy Body Dementia 
PLoS ONE  2016;11(3):e0149349.
Based on animal and ex-vivo experiments, Growth/Differentiation Factor-15 (GDF15, also called Macrophage Inhibitory Cytokine-1, MIC1), a member of the transforming growth factor-beta family, and Matrix Metalloproteinase-9 (MMP9), a member of the matrix metalloprotease family may be potential markers for Lewy body disorders, i.e. Parkinson’s disease with (PDD) and without dementia (PDND) and Lewy body dementia (DLB). GDF15 has a prominent role in development, cell proliferation, differentiation, and repair, whereas MMP9 degrades, as a proteolytic enzyme, components of the extracellular matrix. In this study, cerebrospinal fluid GDF15 and MMP9 levels of 59 PDND, 17 PDD and 23 DLB patients, as well as of 95 controls were determined, and associated with demographic, clinical and biochemical parameters. Our analysis confirmed the already described association of GDF15 levels with age and gender. Corrected GDF15 levels were significantly higher in PDD than in PDND patients, and intermediate in DLB patients. Within Lewy body disorders, GDF15 levels correlated positively with age at onset of Parkinsonism and dementia, Hoehn & Yahr stage and cerebrospinal fluid t-Tau and p-Tau levels, and negatively with the Mini Mental State Examination. Remarkably, it does not relevantly correlate with disease duration. MMP9 was not relevantly associated with any of these parameters. Cerebrospinal GDF15, but not MMP9, may be a potential marker of and in Lewy body disorders.
doi:10.1371/journal.pone.0149349
PMCID: PMC4777571  PMID: 26938614
11.  Genome-wide analysis of genetic correlation in dementia with Lewy bodies, Parkinson's and Alzheimer's diseases 
Neurobiology of Aging  2016;38:214.e7-214.e10.
The similarities between dementia with Lewy bodies (DLB) and both Parkinson's disease (PD) and Alzheimer's disease (AD) are many and range from clinical presentation, to neuropathological characteristics, to more recently identified, genetic determinants of risk. Because of these overlapping features, diagnosing DLB is challenging and has clinical implications since some therapeutic agents that are applicable in other diseases have adverse effects in DLB. Having shown that DLB shares some genetic risk with PD and AD, we have now quantified the amount of sharing through the application of genetic correlation estimates, and show that, from a purely genetic perspective, and excluding the strong association at the APOE locus, DLB is equally correlated to AD and PD.
doi:10.1016/j.neurobiolaging.2015.10.028
PMCID: PMC4759606  PMID: 26643944
Dementia with Lewy bodies; Alzheimer's disease; Parkinson's disease; Genetic correlation
12.  Limited Effect of Dopaminergic Medication on Straight Walking and Turning in Early-to-Moderate Parkinson’s Disease during Single and Dual Tasking 
Background
In Parkinson’s disease (PD), the effects of dopaminergic medication on straight walking and turning were mainly investigated under single tasking (ST) conditions. However, multitasking situations are considered more daily relevant.
Methods
Thirty-nine early-to-moderate PD patients performed the following standardized ST and dual tasks as fast as possible for 1 min during On- and Off-medication while wearing inertial sensors: straight walking and turning, checking boxes, and subtracting serial 7s. Quantitative gait parameters as well as velocity of the secondary tasks were analyzed.
Results
The following parameters improved significantly in On-medication during ST: gait velocity during straight walking (p = 0.03); step duration (p = 0.048) and peak velocity (p = 0.04) during turning; velocity of checking boxes during ST (p = 0.04) and DT (p = 0.04). Velocity of checking boxes was the only parameter that also improved during DT.
