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Cerebellar dysfunction results in impairments in co-ordination or 'ataxia'. Bedside examination of cerebellar function has changed little since the early nineteenth century with the exception being the oculomotor examination which has become instrumented. Otherwise, competence and confidence in performing the clinical assessment relies heavily on the skill and experience of the clinician. Potentially, instrumented objective measurement will more accurately assess the severity of ataxia and the changes brought about by advancing therapies in pharmaceutical trials and in rehabilitation intervention. This study describes instrumented versions of several bedside tests of cerebellar function, including rhythmic tapping of the hand (RTH), finger-nose test (FNT), dysdiadochokinesia (DDK), ramp tracking (RMT), ballistic tracking (BT), rhythmic tapping of the foot (RTF) and the heel shin (HST) examination which were validated against scores from Ataxia Rating Scales (ARS) such as the Scale of Assessment and Rating of Ataxia (SARA). While all of the instrumented tests accurately distinguished between ataxic subjects and controls, there was a difference in performance, with the best four performing upper limb tests being RTH, FNT, DDK and BT. A combination of BT plus RTH provided the best correlation with the SARA and outperformed a combination of all the bedside tests (Spearman 0.8; p < 0.001 compared to 0.68; p < 0.001 for the combined set) in identifying the presence and severity of ataxia. This indicates that there is redundancy in the information provided by the bedside tests and that adding other tests to BT plus RTH does not add accuracy to the assessment of ataxia. This analysis highlighted the need for metrics that could be generalised to each of the assessments of ataxia, so, in turn, domains of stability, timing, accuracy and rhythmicity (STAR domains) were developed and compared to the SARA. The STAR criteria could potentially influence the future of instrumented assessment in CA and pave the way for further research into the objective measurement of the cerebellar examination.

Upper limb function for people with Friedreich ataxia determines capacity to participate in daily activities. Current upper limb measures available do not fully capture impairments related to Friedreich ataxia. We have developed an objective measure, the Ataxia Instrumented Measure-Spoon (AIM-S), which consists of a spoon equipped with a BioKin wireless motion capture device, and algorithms that analyse these signals, to measure ataxia of the upper limb during the pre-oral phase of eating. The aim of this study was to evaluate the AIM-S as a sensitive and functionally relevant clinical outcome for use in clinical trials. A prospective longitudinal study evaluated the capacity of the AIM-S to detect change in upper limb function over 48 weeks. Friedreich ataxia clinical severity, performance on the Nine-Hole Peg Test and Box and Block Test and responses to a purpose-designed questionnaire regarding acceptability of AIM-S were recorded. Forty individuals with Friedreich ataxia and 20 control participants completed the baseline assessment. Thirty individuals with Friedreich ataxia completed the second assessment. The sensitivity of the AIM-S to detect deterioration in upper limb function was greater than other measures. Patient-reported outcomes indicated the AIM-S reflected a daily activity and was more enjoyable to complete than other assessments. The AIM-S is a more accurate, less variable measure of upper limb function in Friedreich ataxia than existing measures. The AIM-S is perceived by individuals with Friedreich ataxia to be related to everyday life and will permit individuals who are non-ambulant to be included in future clinical trials.

Background: Accurate and reliable prediction of changes in the severity of cerebellar ataxia (CA) will be necessary for trials of disease-modifying therapies. Cerebellar dysarthria (CD) is a common feature of CA. This study demonstrated that objective acoustic measures were more sensitive than perceptive analysis through the Scale for the Assessment and Rating of Ataxia (SARA) in assessing the progression of CD, within a time window of two years (mean). Method: Thirty-seven people with CA were tested at baseline (time point 1, TP1) and two years later (time point 2, TP2). A machine-learning framework with a robust three-step feature selection criterion and a Bayesian data-driven clustering technique based on the multivariate mixture extension of the generalized linear mixed model (GLMM) was used. The outcomes included two (time and cepstral-based) objective speech parameters recorded at TP1 and TP2. Subject testing involved dynamic prediction and was conducted using samples from the posterior distributions of parameter estimates and random effects. This study further employed the penalized expected deviance (PED) criterion for model comparison and the selection of the number of groups in the clustering procedure. Results: First, the selected objective speech metrics in the individual patients showed a significant worsening of the speech impairment (p $PED_{Fea1+Fea2}=5175$ ; number of groups = 2) performed more reliably than the univariate models ( $PED_{Fea1}=4225$ , $PED_{Fea2}=3850$ ; number of groups = 2) in discriminating the CA patients. Fourth, the individual-level predictions of the change in profiles of the objective measures over time were performed for the testing data. Conclusion: Such a framework using objective speech metrics indeed holds promise to predict the rate of clinical progression of CD in individuals with CA.

The monitoring of disease progression in certain neurodegenerative conditions can significantly be quantified with the help of objective assessments. The severity assessment of diseases like Friedreich ataxia (FRDA) are usually based on different subjective measures. The ability of a participant with FRDA to perform standard neurological tests is the most common way of assessing disease progression. In this feasibility study, an Ataxia Instrumented Measurement-Cup (AIM-C) is proposed to quantify the disease progression of 10 participants (mean age 39 years, onset of disease 16.3 years) in longitudinal timepoints. The device consists of a sensing system with the provision of extracting both kinetic and kinematic information while engaging in an activity closely associated with activities of daily living (ADL). A common functional task of simulated drinking was used to capture features that possesses disease progression information as well as certain other features which intrinsically correlate with commonly used clinical scales such as the modified Friedreich Ataxia Rating Scale (mFARS), the Functional Staging of Ataxia score and the ADL scale. Frequency and time-frequency domain features allowed the longitudinal assessment of participants with FRDA. Furthermore, both kinetic and kinematic measures captured clinically relevant features and correlated 85% with clinical assessments.

