How should we be using biomarkers in trials of disease modification in Parkinson’s disease?

The recent validation of the alpha synuclein seed amplification assay as a biomarker with high sensitivity and specificity for the diagnosis of Parkinson’s disease has formed the backbone for a proposed staging system for incorporation in Parkinson’s disease clinical studies and trials. The routine use of this biomarker should greatly aid in the accuracy of diagnosis during recruitment of Parkinson’s disease patients into trials (as distinct from patients with non- Parkinson’s disease parkinsonism or non- Parkinson’s disease tremors). There remain however further challenges in the pursuit of biomarkers for clinical trials of disease modifying agents in Parkinson’s disease, namely: optimising the distinction between different alpha synucleinopathies; the selection of subgroups most likely to benefit from a candidate disease modifying agent; as sensitive means of confirming target engagement; and in the early prediction of longer-term clinical benefit. For example; levels of cerebrospinal fluid proteins such as the lysosomal enzyme ß-glucocerebrosidase may assist in prognostication or allow enrichment of appropriate patients into disease modifying trials of agents with this enzyme as the target; the presence of coexisting Alzheimer disease like pathology (detectable through cerebrospinal fluid levels of Amyloid Beta-42 and tau) can predict subsequent cognitive decline; imaging techniques such as free-water or neuromelanin MRI may objectively track decline of Parkinson’s disease even in its later stages. The exploitation of additional biomarkers to the alpha synuclein seed amplification assay will therefore greatly add to our ability to plan trials and assess disease modifying properties of interventions. The choice of which biomarker(s) to use in the context of disease modifying clinical trials will depend on the intervention, the stage (at risk, premotor, motor, complex) of the population recruited and the aims of the trial. The progress already made lends hope that panels of fluid biomarkers in tandem with structural or functional imaging may provide sensitive and objective methods of confirming that an intervention is modifying a key pathophysiological process of Parkinson’s disease. However, correlation with clinical progression does not necessarily equate to causation and the ongoing validation of quantitative biomarkers will depend on insightful clinical-genetic-pathophysiological comparisons incorporating longitudinal biomarker changes from those at genetic risk with evidence of onset of the pathophysiology and those at each stage of manifest clinical Parkinson’s disease

Prospective Memory Impairment in Parkinson Disease without Dementia: Cognitive Mechanisms and Intervention

Cognitive impairment among non-demented individuals with Parkinson disease (PD) produces significant disability, reduced quality of life, and restricted participation. This dissertation will cover PD-related impairment in prospective memory, or the ability to remember to execute delayed intentions at the appropriate moment in the future. Prospective memory impairment in PD is increasingly recognized as a functionally and clinically relevant problem and viable target for cognitive intervention. To lay the groundwork for the development of effective interventions for prospective memory in PD, this dissertation examines the cognitive mechanisms underlying prospective memory impairment in PD and the potential of training in a targeted strategy to improve prospective memory in PD. Specifically, it focuses on the efficacy of an associative encoding strategy called implementation intentions for addressing PD-related deficits in prospective memory in a laboratory setting and as reported in everyday life. Results indicate that implementation intentions training holds promise for improving prospective memory in PD. A synthesis and analysis of the dissertation studies reveals avenues for future research that will bolster the scientific and clinical impact of this line of work

A Differential Deficit in Time- Versus Event-Based Prospective Memory in Parkinson\u27s Disease