Conclusion
These results suggest that dopaminergic medication does not relevantly influence straight walking and turning in early-to-moderate PD during DT.
doi:10.3389/fnagi.2016.00004
PMCID: PMC4728201  PMID: 26858638
Parkinson’s disease; dual tasking; gait; turning; wearable sensors
14.  Prodromal Markers in Parkinson’s Disease: Limitations in Longitudinal Studies and Lessons Learned 
A growing body of evidence supports a prodromal neurodegenerative process preceding the clinical onset of Parkinson’s disease (PD). Studies have identified several different prodromal markers that may have the potential to predict the conversion from healthy to clinical PD but use considerably different approaches. We systematically reviewed 35 longitudinal studies reporting prodromal PD features and evaluated the methodological quality across 10 different predefined domains. We found limitations in the following domains: PD diagnosis (57% of studies), prodromal marker assessments (51%), temporal information on prodromal markers or PD diagnosis (34%), generalizability of results (17%), statistical methods (accounting for at least age as confounder; 17%), study design (14%), and sample size (9%). However, no limitations regarding drop-out (or bias investigation), or report of inclusion/exclusion criteria or prodromal marker associations were revealed. Lessons learned from these limitations and additional aspects of current prodromal marker studies in PD are discussed to provide a basis for the evaluation of findings and the improvement of future research in prodromal PD. The observed heterogeneity of studies, limitations and analyses might be addressed in future longitudinal studies using a, yet to be established, modular minimal set of assessments improving comparability of findings and enabling data sharing and combined analyses across studies.
doi:10.3389/fnagi.2016.00147
PMCID: PMC4916171  PMID: 27445791
Parkinson’s disease; prodromal; cohort; prospective; case-control; clinical; longitudinal; marker
15.  Dual Tasking for the Differentiation between Depression and Mild Cognitive Impairment 
Differentiation of mild cognitive impairment from depression in elderly adults is a clinically relevant issue which is not sufficiently solved. Gait and dual task (DT) parameters may have the potential to complement current diagnostic work-up, as both dementia and depression are associated with changes of gait and DT parameters. Methods: Seven hundred and four participants of the TREND study (Tübinger evaluation of Risk factors for Early detection of NeuroDegeneration) aged 50–80 years were assessed using the Consortium to Establish a Registry for Alzheimer's Disease Plus test battery for testing cognition and Beck's Depression Inventory for evaluation of depression. Based on these results, four groups were defined: acute depressed (N = 53), cognitively mildly impaired (N = 97), acute depressed, and cognitively mildly impaired (N = 15), and controls (N = 536). Participants underwent a 20 m walk and checking boxes task under single (ST) and DT conditions. ST and DT performance and dual task costs (DTC) were calculated. Due to the typical age of increasing incidence of depressive and also cognitive symptoms, the 7th decade was calculated separately. Results: ST speeds of gait and checking boxes, DT walking speed, and walking DTC were significantly different between groups. Healthy controls were the fastest in all paradigms and cognitively mildly impaired had higher DTC than depressed individuals. Additionally, we constructed a multivariate predictive model differentiating the groups on a single-subject level. Conclusion: DT parameters are simply and comfortably measureable, and DTC can easily be determined. The combination of these parameters allows a differentiation of depressed and cognitively mildly impaired elderly adults.
doi:10.3389/fnagi.2016.00235
PMCID: PMC5062919  PMID: 27790136
depression; dual-task costs; gait speed; mild cognitive impairment; working memory
16.  Cognitive Performance Patterns in Healthy Individuals with Substantia Nigra Hyperechogenicity and Early Parkinson’s Disease 
Introduction: Hyperechogenicity of the substantia nigra (SN+) is a risk marker for Parkinson’s disease (PD) which can be detected before the diagnosis. In healthy individuals, SN+ has been associated with slight deficits in specific cognitive functions, suggesting cognitive impairment as a possible pre-diagnostic marker for PD. However, the pattern of cognitive deficits associated with SN+ has not yet been compared with those present in PD.
Methods: Data of 262 healthy individuals with normal echogenicity (SN-) and 48 healthy individuals with SN+ were compared with 82 early stage PD patients using the “Consortium to Establish a Registry for Alzheimer’s disease” test battery. First, the test clusters (factors) were identified using a principal component analysis (PCA). Mean group performance of cognitive tests belonging to distinct factors, according to the PCA, and single subtest performances were compared using analyses of variance. Second, the number of individuals with abnormal cognitive performances (z-score < -1.0) were compared between groups.