Background Cerebellar ataxia refers to the disturbance in movement resulting from cerebellar dysfunction. It manifests as inaccurate movements with delayed onset and overshoot, especially when movements are repetitive or rhythmic. Identification of ataxia is integral to the diagnosis and assessment of severity, and is important in monitoring progression and improvement. Ataxia is identified and assessed by clinicians observing subjects perform standardised movement tasks that emphasise ataxic movements. Our aim in this paper was to use data recorded from motion sensors worn while subjects performed these tasks, in order to make an objective assessment of ataxia that accurately modelled the clinical assessment. Methods Inertial measurement units and a Kinect© system were used to record motion data while control and ataxic subjects performed four instrumented version of upper extremities tests, i.e. finger chase test (FCT), finger tapping test (FTT), finger to nose test (FNT) and dysdiadochokinesia test (DDKT). Kinematic features were extracted from this data and correlated with clinical ratings of severity of ataxia using the Scale for the Assessment and Rating of Ataxia (SARA). These features were refined using Feed Backward feature Elimination (the best performing method of four). Using several different learning models, including Linear Discrimination, Quadratic Discrimination Analysis, Support Vector Machine and K-Nearest Neighbour these extracted features were used to accurately discriminate between ataxics and control subjects. Leave-One-Out cross validation estimated the generalised performance of the diagnostic model as well as the severity predicting regression model. Results The selected model accurately ($$96.4\%$$ 96.4 % ) predicted the clinical scores for ataxia and correlated well with clinical scores of the severity of ataxia ($$rho = 0.8$$ r h o = 0.8 , $$p < 0.001$$ p < 0.001 ). The severity estimation was also considered in a 4-level scale to provide a rating that is familiar to the current clinically-used rating of upper limb impairments. The combination of FCT and FTT performed as well as all four test combined in predicting the presence and severity of ataxia. Conclusion Individual bedside tests can be emulated using features derived from sensors worn while bedside tests of cerebellar ataxia were being performed. Each test emphasises different aspects of stability, timing, accuracy and rhythmicity of movements. Using the current models it is possible to model the clinician in identifying ataxia and assessing severity but also to identify those test which provide the optimum set of data. Trial registration Human Research and Ethics Committee, Royal Victorian Eye and Ear Hospital, East Melbourne, Australia (HREC Reference Number: 11/994H/16).

Medical conditions with effective therapies are usually managed with objective measurement and therapeutic targets. Parkinson’s disease has effective therapies, but continuous objective measurement has only recently become available. This blinded, controlled study examined whether management of Parkinson’s disease was improved when clinical assessment and therapeutic decisions were aided by objective measurement. The primary endpoint was improvement in the Movement Disorder Society-United Parkinson’s Disease Rating Scale’s (MDS-UPDRS) Total Score. In one arm, objective measurement assisted doctors to alter therapy over successive visits until objective measurement scores were in target. Patients in the other arm were conventionally assessed and therapies were changed until judged optimal. There were 75 subjects in the objective measurement arm and 79 in the arm with conventional assessment and treatment. There were statistically significant improvements in the moderate clinically meaningful range in the MDS-UPDRS Total, III, IV scales in the arm using objective measurement, but not in the conventionally treated arm. These findings show that global motor and non-motor disability is improved when management of Parkinson’s disease is assisted by objective measurement.

Background The Personal KinetiGraph® (PKG®) Movement Recording System provides continuous, objective, ambulatory movement data during routine daily activities and provides information on medication compliance, motor fluctuations, immobility, and tremor for patients with Parkinson’s disease (PD). Recent evidence has proposed targets for treatable symptoms. Indications for PKG vary by country and patient selection varies by physician. Methods The analyses were based upon 27,834 complete and de-identified PKGs from January 2012 to August 2018 used globally for routine clinical care. Median scores for bradykinesia (BKS) and dyskinesia (DKS) as well as percent time with tremor (PTT) and percent time immobile (PTI) were included as well as proportions of PKGs above published PKG summary score target values (BKS > 25, DKS > 9, PTT > 1%, PTI > 10%). Two sub-analyses included subjects who had 2+ PKG records and scores above proposed BKS and DKS targets, respectively, on their first PKG. Median BKS and DKS scores for subsequent PKGs (1st, 2nd, etc.) were summarized and limited to those with 100+ subsequent PKGs for each data point. Results Significant differences between countries were found for all 4 PKG parameter median scores (all p ). Overall, 54% of BKS scores were > 25 and ranged from 46 to 61% by country. 10% of all DKS scores were > 9 and ranged from 5 to 15% by country. Sub-analysis for BKS showed global median BKS and DKS scores across subsequent PKGs for subjects who had 2+ PKGs and had BKS > 25 on their first PKG. There were significant changes in BKS from 1st to 2nd-6th PKGs (all p Sub-analysis for DKS showed global median BKS & DKS scores across subsequent PKGs for subjects who had 2+ PKGs and had DKS > 9 on their first PKG. There were significant changes in DKS from 1st to 2nd and 3rd PKGs (both p . Conclusions This analysis shows that in every country evaluated a meaningful proportion of patients have sub-optimal PD motor symptoms and substantial variations exist across countries. Continuous objective measurement (COM) in routine care of PD enables identification and quantification of PD motor symptoms, which can be used to enhance clinical decision making, track symptoms over time and improve PD symptom scores. Thus, clinicians can use these PKG scores during routine clinical management to identify PD symptoms and work to move patients into a target range or a more controlled symptom state.