Objective: The aim of the current study was to clarify the nature and extent of impairment in time- versusevent-based prospective memory in Parkinson’s disease (PD). Prospective memory is thought to involvecognitive processes that are mediated by prefrontal systems and are executive in nature. Given thatindividuals with PD frequently show executive dysfunction, it is important to determine whether theseindividuals may have deficits in prospective memory that could impact daily functions, such as takingmedications. Although it has been reported that individuals with PD evidence impairment in prospectivememory, it is still unclear whether they show a greater deficit for time- versus event-based cues. Method:Fifty-four individuals with PD and 34 demographically similar healthy adults were administered astandardized measure of prospective memory that allows for a direct comparison of time-based andevent-based cues. In addition, participants were administered a series of standardized measures ofretrospective memory and executive functions. Results: Individuals with PD demonstrated impairedprospective memory performance compared to the healthy adults, with a greater impairment demonstratedfor the time-based tasks. Time-based prospective memory performance was moderately correlatedwith measures of executive functioning, but only the Stroop Neuropsychological Screening Test emergedas a unique predictor in a linear regression. Conclusions: Findings are interpreted within the context ofMcDaniel and Einstein’s (2000) multiprocess theory to suggest that individuals with PD experienceparticular difficulty executing a future intention when the cue to execute the prescribed intention requireshigher levels of executive control

Event-related potentials and cognition in Parkinson's disease: An integrative review

Cognitive impairment is a common non-motor symptom of Parkinson’s disease (PD), but the nature of cognitive changes varies considerably between individuals. According to the dual-syndrome hypothesis, one cluster of patients is characterized by deficits in executive function that may be related to fronto-striatal dysfunction. Other patients primarily show non-frontal cognitive impairments that progress rapidly to PD dementia (PDD). We provide a comprehensive review of event-related potential (ERP) studies to identify ERP measures substantiating the heterogeneity of cognitive impairment in PD. Our review revealed evidence for P3b and mismatch-negativity alterations in PDD, but not in non-demented PD, indicating that alterations of these ERPs constitute electrophysiological markers for PDD. In contrast, ERP correlates of executive functions, such as NoGo-P3, N2, and error(-related) negativity (Ne/ERN), appear to be attenuated in non-demented PD patients in a dopamine-dependent manner. Hence, ERP measures confirm and yield distinct electrophysiological markers for the heterogeneity of cognitive impairment in PD. We discuss limitations and open questions of the ERP approach and provide directions and predictions for future ERP research

Neural Correlates of Parkinsonian Syndromes

The thesis investigated objective neuroimaging biomarkers in parkinsonian syndromes, which could be applied to increase diagnostic accuracy. To find convergence of the literature concerning disease-specific patterns in Parkinson’s disease and progressive supranuclear palsy, we conducted meta-analyses. In Parkinson’s disease glucose hypometabolism was re- vealed in bilateral inferior parietal cortex and left caudate nucleus and focal gray matter atrophy in the middle occipital gyrus. In progressive supranu- clear palsy we identified gray matter atrophy in the midbrain and white mat- ter atrophy in the cerebral/cerebellar pedunculi and midbrain. In sum, in Parkinson’s disease hypometabolism outperforms atrophy and in progres- sive supranuclear palsy we validated pathognomonic markers as disease- specific. Our studies create a novel framework to investigate disease- specific regional alterations for use in clinical routine. Further, we inves- tigated neural correlates by voxel-based morphometry and discriminated disease and clinical syndrome by multivariate pattern recognition in sin- gle patients with corticobasal syndrome and corticobasal syndrome with a unique syndrome - alien/ anarchic limb phenomenon. We found gray matter volume differences between patients and controls in asymmetric frontotem- poral/ occipital regions, motor areas, and insulae. The frontoparietal gyrus including the supplementary motor area contralateral to the side of the af- fected limb was specific for alien/ anarchic limb phenomenon. The predic- tion of the disease among controls was 79.0% accurate. The prediction of the specific syndrome within a disease reached an accuracy of 81.3%. In conclusion, we reliably classified patients and controls by objective pattern recognition. Moreover, we were able to predict a specific clinical syndrome within a disease, paving the way to individualized disease prediction.:SELBSTSTÄNDIGKEITSERKLÄRUNG I ACKNOWLEDGMENTS II SUMMARY III ZUSAMMENFASSUNG VIII BIBLIOGRAPHISCHE DARSTELLUNG XIV CONTENTS XVI 1 GENERAL INTRODUCTION 1 1.1 ParkinsonianSyndromes .................... 2 1.2 Parkinson’sDisease ....................... 2 1.2.1 DiagnosticCriteria .................... 3 1.3 ProgressiveSupranuclearPalsy ................ 4 1.3.1 DiagnosticCriteria .................... 5 1.4 CorticobasalDegeneration ................... 5 1.4.1 DiagnosticCriteria .................... 7 1.5 ImagingBiomarkers ....................... 7 1.6 CurrentThesis .......................... 9 1.6.1 MotivationandFramework ............... 9 1.6.2 ResearchQuestions................... 9 2 GENERAL MATERIALS AND METHODS 12 2.1 MagneticResonanceImaging.................. 12 2.2 AnalyticalMethods........................ 13 2.2.1 Meta-Analysis ...................... 13 2.2.2 Voxel-BasedMorphometry ............... 14 2.2.3 Support-Vector Machine Classification . . . . . . . . . 15 2.3 Multi-CentricData ........................ 16 2.4 ClinicalAssessment ....................... 17 3 Study 1 4 Study 2 5 Study 3 6 Study 4 7 Study 5 8 DISCUSSION 73 8.1 MainFindings........................... 73 8.2 Statistical Approaches to Find Imaging Biomarker . . . . . . 76 8.3 Brain Alterations and their Utility as Imaging Biomarker . . . . 77 8.4 Limitations ............................ 78 8.5 Contributions of the Current Thesis and Future Directions . . 79 9 REFERENCES APPENDIX XVIII LIST OF AUTHORSHIP XXVII CURRICULUM VITÆ XXXVII