Results: Verbal memory, semantic and executive function, and praxis were identified as components of cognitive performances. The SN+ group performed significantly worse than the SN- group in tests assessing semantic and executive function, with a non-significant decrease in verbal memory. On the subtest level, individuals of the SN+ group scored significantly lower than the SN- group on the Boston Naming Test (BNT; p = 0.008). In all subtests, the percentages of PD patients with values below the cut-off for abnormal performance were higher than in the SN- group. Moreover, more individuals from the SN+ group scored below the cut-off in the BNT (SN- = 8.4%, SN+ = 20.8%, p = 0.01) and TMT-B (SN- = 6.9%, SN+ = 16.7%, p = 0.02), compared to the SN- group.
Conclusion: This study confirms poorer performance of healthy individuals with SN+ compared to SN- in specific cognitive domains. However, against the SN- group, the cognitive profile of the SN+ group was not fully consistent with the profile of early PD patients. Our data argues that cognitive impairment associated with SN+ might differ slightly from that seen in early PD. Compensational mechanisms in the early phases of neurodegeneration, and the fact that only a subgroup of SN+ will develop PD, may partly explain these differences.
doi:10.3389/fnagi.2016.00271
PMCID: PMC5108760  PMID: 27895578
substantia nigra hyperechogenicity; Parkinson’s disease; cognition; transcranial sonography; prodromal Parkinson’s disease
17.  The Central Biobank and Virtual Biobank of BIOMARKAPD: A Resource for Studies on Neurodegenerative Diseases 
Biobanks are important resources for biomarker discovery and assay development. Biomarkers for Alzheimer’s and Parkinson’s disease (BIOMARKAPD) is a European multicenter study, funded by the EU Joint Programme-Neurodegenerative Disease Research, which aims to improve the clinical use of body fluid markers for the diagnosis and prognosis of Alzheimer’s disease (AD) and Parkinson’s disease (PD). The objective was to standardize the assessment of existing assays and to validate novel fluid biomarkers for AD and PD. To support the validation of novel biomarkers and assays, a central and a virtual biobank for body fluids and associated data from subjects with neurodegenerative diseases have been established. In the central biobank, cerebrospinal fluid (CSF) and blood samples were collected according to the BIOMARKAPD standardized pre-analytical procedures and stored at Integrated BioBank of Luxembourg. The virtual biobank provides an overview of available CSF, plasma, serum, and DNA samples at each site. Currently, at the central biobank of BIOMARKAPD samples are available from over 400 subjects with normal cognition, mild cognitive impairment (MCI), AD, frontotemporal dementia (FTD), vascular dementia, multiple system atrophy, progressive supranuclear palsy, PD, PD with dementia, and dementia with Lewy bodies. The virtual biobank contains information on over 8,600 subjects with varying diagnoses from 21 local biobanks. A website has been launched to enable sample requests from the central biobank and virtual biobank.
doi:10.3389/fneur.2015.00216
PMCID: PMC4606063  PMID: 26528237
biobank; cerebrospinal fluid; dementia; Alzheimer’s disease; Parkinson’s disease; neurodegenerative disorders; body fluids
18.  Association between vestibulo-ocular reflex suppression, balance, gait, and fall risk in ageing and neurodegenerative disease: protocol of a one-year prospective follow-up study 
BMC Neurology  2015;15:192.
Background
Falls frequency increases with age and particularly in neurogeriatric cohorts. The interplay between eye movements and locomotion may contribute substantially to the occurrence of falls, but is hardly investigated. This paper provides an overview of current approaches to simultaneously measure eye and body movements, particularly for analyzing the association of vestibulo-ocular reflex (VOR) suppression, postural deficits and falls in neurogeriatric risk cohorts. Moreover, VOR suppression is measured during head-fixed target presentation and during gaze shifting while postural control is challenged. Using these approaches, we aim at identifying quantitative parameters of eye-head-coordination during postural balance and gait, as indicators of fall risk.
