The effect of age and gender on anti-saccade performance: Results from a large cohort of healthy aging individuals.

By 2050, the global population of people aged 65 years or older will triple. While this is accompanied with an increasing burden of age-associated diseases, it also emphasizes the need to understand the effects of healthy aging on cognitive processes. One such effect is a general slowing of processing speed, which is well documented in many domains. The execution of anti-saccades depends on a well-established brain-wide network ranging from various cortical areas and basal ganglia through the superior colliculus down to the brainstem saccade generators. To clarify the consequences of healthy aging as well as gender on the execution of reflexive and voluntary saccades, we measured a large sample of healthy, non-demented individuals (n = 731, aged 51-84 years) in the anti-saccade task. Age affected various aspects of saccade performance: The number of valid trials decreased with age. Error rate, saccadic reaction times (SRTs), and variability in saccade accuracy increased with age, whereas anti-saccade costs, accuracy, and peak velocity of anti-saccades and direction errors were not affected by age. Gender affected SRTs independent of age and saccade type with male participants having overall shorter SRTs. Our rigid and solid statistical testing using linear mixed-effect models provide evidence for a uniform slowing of processing speed independent of the actually performed eye movement. Our data do not support the assumption of a specific deterioration of frontal lobe functions with aging.

Fall Risk in Relation to Individual Physical Activity Exposure in Patients with Different Neurodegenerative Diseases: a Pilot Study.

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.

Cognitive impairment in Glucocerebrosidase (GBA)-associated PD: Not primarily associated with cerebrospinal fluid Abeta and Tau profiles.

BACKGROUND: A proportion of idiopathic Parkinson's disease patients (PDidiopathic ) with dementia show altered CSF profiles of amyloid ß (Aß) 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 Aß and tau are associated with the prominent cognitive impairment in PDGBA . METHODS: CSF levels of Aß1-42 , 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 Aß1-42 , t-Tau, and p-Tau as seen in healthy controls. In contrast, lower levels of Aß1-42 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 Aß and Tau profiles in CSF. © 2017 International Parkinson and Movement Disorder Society.

Validation of a Step Detection Algorithm during Straight Walking and Turning in Patients with Parkinson's Disease and Older Adults Using an Inertial Measurement Unit at the Lower Back.

INTRODUCTION: Inertial measurement units (IMUs) positioned on various body locations allow detailed gait analysis even under unconstrained conditions. From a medical perspective, the assessment of vulnerable populations is of particular relevance, especially in the daily-life environment. Gait analysis algorithms need thorough validation, as many chronic diseases show specific and even unique gait patterns. The aim of this study was therefore to validate an acceleration-based step detection algorithm for patients with Parkinson's disease (PD) and older adults in both a lab-based and home-like environment. METHODS: In this prospective observational study, data were captured from a single 6-degrees of freedom IMU (APDM) (3DOF accelerometer and 3DOF gyroscope) worn on the lower back. Detection of heel strike (HS) and toe off (TO) on a treadmill was validated against an optoelectronic system (Vicon) (11 PD patients and 12 older adults). A second independent validation study in the home-like environment was performed against video observation (20 PD patients and 12 older adults) and included step counting during turning and non-turning, defined with a previously published algorithm. RESULTS: A continuous wavelet transform (cwt)-based algorithm was developed for step detection with very high agreement with the optoelectronic system. HS detection in PD patients/older adults, respectively, reached 99/99% accuracy. Similar results were obtained for TO (99/100%). In HS detection, Bland-Altman plots showed a mean difference of 0.002 s [95% confidence interval (CI) -0.09 to 0.10] between the algorithm and the optoelectronic system. The Bland-Altman plot for TO detection showed mean differences of 0.00 s (95% CI -0.12 to 0.12). In the home-like assessment, the algorithm for detection of occurrence of steps during turning reached 90% (PD patients)/90% (older adults) sensitivity, 83/88% specificity, and 88/89% accuracy. The detection of steps during non-turning phases reached 91/91% sensitivity, 90/90% specificity, and 91/91% accuracy. CONCLUSION: This cwt-based algorithm for step detection measured at the lower back is in high agreement with the optoelectronic system in both PD patients and older adults. This approach and algorithm thus could provide a valuable tool for future research on home-based gait analysis in these vulnerable cohorts.

Dual-Task Performance in GBA Parkinson's Disease.

INTRODUCTION: Parkinson's disease patients carrying a heterozygous mutation in the gene glucocerebrosidase (GBA-PD) show faster motor and cognitive decline than idiopathic Parkinson's disease (iPD) patients, but the mechanisms behind this observation are not well understood. Successful dual tasking (DT) requires a smooth integration of motor and nonmotor operations. This study compared the DT performances between GBA-PD and iPD patients. METHODS: Eleven GBA-PD patients (p.N370S, p.L444P) and eleven matched iPD patients were included. Clinical characterization included a motor score (Unified PD Rating Scale-III, UPDRS-III) and nonmotor scores (Montreal Cognitive Assessment, MoCA, and Beck's Depression Inventory). Quantitative gait analysis during the single-task (ST) and DT assessments was performed using a wearable sensor unit. These parameters corrected for UPDRS and MoCA were then compared between the groups. RESULTS: Under the DT condition "walking while checking boxes," GBA-PD patients showed slower gait and box-checking speeds than iPD patients. GBA-PD and iPD patients did not show significant differences regarding dual-task costs. CONCLUSION: This pilot study suggests that DT performance with a secondary motor task is worse in GBA-PD than in iPD patients. This finding may be associated with the known enhanced motor and cognitive deficits in GBA-PD compared to iPD and should motivate further studies.

Genome-wide association study in essential tremor identifies three new loci.

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.

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.

Ambulatory Activity Components Deteriorate Differently across Neurodegenerative Diseases: A Cross-Sectional Sensor-Based Study.

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.

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.

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.

Clinical characteristics related to worsening of motor function assessed by the Unified Parkinson's Disease Rating Scale in the elderly population.

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.

GBA-associated Parkinson's disease: reduced survival and more rapid progression in a prospective longitudinal study.

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.

Risk factors and prodromal markers and the development of Parkinson's disease.

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.

Quantitative wearable sensors for objective assessment of Parkinson's disease.

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.

Decreased retinal sensitivity and loss of retinal nerve fibers in multiple system atrophy.

BACKGROUND AND AIM: 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. METHODS: 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. RESULTS: 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 ) < 0.01), while changes in temporal RNFLT measures (p ( temporal-superior ) = 0.42, p ( temporal ) = 0.34, p ( temporal-inferior ) = 0.25) were not statistically significant compared to healthy controls (ANOVA). MSA patients featured a significant global mean deviation (2.74 dB; p < 0.01) without predominant peripheral visual field defects. Statistical analysis of mean defect in the central (0-30°), peripheral (30-90°) or global (0-90°) visual field revealed no significant correlation (r (2) (central) = 0.11, r (2) (peripheral) = 0.04, r (2) (global) = 0.07) with nasal RNFLT in MSA patients. CONCLUSION: MSA patients feature significant reduction in nasal RNFLT and global mean deviation when compared to healthy controls, consistent with the multi-systemic nature of this neurodegenerative disorder. This finding provides first evidence for two independent deteriorations of the visual system in MSA.

Enlarged hyperechogenic substantia nigra as a risk marker for Parkinson's disease.

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.

Cognitive profiles in Parkinson's disease and their relation to dementia: a data-driven approach.

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.

GBA-associated PD. Neurodegeneration, altered membrane metabolism, and lack of energy failure.

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.