Free-living monitoring of Parkinson’s disease: lessons from the field

Wearable technology comprises miniaturized sensors (e.g. accelerometers) worn on the body and/or paired with mobile devices (e.g. smart phones) allowing continuous patient monitoring in unsupervised, habitual environments (termed free-living). Wearable technologies are revolutionising approaches to healthcare due to their utility, accessibility and affordability. They are positioned to transform Parkinson’s disease (PD) management through provision of individualised, comprehensive, and representative data. This is particularly relevant in PD where symptoms are often triggered by task and free-living environmental challenges that cannot be replicated with sufficient veracity elsewhere. This review concerns use of wearable technology in free-living environments for people with PD. It outlines the potential advantages of wearable technologies and evidence for these to accurately detect and measure clinically relevant features including motor symptoms, falls risk, freezing of gait, gait, functional mobility and physical activity. Technological limitations and challenges are highlighted and advances concerning broader aspects are discussed. Recommendations to overcome key challenges are made. To date there is no fully validated system to monitor clinical features or activities in free living environments. Robust accuracy and validity metrics for some features have been reported, and wearable technology may be used in these cases with a degree of confidence. Utility and acceptability appears reasonable, although testing has largely been informal. Key recommendations include adopting a multi-disciplinary approach for standardising definitions, protocols and outcomes. Robust validation of developed algorithms and sensor-based metrics is required along with testing of utility. These advances are required before widespread clinical adoption of wearable technology can be realise

Predicting cognitive impairment in Parkinson's disease using neurophysiology and biochemical parameters as biomarkers

