An Evaluation of KELVIN, an Artificial Intelligence Platform, as an Objective Assessment of the MDS UPDRS Part III

BACKGROUND: Parkinson's disease severity is typically measured using the Movement Disorder Society Unified Parkinson's disease rating scale (MDS-UPDRS). While training for this scale exists, users may vary in how they score a patient with the consequence of intra-rater and inter-rater variability. OBJECTIVE: In this study we explored the consistency of an artificial intelligence platform compared with traditional clinical scoring in the assessment of motor severity in PD. METHODS: Twenty-two PD patients underwent simultaneous MDS-UPDRS scoring by two experienced MDS-UPDRS raters and the two sets of accompanying video footage were also scored by an artificial intelligence video analysis platform known as KELVIN. RESULTS: KELVIN was able to produce a summary score for 7 MDS-UPDRS part 3 items with good inter-rater reliability (Intraclass Correlation Coefficient (ICC) 0.80 in the OFF-medication state, ICC 0.73 in the ON-medication state). Clinician scores had exceptionally high levels of inter-rater reliability in both the OFF (0.99) and ON (0.94) medication conditions (possibly reflecting the highly experienced team). There was an ICC of 0.84 in the OFF-medication state and 0.31 in the ON-medication state between the mean Clinician and mean Kelvin scores for the equivalent 7 motor items, possibly due to dyskinesia impacting on the KELVIN scores. CONCLUSION: We conclude that KELVIN may prove useful in the capture and scoring of multiple items of MDS-UPDRS part 3 with levels of consistency not far short of that achieved by experienced MDS-UPDRS clinical raters, and is worthy of further investigation

Examining evidence based resistance plus balance training in community-dwelling older adults with complex health care needs: Trial protocol for the Muscling Up Against Disability project

Available online 6 October 2016Abstract not availableJustin W.L. Keogh, Tim Henwood, Paul Gardiner, Anthony Tuckett, Brent Hodgkinson, Kevin Rous

Utilizzo di sensori inerziali indossabili nella valutazione motoria del paziente affetto da malattia di Parkinson: una Scoping Review

Background: la malattia di Parkinson è un disturbo neurodegenerativo che implica sia sintomi motori che non motori, invalidanti per la vita del paziente. Per ridurre l’impatto dei sintomi sulla qualità di vita è richiesta una complessa gestione della terapia, che si basa su un’accurata valutazione. Gli strumenti di valutazione sono molteplici, la necessità è quella di individuare metodi validi, accurati e rapidi. Obbiettivo: l’obbiettivo della presente scoping review è quello di indagare l’utilizzo di sensori inerziali indossabili nella valutazione dei sintomi motori di pazienti affetti da Malattia di Parkinson. Metodi: la ricerca è stata condotta sulle principali banche dati PubMed, PEDro, Cochrane Library. Gli studi integrati sono stati scelti sulla base di specifici criteri di inclusione ed esclusione. Non sono state applicate restrizioni riguardo alla tipologia delle pubblicazioni. Sono stati applicati limiti di lingua. Risultati: tramite il processo di identificazione degli studi sono stati individuati 1124 risultati. Gli studi inseriti nell’elaborato sono 25, pubblicati in un arco temporale compreso tra il 2012 e il 2023. Conclusioni: gli articoli presi in considerazione reputano i sensori inerziali indossabili come un valido strumento di valutazione dei sintomi motori. La limitazione nel numero di campioni e la scarsa diffusione nella pratica clinica li rendono parte di un campo di studi ancora in fase di sviluppo

Ambulatory monitoring of motor functions in patients with Parkinson's disease using kinematic sensors