Methods/Design
Patients with Progressive Supranuclear Palsy (PSP) or Parkinson’s disease (PD), age- and sex-matched healthy older adults, and a cohort of young healthy adults will be recruited. Baseline assessment will include a detailed clinical assessment, covering medical history, neurological examination, disease specific clinical rating scales, falls-related self-efficacy, activities of daily living, neuro-psychological screening, assessment of mobility function and a questionnaire for retrospective falls. Moreover, participants will simultaneously perform eye and head movements (fixating a head-fixed target vs. shifting gaze to light emitting diodes in order to quantify vestibulo-ocular reflex suppression ability) under different conditions (sitting, standing, or walking). An eye/head tracker synchronized with a 3-D motion analysis system will be used to quantify parameters related to eye-head-coordination, postural balance, and gait. Established outcome parameters related to VOR suppression ability (e.g., gain, saccadic reaction time, frequency of saccades) and motor related fall risk (e.g., step-time variability, postural sway) will be calculated. Falls will be assessed prospectively over 12 months via protocols and monthly telephone interviews.
Discussion
This study protocol describes an experimental setup allowing the analysis of simultaneously assessed eye, head and body movements. Results will improve our understanding of the influence of the interplay between eye, head and body movements on falls in geriatric high-risk cohorts.
Electronic supplementary material
The online version of this article (doi:10.1186/s12883-015-0447-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12883-015-0447-5
PMCID: PMC4600299  PMID: 26452640
Vestibulo-ocular reflex suppression; VOR; Falls; Postural stability; Gait; Balance; Neurodegeneration; Parkinson’s Disease; Parkinsonism; Older persons
19.  Age and Vascular Burden Determinants of Cortical Hemodynamics Underlying Verbal Fluency 
PLoS ONE  2015;10(9):e0138863.
Background
Aging processes and several vascular burden factors have been shown to increase the risk of dementia including Alzheimer's disease. While pathological alterations in dementia precede diagnosis by many years, reorganization of brain processing might temporarily delay cognitive decline. We hypothesized that in healthy elderly individuals both age-related neural and vascular factors known to be related to the development of dementia impact functional cortical hemodynamics during increased cognitive demands.
Methods
Vascular burden factors and cortical functional hemodynamics during verbal fluency were assessed in 1052 non-demented elderly individuals (51 to 83 years; cross-sectional data of the longitudinal TREND study) using functional near-infrared spectroscopy (fNIRS). The prediction of functional hemodynamic responses by age in multiple regressions and the impact of single and cumulative vascular burden factors including hypertension, diabetes, obesity, smoking and atherosclerosis were investigated.
Results
Replicating and extending previous findings we could show that increasing age predicted functional hemodynamics to be increased in right prefrontal and bilateral parietal cortex, and decreased in bilateral inferior frontal junction during phonological fluency. Cumulative vascular burden factors, with hypertension in particular, decreased left inferior frontal junction hemodynamic responses during phonological fluency. However, age and vascular burden factors showed no statistical interaction on functional hemodynamics.
Conclusion
Based on these findings, one might hypothesize that increased fronto-parietal processing may represent age-related compensatory reorganization during increased cognitive demands. Vascular burden factors, such as hypertension, may contribute to regional cerebral hypoperfusion. These neural and vascular hemodynamic determinants should be investigated longitudinally and combined with other markers to advance the prediction of future cognitive decline and dementia.
doi:10.1371/journal.pone.0138863
PMCID: PMC4578891  PMID: 26394050
20.  Quantitative home-based assessment of Parkinson’s symptoms: The SENSE-PARK feasibility and usability study 
BMC Neurology  2015;15:89.
Background
Currently, assessment of symptoms associated with Parkinson’s disease is mainly performed in the clinic. However, these assessments have limitations because they provide only a snapshot of the condition.
Methods
The feasibility and usability of an objective, continuous and relatively unobtrusive system (SENSE-PARK System), which consists of wearable sensors (three worn during the day and one worn at night), a smartphone-based App, a balance board and computer software, was tested 24/7 over 12 weeks in a study including 22 PD patients. During the first four weeks of the study, patients did not get feedback about their performance, during the last eight weeks they did. The study included seven clinical visits with standardized interviews, and regular phone contact. The primary outcome was the number of drop-outs during the study. As secondary outcomes, the Post-Study System Usability Questionnaire (PSSUQ), score and information obtained from the standardized interviews were used to evaluate the usability of the system.