PhD ThesisParkinson’s disease (PD) is a common neurodegenerative condition with multiple associated non-motor symptoms. Of these, dementia is a frequent debilitating complication of the disorder, with significant morbidity and mortality. Some forms of mild cognitive impairment in PD (PD-MCI) may represent a pre-dementia state and certain clinical, laboratory and neurophysiological parameters may increase the accuracy of prediction of cognitive decline. If validated, these markers would offer the opportunity for disease modification and therapeutic intervention at a critical early stage of the illness, when the viable neuronal population is greater. The key aim of this thesis was to characterise cognitive impairment in PD in a cohort of newly diagnosed cases, and evaluate how a panel of biomarkers correlated with cognitive phenotypes to predict risk of future cognitive decline. The main findings were that PD-MCI was common, and was associated with a distinct clinical phenotype. Memory impairment was the most common single domain affected, although the majority of those with PD-MCI were classified as nonamnestic single domain subtype. A significant correlation was found between pattern recognition memory, sensitive to temporal lobe impairments, and cerebrospinal amyloid-β 1-42 levels, thought to represent amyloid-β metabolism and deposition Both amyloid-β 1-42 and 1-40 levels were significantly lower in those with impaired cognition. In addition, short latency afferent inhibition, a neurophysiological in vivo non-invasive measurement of cholinergic function, was also reduced in participants with mild cognitive impairment. These findings suggest that cholinergic dysfunction and amyloid deposition may contribute to the underlying pathophysiology of early PD- MCI. The major conclusion from this thesis is that PD-MCI is heterogeneous and more frequent than previously reported in early disease. This is associated with abnormalities of amyloid processing and cholinergic dysfunction, and may highlight those at risk of developing dementia. Longitudinal assessment of these individuals will enable us to determine and better model those measures predictive of cognitive decline at an early disease stage.Parkinson’s UK, The Michael J Fox Foundation, Newcastle University Lockhart Fun

The Influence of Plantar Cutaneous Stimulation on a Functional Test of Gait in Parkinson’s Disease

Although possible deficits in proprioception have been implicated as a cause of gait impairments in individuals with Parkinson’s disease (PD), little research has been done to investigate improving this possible deficit as a method to influence mobility. The overall purpose of the current thesis was to investigate the influence of increased plantar stimulation on stability and gait impairments. This study also investigated the contribution of attention to locomotion in PD. The two studies comprising this thesis addressed the possible influence of the ribbed insoles in the initial response of PD participants as well as the long-term use of the insole. The first study focused on developing a task to assess the influence of the facilitatory insoles on gait for individuals with PD compared to healthy control participants. For the purpose of evaluating the facilitatory insoles in a functionally relevant task participants performed a modified “Timed Up and Go” task with an additional secondary motor task. The secondary task of carrying a tray with glasses demonstrated that attention plays a large role in the production and maintenance of gait as gait deficits became more pronounced. However, the facilitatory insoles also influenced gait parameters which demonstrated that the possible deficits in proprioception contribute to the gait impairments in PD. The initial response to the insoles, in the first study, did not improve gait parameters, which suggests that PD participants may need more time to adjust to the increased plantar stimulation. The second study investigated the influence of the facilitatory insoles when they are worn for a longer period of time. Participants wore either the facilitatory insoles or blank insoles while completing the PD Sensory Attention Focussed Exercise (PD SAFEx) rehabilitation program. Results demonstrated that when the facilitatory insoles are worn long-term, they can benefit the turning and straight-line walking in individuals with PD. PD participants became more confident in their ability to turn as they exerted less control over their centre of mass. Participants also displayed a decreased base of support and time spent in double limb support without negatively affecting lateral stability. These improvements suggest that the facilitatory insoles, when worn long-term, allow for a more normalized pattern of gait for individuals with PD. The TUG task used in this thesis proved to be a good measure to evaluate changes in stability and gait parameters in PD participants. Long-term use of the facilitatory insoles demonstrated improvements in stability and gait deficits during difficult aspects of gait such as turning. This suggests that the facilitatory insoles would be a simple and effective intervention to use, however further investigation should occur to ensure that the improvements will continue when facilitatory insoles are used on a daily basis. As well, investigation into the long-term use of other types of cutaneous stimulation such as vibratory insoles would be beneficial for the PD population

Neuropsychiatric and cognitive symptoms in Parkinson’s disease: the contribution to subtype classification, to differential diagnosis, their clinical and instrumental correlations