Parkinson's disease (PD) is the second most common neurodegenerative disease in the general population. Cardinal symptoms of Parkinson's disease are resting tremor, rigidity, akinesia and bradykinesia and in advanced stages, gait impairments, postural instability and complications of chronic treatment with levodopa such as motor dysfunctions and dyskinesia. Multitude and complexity of these motor symptoms and their variability over the time have made assessment of them a difficult task. Moreover, following the fluctuations of motor performance (ON/OFF fluctuations) of the PD patients throughout their daily activities by quantifying their motor symptoms is a major challenge. The aim of this thesis was to design and validate a portable ambulatory movement analysis system for long-term monitoring and qualitative and quantitative assessment of motor abnormalities of PD patients during daily activities. We have designed a new measurement system consisting of five independent, lightweight, autonomous sensing units based on kinematic sensors that can continuously record body movements during daily life. Using this system and by performing several clinical studies, both in controlled conditions and on free moving patients, we have prepared a database of different movement patterns of PD patients. This database was the basis to design several new algorithms for the analysis of tremor, bradykinesia, gait and posture. An accurate algorithm based on spectral estimation has been proposed to detect and quantify tremor during daily activities of PD patients with a resolution down to three seconds using gyroscopes attached to the forearms. By quantifying the speed, range and the frequency of the movements, we have proposed a new method to assess the bradykinesia and tested it both in controlled and free conditions. We found out that in the free moving patients, the outcomes of this algorithm show significant and good correlation to the established clinical scores. Regarding the detection and analysis of gait, we have developed and tested a method based on four sensors attached to the lower limbs that provided spatio-temporal parameters of gait with good accuracy. We further improved our method using a new biomechanical model that could predict the movements of thighs from the movements of shanks during walking. This way we could reduce the number of sensor sites on the body while keeping the same accuracy in estimation of the spatio-temporal parameters of gait. By combining a statistical classifier, to detect transitions between sitting and standing postures, and a fuzzy classifier, to detect the basic body postures, we have developed an algorithm to classify basic body posture allocations both in PD patients and aged matched healthy subjects. Finally, while currently no other objective ambulatory method exists to accurately detect the periods of ON and OFF in PD patients, by combining the outcomes of the above algorithms (tremor, gait, bradykinesia and posture) using a statistical approach, we have proposed a method to detect periods of these two states with a resolution of 10 minutes in free moving patients. We believe that the proposed system has a high potential both for the clinical applications and research purposes related to the patient with Parkinson's disease and possibly other neurological movement disorders

PHARMACOKINETIC AND PHARMCODYNAMIC STUDIES OF APOMORPHINE IN THE TREATMENT OF IDIOPATHIC PARKINSON'S DISEASE

There were two aspects to the study of apomorphine in the treatment of Parkinson' s disease: (i) a clinical pharmacokinetic-pharmacodynamic (PK-PD) study was designed and implemented in response to the challenges of apomorphine dose-titration in Parkinson's disease, and in view of the scarcity of available literature on the PK-PD relationships of apomorphine in Parkinson's disease, (ii) the PK(and tolerability)of apomorphine dosing using novel delivery/formulation combinations were explored in view of the inherent limitations associated with the conventional (ie. subcutaneous) route of administration of apomorphine (e.g. cutaneous nodule formation, needle-phobia). An HPLC assay was developed for the quantification of apomorphine in plasma, and stability issues relating to sample storage and assay were investigated. With regards to the first aspect of the research, simultaneous PK-PD modelling was performed, using an effect compartment model to account for counterclockwise hysteresis in a sub-group of patients. According to the traditional two-stage approach to data analysis, mean (standard deviation) clearance following subcutaneous bolus was 2.2 (0.5) L/kg/h, (apparent) volume of distribution was 1.9 (0.8) L/kg, absorption half-life was 4.1 (2.1) minutes and elimination half-life was 69.5 (21.1)minutes (n=7). Equilibration half-life was estimated for two patients at 8.3 and 16.5 minutes. Focus was given to investigating the relevance of a potential correlation (which had previously been identified using in-house pilot data) between post-distributional apomorphine PK and apomorphine-induced anti-parkinsonian response in patients with Parkinson's disease. It was hypothesised that this particular correlation may be of use in a dose-optimisation scheme. However it was demonstrated that, in the patients studied, the concept could not be applied to apomorphine dose-optimisation. The novel delivery systems under scrutiny were: (i) Britaject® (Britannia Pharmaceuticals Ltd.) apomorphine formulation administered subcutaneously using a needle-free (jet) injector (J-TIP®, National Medical Products Inc.), (ii) an intranasal apomorphine powder formulation delivered using a turbospin insufflator (CDFS), and (iii) an apomorphine hydrogel co-polymer produced as a dosage-form for buccal delivery (Controlled Therapeutics (Scotland) Ltd.). As a result of this work, a rationale for subsequent development of the novel systems was provided. Indeed, the needle-free and buccal systems were, in their existing format, shown not to convey a net advantage over the existing system. However the intranasal formulation, with a mean (standard deviation) relative bioavailability of 41 (18)% (n=16) compared to subcutaneous bolus administration (and with a favourable outcome as regards to tolerability), was considered to be potentially suitable for further development