Gait disturbance is one of the most pronounced and disabling symptoms of cerebellar disease (CD). Generally, gait studies quantify human gait characteristics under natural walking speeds while mainly considering upper body movements. Therefore, the primary goal of this study was to investigate the influence of different walking speeds on different gait parameters of both the upper and lower body, as a result of disabilities caused by Cerebellar Ataxia (CA). We employed wearable sensor technology to identify the kinematic characteristics which best identify the gait abnormalities seen in CA. Measurements were made at self-selected slow, preferred and fast walking speeds. Velocity irregularity and resonant frequency characteristics were identified as key features of truncal and lower limb movements respectively. Subsequently, the differentiating features for both trunk and lower limb movements were combined to produce an even greater separation between the patients and the normal subjects, as well as better correlation with the expert clinical assessment (ECA) (0.86) and the Scale for the Assessment and Rating of Ataxia (SARA) (0.62). The different speed of walking conditions resulted in varying degrees of the separation and the correlation. Moreover, the contribution of the extracted features was examined using the random forest algorithm. Clinically observable truncal medio-lateral movements express the disability at relatively slow gait speeds while the anterior-posterior movements captured by the sensory mechanisms characterises the disability across all walking speeds. The importance of selected dominant features from the trunk and lower limb suggest that overall clinical assessments are predominantly influenced by the lower body peripheral movements, particularly at higher cadences.

Cerebellar damage can result in peripheral dysfunction manifesting as poor and inaccurate coordination, irregular movements, and tremors. Conventionally, the severity assessment of Cerebellar ataxia (CA) is primarily based on expert clinical opinion and hence likely to be subjective. In order to establish inter-rater concordance with enhanced reliability and effectiveness in the assessment of upper limb function, a novel automated system employing Microsoft Kinect© is considered to capture the motion of the patient’s finger for objective assessment. This essentially mimics the commonly used finger tracking task clinically assessed through subjective observation. A clinical trial was conducted involving 42 CA patients and 18 age-matched healthy subjects. The relevant kinematically diagnostic features of CA patients allowed a classification accuracy of 97% using the Bayesian Quadratic Discriminant Analysis (QDA). The correlation (severity) between the extracted features and the independent severity scores from expert clinicians were collated to achieve a high correlation ( ${r} = {0.86}$ , ${p} ) with the Scale for the Assessment and Rating of Ataxia (SARA). The proposed system can efficiently generate objective information of severity as a result of features that are not necessarily observable during standard bedside clinical testing. Furthermore, the superior performance of the Ballistic (finger chase) test indeed supports the credence of the Ramp test redundancy that exists among the wider clinical community.

Effective monitoring of the progression of neurodegenerative conditions can be significantly improved by objective assessments. Clinical assessments of conditions such as Friedreich's Ataxia (FA), currently rely on subjective measures commonly practiced in clinics as well as the ability of the affected individual to perform conventional tests of the neurological examination. In this study, we propose an ataxia measuring device, in the form of a pressure canister capable of sensing certain kinetic and kinematic parameters of interest to quantify the impairment levels of participants particularly when engaged in an activity that is closely associated with daily living. In particular, the functional task of simulated drinking was utilised to capture characteristic features of disability manifestation in terms of diagnosis (separation of individuals with FA and controls) and severity assessment of individuals diagnosed with the debilitating condition of FA. Time and frequency domain analysis of these biomarkers enabled the classification of individuals with FA and control subjects to reach an accuracy of 98% and a correlation level reaching 96% with the clinical scores.

Characterisation and diagnosis of idiopathic Parkinson’s disease (iPD) is a current challenge that hampers both clinical assessment and clinical trial development with the potential inclusion of non-PD cases. Here, we used a targeted mass spectrometry approach to quantify 38 metabolites extracted from the serum of 231 individuals. This cohort is currently one of the largest metabolomic studies including iPD patients, drug-naïve iPD, healthy controls and patients with Alzheimer’s disease as a disease-specific control group. We identified six metabolites (3-hydroxykynurenine, aspartate, beta-alanine, homoserine, ornithine (Orn) and tyrosine) that are significantly altered between iPD patients and control participants. A multivariate model to predict iPD from controls had an area under the curve (AUC) of 0.905, with an accuracy of 86.2%. This panel of metabolites may serve as a potential prognostic or diagnostic assay for clinical trial prescreening, or for aiding in diagnosing pathological disease in the clinic.

Predation mortality can influence the distribution and abundance of fish populations. While predation is often assessed using direct observations of prey consumption, potential predation can be predicted from co-occurring predator and prey densities under varying environmental conditions. Juvenile Pacific salmonOncorhynchusspp. (i.e., smolts) from the Columbia River Basin experience elevated mortality during the transition from estuarine to ocean habitat, but a thorough understanding of the role of predation remains incomplete. We used a Holling type II functional response to estimate smolt predation risk based on observations of piscivorous seabirds (sooty shearwater [Ardenna griseus] and common murre [Uria aalge]) and local densities of alternative prey fish including northern anchovy (Engraulis mordax) in Oregon and Washington coastal waters during May and June 2010–2012. We evaluated predation risk relative to the availability of alternative prey and physical factors including turbidity and Columbia River plume area, and compared risk to returns of adult salmon. Seabirds and smolts consistently co-occurred at sampling stations throughout most of the study area (mean = 0.79 ± 0.41, SD), indicating that juvenile salmon are regularly exposed to avian predators during early marine residence. Predation risk for juvenile coho (Oncorhynchus kisutch), yearling Chinook salmon (O.tshawytscha), and subyearling Chinook salmon was on average 70% lower when alternative prey were present. Predation risk was greater in turbid waters, and decreased as water clarity increased. Juvenile coho and yearling Chinook salmon predation risk was lower when river plume surface areas were greater than 15,000 km2, while the opposite was estimated for subyearling Chinook salmon. These results suggest that plume area, turbidity, and forage fish abundance near the mouth of the Columbia River, all of which are influenced by river discharge, are useful indicators of potential juvenile salmon mortality that could inform salmonid management.