Results
All patients completed the study. The participants rated the usability of the SENSE-PARK System with a mean score of 2.67 (±0.49) on the PSSUQ. The interviews revealed that most participants liked using the system and appreciated that it signaled changes in their health condition.
Conclusions
This 12 week controlled study demonstrates that the acceptance level of PD patients using the SENSE-PARK System as a home-based 24/7 assessment is very good. Particular emphasis should be given to a user-friendly design. Motivation to wear such a system can be increased by providing direct feedback about the individual health condition.
doi:10.1186/s12883-015-0343-z
PMCID: PMC4460963  PMID: 26059091
Parkinson’s disease; Self-assessment; Home-based; Usability; Feasibility
21.  The Brain Response to Peripheral Insulin Declines with Age: A Contribution of the Blood-Brain Barrier? 
PLoS ONE  2015;10(5):e0126804.
Objectives
It is a matter of debate whether impaired insulin action originates from a defect at the neural level or impaired transport of the hormone into the brain. In this study, we aimed to investigate the effect of aging on insulin concentrations in the periphery and the central nervous system as well as its impact on insulin-dependent brain activity.
Methods
Insulin, glucose and albumin concentrations were determined in 160 paired human serum and cerebrospinal fluid (CSF) samples. Additionally, insulin was applied in young and aged mice by subcutaneous injection or intracerebroventricularly to circumvent the blood-brain barrier. Insulin action and cortical activity were assessed by Western blotting and electrocorticography radiotelemetric measurements.
Results
In humans, CSF glucose and insulin concentrations were tightly correlated with the respective serum/plasma concentrations. The CSF/serum ratio for insulin was reduced in older subjects while the CSF/serum ratio for albumin increased with age like for most other proteins. Western blot analysis in murine whole brain lysates revealed impaired phosphorylation of AKT (P-AKT) in aged mice following peripheral insulin stimulation whereas P-AKT was comparable to levels in young mice after intracerebroventricular insulin application. As readout for insulin action in the brain, insulin-mediated cortical brain activity instantly increased in young mice subcutaneously injected with insulin but was significantly reduced and delayed in aged mice during the treatment period. When insulin was applied intracerebroventricularly into aged animals, brain activity was readily improved.
Conclusions
This study discloses age-dependent changes in insulin CSF/serum ratios in humans. In the elderly, cerebral insulin resistance might be partially attributed to an impaired transport of insulin into the central nervous system.
doi:10.1371/journal.pone.0126804
PMCID: PMC4429020  PMID: 25965336
22.  Digitomotography in Parkinson’s Disease: A Cross-Sectional and Longitudinal Study 
PLoS ONE  2015;10(4):e0123914.
Motor symptoms in Parkinson’s disease (PD) are usually assessed with semi-quantitative tests such as the Unified PD Rating Scale (UPDRS) which are limited by subjectivity, categorical design, and low sensitivity. Particularly bradykinesia as assessed e.g. with speeded index finger tapping exhibits low validity measures. This exploratory study set out to (i) assess whether force transducer-based objective and quantitative analysis of motor coordination in index finger tapping is able to distinguish between PD patients and controls, and (ii) assess longitudinal changes. Sixteen early-stage and 17 mid-stage PD patients as well as 18 controls were included in the cross-sectional part of the study; thirteen, 16 and 16 individuals of the respective groups agreed in a reassessment 12 months later. Frequency, force, rhythmicity, regularity and laterality of speeded and metronome paced tapping were recorded by digitomotography using a quantitative motor system ("Q-Motor"). Analysis of cross-sectional data revealed most consistent differences between PD patients and controls in variability of tap performance across modalities assessed. Among PD patients, variability of taps and the ability to keep a given rhythm were associated with UPDRS motor and finger tapping scores. After 12 months, laterality parameters were reduced but no other parameters changed significantly. This data suggests that digitomotography provides quantitative and objective measures capable to differentiate PD from non-PD in a small cohort, however, the value of the assessment to track PD progression has to be further evaluated in larger cohorts of patients.
doi:10.1371/journal.pone.0123914
PMCID: PMC4406446  PMID: 25902182
23.  Naturally Occurring Alpha-Synuclein Autoantibodies in Parkinson’s Disease: Sources of (Error) Variance in Biomarker Assays 
PLoS ONE  2014;9(12):e114566.