Physical activity in Parkinson’s disease : measurement, correlates and effects of balance training

Aim: The overall aim of this thesis was to investigate correlates of physical activity in older adults with Parkinson’s disease and to evaluate the effects, both short- and long term, of the HiBalance program on physical activity and sedentary. Further, to investigate the associated factors of a training effect on physical activity. To this end disease-specific physical activity estimates are needed. Methods: In Paper 1 accelerometer cut points for different walking speeds were defined. Thirty older adults with mild-to-moderate Parkinson’s disease walked at self-defined speeds of brisk, normal and slow speeds for three minutes in an indoor corridor. Walking speed was used as a reference measure, and cut points were generated using ROC curves. The cut points were cross-validated and Cohen´s quadratic weighted Kappa was calculated. In Paper II, correlates of both total physical activity and cut point-defined brisk walking were investigated by applying correlation analysis followed by multiple linear regression to accelerometer data. In Paper III, short- and long-term effects of the HiBalance program on physical activity and sedentary behavior were evaluated, using mixed analysis of variance and a multilevel model. Further, associated factors to a training effect on physical activity were investigated using a multiple linear regression. Results: Optimal cut points for the vertical axis were ≤328 and ≥730 counts / 15 seconds for walking speeds at ≤1.0 m/s and >1.3 m/s, respectively. Sensitivity ranged between 68-100 %, with specificity between 75-82 %, whilst validation and Kappa analysis showed 74% absolute agreement and a substantial agreement of κ = 0.79 (95% CI 0.70–0.89), respectively. Exploration of correlates of total physical activity and amount of brisk walking led to two linear regression models. Motor impairment, physical function, body mass index and dyskinesia were significantly associated with total physical activity, explaining 34% of the variance, whilst physical function and balance control were significant factors related to brisk walking, explaining 22% of variance. Short- and long-term effect analysis revealed that brisk walking was the only factor showing a significant interaction effect of group and time. Moreover, the effect on brisk walking dissipated 6 months after intervention. Analysis of the training effect on physical activity revealed that intervention group affiliation and spring season were significantly associated to an increase in brisk walking, while increased balance after training was not. Conclusion: This thesis provides cut points for physical activity measurement in older adults with Parkinson’s disease. Results also suggest that correlates of total physical activity and brisk walking differ, and evidence of factors not previously shown to be associated with PA in this population, is provided. Moreover, the HiBalance program leads to an increased amount of brisk walking in daily living, yet this increase is not linked to improved balance control. Also, clinicians should be aware of the seasonal effect on ambulatory activity in this population, and that the intervention effect dissipates after half a year, thereby warranting recurrent training

The role of somatosensory afferences in Parkinson's disease

Parkinson’s disease (PD) is the second most common neurodegenerative disorder in the world. The primary motor symptom of PD is bradykinesia, a slowing and reduction in amplitude of voluntary movement. Here, I aim to test some neurophysiological aspects of PD. Furthermore, I explored the possibility to develop non-invasive treatment for this group of patients. The first two studies tested the contribution of a specific phenomenon labelled sensory attenuation or sensory gating in the motor symptoms of PD, especially bradykinesia. I found that the sensory attenuation is abnormal in this group of patients. Especially, PD patients OFF medications showed a reduced sensory attenuation measured as the amplitude of the somatosensory evoked potentials. Interestingly, I found that the sensory attenuation was equal to the healthy age matched controls when the patients were tested in ON pharmacological state. Additionally, this research tested a theory of the functional role of sensorimotor beta oscillations that could explain beta power modulations in healthy subjects and the increase in beta power observed in PD patients. My results were in line with the previous data presented in the literature. Indeed, I found the increase beta power in both my two cohorts of PD patients. Finally, I tested a potential correlation between the abnormalities of these two phenomena in PD: reduced sensory attenuation and increased beta oscillations. I did not find any significant correlation between the two phenomena. They might be two different neurophysiological mechanisms 5 underlying this disease. However, further studies are necessary to investigate this hypothesis. Having tested the influence of the somatosensory signal in some motor symptoms, the second part of the thesis was focused on the development of non-invasive treatments of bradykinesia in PD. I tested the impact of vibratory stimuli to improve these motor signs. In particular, several frequencies of vibration have been tested through different devices applied to the wrist. The device was called “Emma watch” and I found that the application of vibration with the modulation of 60 bpm improved the bradykinesia in PD patients Finally, I presented a case study regarding the benefit of vibratory stimulation on the freezing of gait thought shoe insoles generating vibration. The tested patient showed an improvement of the frequency of the freezing episodes after a week wearing the insoles, which generated vibration at 200 Hz