IntroductionCholesterol levels have been associated with age-related cognitive decline, however, such an association has not been comprehensively explored in people with Parkinson’s disease (PD). To address this uncertainty, the current cross-sectional study examined the cholesterol profile and cognitive performance in a cohort of PD patients.MethodsCognitive function was evaluated using two validated assessments (ACE-R and SCOPA-COG) in 182 people with PD from the Australian Parkinson’s Disease Registry. Total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and Triglyceride (TRG) levels were examined within this cohort. The influence of individual lipid subfractions on domain-specific cognitive performance was investigated using covariate-adjusted generalised linear models.ResultsFemales with PD exhibited significantly higher lipid subfraction levels (TC, HDL, and LDL) when compared to male counterparts. While accounting for covariates, HDL levels were strongly associated with poorer performance across multiple cognitive domains in females but not males. Conversely, TC and LDL levels were not associated with cognitive status in people with PD.ConclusionHigher serum HDL associates with poorer cognitive function in females with PD and presents a sex-specific biomarker for cognitive impairment in PD.

Cerebellar ataxia (CA) refers to the disordered movement that occurs when the cerebellum is injured or affected by disease. It manifests as uncoordinated movement of the limbs, speech, and balance. This study is aimed at the formation of a simple, objective framework for the quantitative assessment of CA based on motion data. We adopted the Recurrence Quantification Analysis concept in identifying features of significance for the diagnosis. Eighty-six subjects were observed undertaking three standard neurological tests (Romberg's, Heel-shin and Truncal ataxia) to capture 213 time series inertial measurements each. The feature selection was based on engaging six different common techniques to distinguish feature subset for diagnosis and severity assessment separately. The Gaussian Naive Bayes classifier performed best in diagnosing CA with an average double cross-validation accuracy, sensitivity, and specificity of 88.24%, 85.89%, and 92.31%, respectively. Regarding severity assessment, the voting regression model exhibited a significant correlation (0.72 Pearson) with the clinical scores in the case of the Romberg's test. The Heel-shin and Truncal tests were considered for diagnosis and assessment of severity concerning subjects who were unable to stand. The underlying approach proposes a reliable, comprehensive framework for the assessment of postural stability due to cerebellar dysfunction using a single inertial measurement unit.

Cerebellar ataxia (CA) results from injury to or disease of the cerebellum. It describes the resulting motor dysfunction, characterised by inaccuracy, incoordination and delay in initiation of movement, tremor, and imbalance. Assessment of ataxia to diagnose and monitor progress is by clinical observance of the performance of standard motor tasks. An accurate instrumented measurement of CA would therefore be of great interest. This study was aimed at assessing upper-limb ataxia during ballistic tracking of a computer-generated target in individuals with CA and controls using motion measures obtained from a Kinect camera and a wearable motioncaptured device. A set of features derived from these motion measurements were used to develop a method for objective quantification of CA. Difference between ataxic and non-ataxic movements can be readily be observed in features from both devices (p = 0.008) and their values associated with a standard clinical scale (rho = 0.80, p < 0.001). The combination of multimodal features improved the ability to distinguish between CA subjects and controls and to measure the severity of upper limb ataxia.

Cerebellar Ataxia is a neurological disorder without an approved treatment. Patients will have impaired and uncoordinated motor functionality making them unable to complete their day-to-day activities. Ataxia clinics are established around the world to facilitate research and rehabilitate patients. However, the patients are generally evaluated by human – observation. Therefore, machine learning based data analysis is popular on motion captured via sensors. There are many neurological tests designed to analyse the motor impairments in different domains (such as upper limb, lower limb, gait, balance and speech). Clinicians follow scoring protocols to record the severity of patients for each domain test. This paper delivers a clinical assessment platform combining 12 neurological tests in 5 domains. It captures motion (from BioKin sensors), haptic and audio data (from the tablet or laptop screen). A data analysis system is hosted in a remote server which evaluates data to produce a severity score via different models built for each neurological test. The assessment platform clients and server communicate via a cloud buffer system. The scores input by the clinicians and predicted by the machine learning models are logged in the cloud database. This enables clinicians and doctors to view and compare the history of patient diagnosis. The server system is structured for automated score model upgrades via prompted approval. Thus, the most viable scoring model could be accommodated for each test based on longitudinal studies.

Background Cognitive impairment is an important and diverse symptom of Parkinson’s disease (PD). Sex is a purported risk variable for cognitive decline in PD, but has not been comprehensively investigated. Objectives This cross-sectional and longitudinal study examined sex differences in global and domain-specific cognitive performance in a large PD cohort. Methods Cognitive function was evaluated using the Addenbrooke’s Cognitive Examination in 392 people with PD (PwP) from the Australian Parkinson’s Disease Registry. The influence of sex on domain-specific cognitive performance was investigated using covariate-corrected generalised linear models. In a repeated measures longitudinal subset of 127 PwP, linear mixed models were used to assess the impact of sex on cognition over time, while accounting for covariates. Results Cross-sectional-corrected modelling revealed that sex was significantly predictive of cognitive performance, with males performing worse than females on global cognition, and memory and fluency domains. Longitudinally, sex was significantly predictive of cognitive decline, with males exhibiting a greater reduction in global cognition and language, whereas females showed a greater decline in attention/orientation, memory and visuospatial domains, despite starting with higher baseline scores. At follow-up, a significantly higher proportion of males than females fulfilled criteria for mild cognitive impairment or PD dementia. Conclusions Sex was revealed as a significant determinant of overall cognitive performance as well as specific cognitive domains, with a differential pattern of decline in male and female participants. Such sex-specific findings appear to explain some of the heterogeneity observed in PD, warranting further investigation of mechanisms underlying this sexual dimorphism.

Human observer-based assessments of Cerebellar Ataxia (CA) are subjective and are often inadequate to track mild motor symptoms. This study examines the potential use of a comprehensive sensor-based approach for objective evaluation of CA in five domains (speech, upper limb, lower limb, gait and balance) through the instrumented versions of nine bedside neurological tests. A total of twenty-three participants diagnosed with CA to varying degrees and eleven healthy controls were recruited. Data was collected using wearable inertial sensors and Kinect camera. In our study, an optimal feature subset based on feature importance in the Random Forest classifier model demonstrated an impressive performance accuracy of 97% (F1 score = 95.2%) for CA-control discrimination. Our experimental findings also indicate that the Romberg test contributed most, followed by the peripheral tests, while the Gait test contributed least to the classification. Sensor-based approaches, therefore, have the potential to complement existing clinical assessment techniques, offering advantages in terms of consistency, objectivity and informed clinical decision-making.