Alpha-synuclein (α-Syn) plays a pivotal role in the pathophysiology of Parkinson’s disease (PD), which can partly be modulated by innate and adaptive immune functions, and vice versa. Here, naturally occurring α-Syn autoantibodies (α-Syn-nAbs) may be effective against α-Syn pathoetiology and may serve as a PD biomarker. However, serum and cerebrospinal fluid α-Syn-nAbs levels still lack consistent evidence as required for a reliable PD biomarker. Serum and cerebrospinal fluid α-Syn-nAbs levels of 66 PD patients and 69 healthy controls were assessed using a validated ELISA assay. Moreover, potential sources of error variance including unspecific ELISA background signals, free serum hemoglobin concentrations, α-Syn plate coating procedures, and differences in α-Syn-nAbs standards, were investigated. PD patients and controls did not differ in serum (p = .49) nor cerebrospinal fluid (p = .29) α-Syn-nAbs levels. Interestingly, free serum hemoglobin concentrations were negatively correlated with α-Syn-nAbs levels in controls (Spearman  = −.41, p<.001), but not in PD patients ( = .16, p = .21). ELISA α-Syn plate coating procedures impacted inter-assay variability (same day coating: 8–16%; coating on different days: 16–58%). α-Syn-nAbs standards from different purification batches differed regarding optical density measured in ELISAs suggesting differences in α-Syn affinity. While α-Syn-nAbs levels may represent a potential PD biomarker, several methodological issues have to be considered to increase reproducibility of α-Syn-nAbs findings. Further studies using standardized protocols minimizing sources of error variance may be necessary to establish a reliable PD α-Syn-nAbs biomarker.
doi:10.1371/journal.pone.0114566
PMCID: PMC4255021  PMID: 25470145
24.  Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies 
Human molecular genetics  2014;23(23):6139-6146.
Clinical and neuropathological similarities between dementia with Lewy bodies (DLB), Parkinson’s and Alzheimer’s diseases (PD and AD, respectively) suggest that these disorders may share etiology. To test this hypothesis, we have performed an association study of 54 genomic regions, previously implicated in PD or AD, in a large cohort of DLB cases and controls. The cohort comprised 788 DLB cases and 2624 controls. To minimize the issue of potential misdiagnosis, we have also performed the analysis including only neuropathologically proven DLB cases (667 cases). The results show that the APOE is a strong genetic risk factor for DLB, confirming previous findings, and that the SNCA and SCARB2 loci are also associated after a study-wise Bonferroni correction, although these have a different association profile than the associations reported for the same loci in PD. We have previously shown that the p.N370S variant in GBA is associated with DLB, which, together with the findings at the SCARB2 locus, suggests a role for lysosomal dysfunction in this disease. These results indicate that DLB has a unique genetic risk profile when compared with the two most common neurodegenerative diseases and that the lysosome may play an important role in the etiology of this disorder. We make all these data available.
doi:10.1093/hmg/ddu334
PMCID: PMC4222357  PMID: 24973356
25.  Post-Cueing Deficits with Maintained Cueing Benefits in Patients with Parkinson’s Disease Dementia 
In Parkinson’s disease (PD), internal cueing mechanisms are impaired leading to symptoms like hypokinesia. However, external cues can improve movement execution by using cortical resources. These cortical processes can be affected by cognitive decline in dementia. It is still unclear how dementia in PD influences external cueing. We investigated a group of 25 PD patients with dementia (PDD) and 25 non-demented PD patients (PDnD) matched by age, sex, and disease duration in a simple reaction time task using an additional acoustic cue. PDD patients benefited from the additional cue in similar magnitude as did PDnD patients. However, withdrawal of the cue led to a significantly increased reaction time in the PDD group compared to the PDnD patients. Our results indicate that even PDD patients can benefit from strategies using external cue presentation but the process of cognitive worsening can reduce the effect when cues are withdrawn.
doi:10.3389/fneur.2014.00236
PMCID: PMC4235071  PMID: 25477860
Parkinson’s disease; dementia; external cueing; reaction time; non-pharmacological therapy; basal ganglia; permanent cueing

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