Late onset depression: Association with clinical and imaging indicators of prodromal Parkinson’s disease

The pathology of late onset depression (LOD) is unclear, with vascular and structural abnormalities reported through the use of magnetic resonance imaging (MRI). Parkinson’s disease (PD) can be preceded by LOD several years before overt motor symptoms. Use of the Dopamine Transporter Single Photo Emission Computerised Tomography (DAT SPECT) has been approved by the Food and Drugs Administration (FDA) for imaging pre synaptic dopaminergic dysfunction; aiding diagnosis in disorders such as PD. We investigated; a) presence of early clinical features associated with PD in patients with LOD (pLOD), b) dopaminergic functioning in pLOD, c) structural and vascular pathology associated with LOD. This thesis also compared visual and semi quantitative analysis (SQA) methods when rating DAT SPECTs. When compared with healthy controls (HC) (n=30) overall, pLOD (n=36) scored significantly higher on symptoms of apathy, REM sleep behaviour disorder (RBD), sleep symptoms associated with PD and autonomic and motor dysfunction. Seven pLOD were visually rated with abnormal uptake in comparison to one HC, also confirmed by the SQA which additionally found that overall, pLOD (n=29 with a DAT SPECT) had significantly lower binding in the caudate nuclei (CN). The pLOD with visually abnormal SPECTs had significantly lower clinical scores relating to olfactory dysfunction, cognition and autonomic dysfunction compared to pLOD with normal SPECTs. There were no significant group differences in structural or vascular pathology. There were significant correlations between age and left and right hippocampi (HIPP) and amygdala (AMY) and global white matter (WM) and grey matter (GM) volumes in pLOD (n=28 with an MRI). Overall, in controls (n=25), age and gender correlated with global WM. Severity of depression was not associated with regional volumes. An audit of the correct use of clinical indications for the DAT SPECT at an NHS trust confirmed correct use in all cases (n=74) and a comparison of visual and SQA methods when rating DAT SPECTS in clinical cases also confirmed very good agreement between methods

Identification of biomarkers and modifiable risk factors for Parkinson's disease dementia

Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide and afflicts approximately 1% of individuals over age 65. The dementia that develops in association with PD is devastating to both the patient and their family and common, with more than 80% of individuals with PD developing dementia by 15 years after symptom onset. Current treatments for both PD and PD-dementia (PDD) have unacceptable side effects and there are no disease modifying therapies. An improved understanding of the pathophysiology of PD and PDD, however, is leading to testing of therapeutics that are targeted to specific pathways that have been implicated in PD pathophysiology. This pathophysiology is reviewed in Chapter 1, with an emphasis in the c-Abl molecule pathways role in PD pathophysiology. A biomarker for both PD and PDD would greatly improve our diagnosis, prognosis, and potentially the efficacy of these new treatment trials. Chapter 2 therefore considers whether poly (ADP-ribose), a molecule downstream in the c-Abl pathway, is a potential biomarker for PDD. Finally, we need to improve the outcomes for our current patients and Chapter 3 explores the role of a modifiable risk factor, namely vascular disease and subsequent vascular pathology, in the development of PDD. Together, these investigations broaden our understanding of PDD and are a step toward improved treatment for individuals with this devastating disease