Development of “Wearing Off” (WO) of motor and non-motor function in Parkinson’s disease (PD) adversely affects quality of life. This suggest that identifying and treating WO is important. However, identification of WO depends on people with PD (PwP) recognising and reporting WO and there is a perception that WO may be significantly underestimated. We investigate the feasibility of identifying “Wearing Off” using objective measurement and assess the clinical benefit in rectifying it. In this study, 200 PwP were studied for evidence of WO using a continuously worn wearable system. Eighty-five patients (43%) were found to have WO and treatment was changed to mitigate the effects of WO. Factors, such as duration of disease, high baseline MDS-UPDRS (motor component), high Percent Time in Bradykinesia (PTB), high Levodopa Equivalent Daily Dose (LEDD), frequent Levodopa doses and younger age of onset, are associated with severity of motor complications. Patients with more severe WO experienced worse motor and non-motor symptoms and lower quality of life. Quality of life significantly improved in PwP when WO was treated. The findings reported in this study provide evidence that identifying and treating WO improves outcomes of PwP and that objective measurements may help clinicians to identify and treat WO.

The progression of neurodegenerative conditions can be effectively monitored and improved by using objective assessments. The conditions such as Friedreich Ataxia (FA) are clinically assessed by means of subjective measures commonly practised in clinics. Here, we propose a device capable of measuring ataxia, in the form of a `cup' capable of sensing certain kinematic parameters of interest while engaging in an activity that is closely related to daily living. In this study, the functional task of 'drinking' was utilised to diagnose participants with FA and capture features in terms of diagnosis (separation) and correlation with the clinical scales. Frequency domain analysis was incorporated enabling the classification of control subjects and FA patients to an accuracy of 88% with a correlation of 90% with the clinical scores.

The response to levodopa (LR) is important for managing Parkinson's Disease and is measured with clinical scales prior to (OFF) and after (ON) levodopa. The aim of this study was to ascertain whether an ambulatory wearable device could predict the LR from the response to the first morning dose. The ON and OFF scores were sorted into six categories of severity so that separating Parkinson's Kinetigraph (PKG) features corresponding to the ON and OFF scores became a multi-class classification problem according to whether they fell below or above the threshold for each class. Candidate features were extracted from the PKG data and matched to the class labels. Several linear and non-linear candidate statistical models were examined and compared to classify the six categories of severity. The resulting model predicted a clinically significant LR with an area under the receiver operator curve of 0.92. This study shows that ambulatory data could be used to identify a clinically significant response to levodopa. This study has also identified practical steps that would enhance the reliability of this test in future studies.

Cerebellar ataxia (CA) refers to the impaired balance and coordination resulting from injury or degeneration of the cerebellum. Testing balance is one of the simplest means of assessing CA. This study compares instrumented assessment and clinical assessment scales of the balance test called Romberg's test. Inertial Measurement Unit (IMU) data were collected from a sensor attached to their chest of 53 subjects while they performed the test. The corresponding clinical scores were also tabulated. Using this data, 99 features were extracted to quantify acceleration, tremor and displacement of body sway. These features were filtered to identify the subset that better characterize the distinctive behavior of CA subjects. Elastic Net Regression model resulted a greater agreement (0.70 Pearson coefficient) with the clinical SARA scores. The overall results indicated that data from a single IMU sensor is sufficient to accurately assess balance in CA. The significance of this study is that evaluation of balance using Recurrence Quantification Analysis produces a comprehensive framework for the assessment of CA.

Friedreich ataxia (FRDA), the most common of the inherited ataxias, is a degenerative disease that progressively affects walking and other functions leading to significant impairment associated with a shortened lifespan. It is important to monitor the progression of ataxia over periods of time for clinical and therapeutic interventions. This study was aimed at investigating the use of our instrumented measurement scheme of utilizing a motion detecting spoon in a self-feeding activity to quantify the longitudinal effect of FRDA on upper limb function. Forty individuals diagnosed with FRDA (32.8±14.9 years old) were recruited in a 12-month longitudinal study consisting of equal number of males and females (20). A set of biomarkers was extracted from the temporal and texture analysis of the movement time series data that objectively detected subtle changes during follow-up testing. The results indicated that both analyses generated features that resembled clinical ratings. Although the diagnosis and severity related performances were readily observed by temporal features, the longitudinal progression was better captured by the textural features (p = 0.029). The estimation of severity by mean of random forest regression model and LASSO exhibited a high degree of parity with the standard clinical scale (rho = 0.73, p < 0.001).

Gain-of-function polymorphisms in the transcription factor IFN regulatory factor 5 (IRF5) are associated with an increased risk of developing systemic lupus erythematosus. However, the IRF5-expressing cell type(s) responsible for lupus pathogenesis in vivo is not known. We now show that monoallelic IRF5 deficiency in B cells markedly reduced disease in a murine lupus model. In contrast, similar reduction of IRF5 expression in macrophages, monocytes, and neutrophils did not reduce disease severity. B cell receptor and TLR7 signaling synergized to promote IRF5 phosphorylation and increase IRF5 protein expression, with these processes being independently regulated. This synergy increased B cell-intrinsic IL-6 and TNF-α production, both key requirements for germinal center (GC) responses, with IL-6 and TNF-α production in vitro and in vivo being substantially lower with loss of 1 allele of IRF5. Mechanistically, TLR7-dependent IRF5 nuclear translocation was reduced in B cells from IRF5-heterozygous mice. In addition, we show in multiple lupus models that IRF5 expression was dynamically regulated in vivo with increased expression in GC B cells compared with non-GC B cells and with further sequential increases during progression to plasmablasts and long-lived plasma cells. Overall, a critical threshold level of IRF5 in B cells was required to promote disease in murine lupus.