Il piano di ricerca è volto ad approfondire il contributo dei sintomi neuropsichiatrici e cognitivi nelle diverse fasi della Malattia di Parkinson (MP). In particolare, l’argomento di studio è focalizzato sull’analisi dei sintomi cognitivi e neuropsichiatrici nella MP, affrontando queste tematiche anche mediante l’utilizzo di tecniche di neuroimaging, in pazienti drug-naïve, in fase precoce di malattia ed in fase avanzata. Nei pazienti drug-naïve, la ricerca è stata finalizzata alla caratterizzazione dei sintomi neuropsichiatrici e cognitivi nei sottotipi motori (i.e., tremorigeni vs acinetico-rigidi) e rispetto alla lateralità di esordio degli stessi (i.e., lateralità destra vs lateralità sinistra). Nei pazienti in fase precoce di malattia, è stato indagato il contributo dei sintomi neuropsichiatrici e cognitivi nella diagnosi differenziale tra MP e Paralisi Sopranucleare Progressiva (PSP) in pazienti valutati entro i 24 mesi dall’esordio motorio, finestra temporale in cui spesso si assiste ad un overlapping dei sintomi motori. Nei pazienti in fase avanzata di malattia, la ricerca è stata finalizzata alla caratterizzazione, mediante i sintomi neuropsichiatrici e cognitivi, del Gioco D’Azzardo Patologico (gambling) rispetto agli altri tipi di Disturbi del controllo degli Impulsi (ICDs). Ancora nell’ambito dell’ICDs, è stato sviluppato uno studio di neuroimaging, volto ad identificare i correlati morfostrutturali (spessori corticali e volumi dei nuclei sottocorticali) di tali disturbi. Infine, si sono identificati i sintomi neuropsichiatrici e cognitivi che possono impedire l’esecuzione di un esame di Risonanza Magnetica (RM), al fine, in ambito clinico, di preparare adeguatamente all’esame i pazienti più a rischio di mancato svolgimento e con l’intento di indagare, in ambito di ricerca, la reale rappresentatività campionaria dei pazienti inseriti in studi di RM

Predicting Progression in Parkinson's Disease Using Baseline and 1-Year Change Measures.

BackgroundImproved prediction of Parkinson's disease (PD) progression is needed to support clinical decision-making and to accelerate research trials.ObjectivesTo examine whether baseline measures and their 1-year change predict longer-term progression in early PD.MethodsParkinson's Progression Markers Initiative study data were used. Participants had disease duration ≤2 years, abnormal dopamine transporter (DAT) imaging, and were untreated with PD medications. Baseline and 1-year change in clinical, cerebrospinal fluid (CSF), and imaging measures were evaluated as candidate predictors of longer-term (up to 5 years) change in Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) score and DAT specific binding ratios (SBR) using linear mixed-effects models.ResultsAmong 413 PD participants, median follow-up was 5 years. Change in MDS-UPDRS from year-2 to last follow-up was associated with disease duration (β= 0.351; 95% CI = 0.146, 0.555), male gender (β= 3.090; 95% CI = 0.310, 5.869), and baseline (β= -0.199; 95% CI = -0.315, -0.082) and 1-year change (β= 0.540; 95% CI = 0.423, 0.658) in MDS-UPDRS; predictors in the model accounted for 17.6% of the variance in outcome. Predictors of percent change in mean SBR from year-2 to last follow-up included baseline rapid eye movement sleep behavior disorder score (β= -0.6229; 95% CI = -1.2910, 0.0452), baseline (β= 7.232; 95% CI = 2.268, 12.195) and 1-year change (β= 45.918; 95% CI = 35.994,55.843) in mean striatum SBR, and 1-year change in autonomic symptom score (β= -0.325;95% CI = -0.695, 0.045); predictors in the model accounted for 44.1% of the variance.ConclusionsBaseline clinical, CSF, and imaging measures in early PD predicted change in MDS-UPDRS and dopamine-transporter binding, but the predictive value of the models was low. Adding the short-term change of possible predictors improved the predictive value, especially for modeling change in dopamine-transporter binding