Parametric analysis of Cerebellar Ataxia (CA) could be of immense value compared to its subjective clinical assessments. This study focuses on a comprehensive scheme for objective assessment of CA through the instrumented versions of 9 commonly used neurological tests in 5 domains- speech, upper limb, lower limb, gait and balance. Twenty-three individuals diagnosed with CA to varying degrees and eleven age-matched healthy controls were recruited. Wearable inertial sensors and Kinect camera were utilised for data acquisition. Binary and multilabel discrimination power and intra-domain relationships of the features extracted from the sensor measures and the clinical scores were compared using Graph Theory, Centrality Measures, Random Forest binary and multilabel classification approaches. An optimal subset of 13 most important Principal Component (PC) features were selected for CA-control classification. This classification model resulted in an impressive performance accuracy of 97% (F1 score = 95.2%) with Holmesian dimensions distributed as 47.7% Stability, 6.3% Timing, 38.75% Accuracy and 7.24% Rhythmicity. Another optimal subset of 11 PC features demonstrated an F1 score of 84.2% in mapping the total 27 PC across 5 domains during CA multilabel discrimination. In both cases, the balance (Romberg) test contributed the most (31.1% and 42% respectively), followed by the peripheral tests whereas gait (Walking) test contributed the least. These findings paved the way for a better understanding of the feasibility of an instrumented system to assist informed clinical decision-making.

The objective assessment of motor impairment resulting from neurological disorders forms the basis for effective rehabilitation and therapeutic programs. Such assessments conducted through the engagement of suitable daily activities can serve as an effective surrogate measure for the assessment of independent living. This study considers an instrumented spoon in the assessment of upper-limb functionality through the self-feeding activity of a group of individuals clinically diagnosed with the debilitating condition, Friedreich ataxia (FRDA). Thirty-five subjects with FRDA (34 ± 14 years old) and 14 age-matched healthy subjects performed three cycles of self-feeding consisting of grasping, scooping, transferring food to mouth and returning the spoon. Parameters relating to the feeding rate, trajectory of the rotation, range of motion and movement variability with specific attention to each segment were considered for the capture of ataxia pertaining to the disability. Movement variability measured by Dynamic Time Warping (DTW) resulted in an average accuracy of 96% in the diagnosis of ataxia (separation of the two cohorts). The severity of ataxia estimated using a combination of features from Random Forest (RF) increased the correlation with the clinical estimates of ataxia by 13% and achieved higher coefficient (0.72 in patient scale) than the currently used tests (Box & Block, Pegboard). While the overall results provided an objective, daily activity based means of capturing intrinsic abnormalities, the different segments of the task demonstrated the presence of ataxia in a spatial context concurring with relevant clinical observations.

Background and Objective There is convincing evidence that small CGG expansion (41-54 repeats): FMR1 "gray zone" alleles (GZ) contribute to the risk of parkinsonism in males, but there is insufficient corresponding data in females. This study intends to fill this gap. Methods We screened whole-blood-derived DNA from a cohort of 601 females diagnosed with idiopathic PD, and from dry Guthrie blood spots from a local sample of 1,005 female newborns (population controls), for the size of the FMR1 CGG repeat using a PCR technique. Results We found a significant excess (8.2%) of GZ carriers compared with 5.2% in the control sample, with a P value of 0.009 for the difference in proportions. Conclusion FMR1 gray zone alleles are a significant risk factor for parkinsonism in females. These population data and occasional reports of FXTAS-like or parkinsonian manifestations in carriers suggest possible mechanisms whereby the effects of these alleles synergize with the existing pathologies underpinning parkinsonism. © 2018 International Parkinson and Movement Disorder Society.

Background: It is unclear to which degree Levodopa (L-dopa) remains effective also in the late stage of Parkinson's disease (PD) and to which degree motor fluctuations and dyskinesias remain a problem. Objective: To assess responsiveness of motor symptomatology to L-dopa in a group of patients with late stage PD. Moreover, to investigate the extent to which motor fluctuations and dyskinesias occur. Methods: Thirty PD patients in Hoehn and Yahr (HY) stages IV and V in "on" were included. L-dopa responsiveness was assessed with a standardized L-dopa test in the defined "off" and defined "on" states. Motor function was assessed by the Unified PD Rating Scale (UPDRS) III and timed tests. Motor fluctuations and dyskinesias were assessed by the UPDRS IV. The participants were further monitored for 10 days with a mobile movement-Analyses-system, the Parkinson's Kinetigraph (PKG). The median (q1-q3) L-dopa equivalent daily dose (LEDD) was 799 (536-973) mg. Results: The UPDRS III score improved with ≥15% in 15 (50%) and with ≥30% in six (20%) participants during the L-dopa test. The median (q1-q3) UPDRS III score in "off" was 46 (37-53) and in "on" 36 (28-46). Twenty-one (70%) of the participants reported either predictable or unpredictable "off" fluctuations (items 36-37). The prevalence of dyskinesias (item 32, duration of dyskinesias ≥1) was 47%. The PKG indicated that dyskinesias primarily were mild and that a majority had a pronounced "off" symptomatology, spending a large proportion of the day either asleep or very inactive. Conclusions: Half of a group of patients with late stage PD had an L-dopa response of ≥15% on the UPDRS III. According to the UPDRS IV, a majority of the patients had motor fluctuations and about half had dyskinesias, although the PKG results suggested that these were not very severe. (Less)

Macroautophagy/autophagy is the main intracellular catabolic pathway in neurons that eliminates misfolded proteins, aggregates and damaged organelles associated with ageing and neurodegeneration. Autophagy is regulated by both MTOR-dependent and -independent pathways. There is increasing evidence that autophagy is compromised in neurodegenerative disorders, which may contribute to cytoplasmic sequestration of aggregation-prone and toxic proteins in neurons. Genetic or pharmacological modulation of autophagy to promote clearance of misfolded proteins may be a promising therapeutic avenue for these disorders. Here, we demonstrate robust autophagy induction in motor neuronal cells expressing SOD1 or TARDBP/TDP-43 mutants linked to amyotrophic lateral sclerosis (ALS). Treatment of these cells with rilmenidine, an anti-hypertensive agent and imidazoline-1 receptor agonist that induces autophagy, promoted autophagic clearance of mutant SOD1 and efficient mitophagy. Rilmenidine administration to mutant SOD1G93A mice upregulated autophagy and mitophagy in spinal cord, leading to reduced soluble mutant SOD1 levels. Importantly, rilmenidine increased autophagosome abundance in motor neurons of SOD1G93A mice, suggesting a direct action on target cells. Despite robust induction of autophagy in vivo, rilmenidine worsened motor neuron degeneration and symptom progression in SOD1G93A mice. These effects were associated with increased accumulation and aggregation of insoluble and misfolded SOD1 species outside the autophagy pathway, and severe mitochondrial depletion in motor neurons of rilmenidine-treated mice. These findings suggest that rilmenidine treatment may drive disease progression and neurodegeneration in this mouse model due to excessive mitophagy, implying that alternative strategies to beneficially stimulate autophagy are warranted in ALS.

Traumatic brain injury results in devastating long-term functional damage due to the growth inhibition of the inflammatory response, and in particular, the complex response of astrocytes. Sustained, nonsteroidal anti-inflammatory approaches that can attenuate this response are of interest to improve therapeutic outcomes, particularly when combined with a tissue engineering construct that recapitulates the physiological microenvironment to facilitate functional repair. Here, we present a multifaceted, therapeutic extracellular-matrix mimic consisting of a coassembled scaffold with a laminin-inspired self-assembling peptide hydrogel, Fmoc-DIKVAV, and the anti-inflammatory macromolecule, fucoidan. At 7 days post-injury, our novel multicomponent hydrogel system presenting biologically relevant nanofibers and the anti-inflammatory fucoidan attenuated the primary glial scar to half that of a stab (control) injury. Further, the presentation of fucoidan increased the organization of astrocytes within the glial scar, while also significantly changing the morphology of astrocytes distal from the administered hydrogel and further into the parenchyma. This demonstrates that the anti-inflammatory fucoidan, present on the surface of the Fmoc-DIKVAV nanofibers, causes a change in astrocyte phenotype post-injury attenuating "reactive" astrocytosis. For the first time, we present a multicomponent tissue engineering construct to promote a growth-permissive environment

A longstanding obstacle to cancer eradication centers on the heterogeneous nature of the tissue that manifests it. Variations between cancer cell resistance profiles often result in a survival percentage following classic therapeutics. As an alternative, photodynamic therapys' (PDT) unique non-specific cell damage mechanism and high degree of application control enables it to potentially deliver an efficient treatment regime to a broad range of heterogeneous tissue types thereby overcoming individual resistance profiles. This study follows on from previous design, characterization and solubility analyses of three novel carbohydrate-ligated zinc-porphyrazine (Zn(II)Pz) derivatives. Here we report on their PDT application potential in the treatment of five common cancer tissue types in vitro. Following analyses of metabolic homeostasis, toxicity and cell death induction, overall Zn(II)Pz-PDT proved comparably efficient between all cancer tissue populations. Differential localization patterns of Zn(II)Pz derivatives between cell types did not appear to influence the overall PDT effect. All cell types exhibited significant disruptions to mitochondrial activity and associated ATP production levels. Toxicity and chromatin structure profiles revealed indiscernible patterns of damage between Zn(II)Pz derivatives and cell type. The subtle differences observed between individual Zn(II)Pz derivatives is most likely due to a combination of carbohydrate moiety characteristics on energy transfer processes and associated dosage optimization requirements per tissue type. Collectively, this indicates that resistance profiles are negated to a significant extent by Zn(II)Pz-PDT making these derivatives attractive candidates for PDT applications across multiple tissue types and subtypes.

While objective measurement is routine in clinical care of most conditions, this has not been the case for Parkinson's Disease. Recent innovations make objective measurement in Parkinson's Disease possible and its utility and how this should be assessed is discussed here. Areas covered: Whilst therapies are effective in Parkinson's Disease, symptoms fluctuate in relation to treatment over the course of the day. Objective measurement makes it possible to assess symptom control, whether treatment is required and whether it achieved control. Objective measurement makes it possible to consider targets for therapeutic control and to begin an assessment of the value of improved control. Evidence for the effect of improved measurement on outcomes is only beginning to emerge. As symptom severity relates to quality of life and costs, reducing clinical scores and fluctuations through objective measurement is in the interest of both the patient and the health system. Expert commentary: In broad terms objective measurement should be used to identify patients whose symptoms lie outside the target range and then to assess whether therapy was effective in bringing them into control. While this is relevant to all stages of Parkinson's Disease specific clinical situations where this had greatest impact are discussed.

Generation of new dopamine (DA) neurons in the adult midbrain is a controversial issue in development of better treatments for Parkinson's disease (PD). Previous research suggests Nestin-expressing neural precursor cells (NPCs) have a propensity to differentiate into neurons here, including DA neurons. In the present study we sought confirmation of this by studying gene expression in single Nestin-expressing cells and their progeny/ontogeny within the adult mouse midbrain. Cells were identified by administering a pulse of Tamoxifen to adult Nestin-CreERT2 × R26eYFP transgenic mice. Samples of cytoplasm were harvested 4 days to 8 months later from individual eYFP+ cells in acutely prepared midbrain slices and analysed by RT-qPCR for gene expression. Remarkably, most eYFP+ cells co-expressed genes associated with mature (including DA) neurons (i.e. NeuN, Gad1, Gad2, vGlut2, TH and/or D2R) and neurogenesis (i.e. Ki67, Dcx, Ncam, Pax6, Ngn2 and/or Msx1), and this was true at all time-points following Tamoxifen. Indeed, cell proliferation genes (Nestin, Ki67) were exclusively expressed by eYFP+ cells with mature neuronal morphology and gene expression, and only at early time-points after Tamoxifen. Expression of proneuronal genes (Pax6, Msx1, Ngn2) was, however, higher in eYFP+ cells with immature morphology compared with mature morphology. Gene expression bore no relationship to cell location indicating that, in contrast to development, Nestin-expressing cells arise throughout the midbrain parenchyma and do not migrate long distances. On the other hand, gene expression did change with time after Tamoxifen, although not in a way consistent with neurogenesis. Overall, our results suggest that Nestin expression in the adult midbrain occurs in mature neurons, casting doubt on the premise of neurogenesis from Nestin+ NPCs here.

The phenomenological effects of deep brain stimulation (DBS) on the self of the patient remains poorly understood and under described in the literature, despite growing evidence that a significant number of patients experience postoperative neuropsychiatric changes. To address this lack of phenomenological evidence, we conducted in-depth, semistructured interviews with 17 patients with Parkinson's disease who had undergone DBS. Exploring the subjective character specific to patients' experience of being implanted gives empirical and conceptual understanding of the potential phenomenon of DBS-induced self-estrangement. Our study concluded that (1) the more patients preoperatively felt alienated by their illness, the more they experienced postoperative self-estrangement, and (2) the notion of self-estrangement seems to exist in association with certain common qualitative characters, namely, loss of control, which reflects a deteriorative estrangement, and distorted perception of capacities, which reveals a ...

Continuous and objective assessment is essential for accurate monitoring of the progression of neurodegenerative conditions such as Friedreich ataxia. However, current clinical assessments predominantly rely on the ability of the affected individual to complete specific clinical tests which may not capture the intricate kinematic details associated with ataxia Moreover, such testing often consists of a level of subjectivity of the assessing clinician. In this paper, we propose an objective measuring instrument, in the form of a spoon, equipped with the Internet-of-Things (IoT) based system and relevant machine learning techniques to quantitatively assess impairment levels while engaged in routine daily activity. In a clinical study involving individuals diagnosed with Friedreich ataxia, movement patterns during a simulated eating task were captured and kinematic biomarkers were extracted that were consistent with the frequently-used clinical rating scales. Multivariate analysis of these biomarkers allows us to accurately classify individuals with Friedreich ataxia and control subjects to an accuracy of 91%. Furthermore, the kinematic information captured from the spoon can be used to introduce an alternative assessment scheme with a greater sensitivity to ataxic movements and with less inter-rater discrepancy.

Cerebellar Ataxia (CA) is a neurological condition that leads to uncoordinated muscle movements, even affecting the production of speech. Effective biomarkers are necessary to produce an objective decision-making support tool for early diagnosis of CA in non-clinical environments. This paper investigates the reliability and effectiveness of vocal tract acoustic biomarkers for assessing CA speech. These features were tested on a database consisting of 52 clinically rated tongue-twister phrase ’British Constitution’ and its 4 consonant-vowel (CV) excerpts /ti/, /ti/’, /tu/, /tion/ acquired from 30 ataxic patients and 22 healthy controls. Such a marker could be applied to objectively assess the severity of CA from a simple speaking test, contributing to the possibility of being translated into a computer based automatic module to screen the disease from the speech. All the vocal tract features explored in this study were statistically significant using Kolmogorov-Smirnov test at 5% level in distinguishing healthy and CA speech. Several machine learning classifiers with 5-fold cross-validations were implemented on the vocal features. It was observed that the intensity ratios corresponding to the 4 C-V excerpts in CA group showed an increased variability and produced the best classification accuracy of 84.6% using KNN classifier. Results motivate the use of vocal tract features for monitoring CA speech.

Upper limb impairment with various symptoms including incoordination, tremors and prolonged motion are important factors of motor disturbance in Cerebellar ataxia (CA). Accurate assessment is a key element in the diagnosis and progress monitoring of conditions such as CA. Often such assessments are mostly based on the observations of the clinicians and hence, are inherently subjective. In this paper, we propose a system that consists of two automated assessment schemes which employ a depth camera and an inertial measurement unit (IMU) sensor for the quantification of upper limb ataxia in the treatment of CA. The assessment includes an automated finger chase in which the patients were asked to follow a target point on the screen using their index finger and another assessment in which the patients were asked to tap their finger continuously on a surface at a comfortable rate. The overall system was tested for 44 CA patients and 14 age matched healthy individuals. The combination of features of the two tests provided us with an objective measurement which identifies CA patients to a higher degree of accuracy (Quadratic Discriminant Analysis, 93.1%) in addition to providing a high correlation (r = 0.8, p < 0.001) with the the Scale for the Assessment and Rating of Ataxia (SARA) based severity evaluation of patients.

In this study, we employed wearable sensor technology to identify the kinematic features that are associated with the gait abnormalities seen in cerebellar ataxia. Measurements were made at self-selected slow, preferred and fast walking speeds with three sensors attached to the participant’s body. Velocity irregularity and resonant frequency characteristics were identified as key features of interest concerning truncal and lower limb movements. Using the principal component analysis, differentiating features of both trunk and lower limb movements were combined to produce an enhanced distinction between the patients and the normal subjects, in addition to obtaining a better correlation with the expert clinician’s assessments. The different speed of walking contributed to separation and correlation with medical severity rating scales such as SARA to varying degrees The results of truncal movement in the medio-lateral plane (at the slow gait speed) and antero-posterior movement (at all 3 gait speeds) provided the effective metrics in the diagnosis and severity rating of ataxic gait of CA patients. Furthermore, from the selected dominant features of the trunk and lower limb, principal component description suggested that overall clinical assessments are predominantly influenced by the lower body peripheral movements particularly at higher walking speeds.