The Effects of SNCA rs894278 on Resting-State Brain Activity in Parkinson’s Disease

The pathogenesis of Parkinson’s disease (PD) is not well established. The rs894278 polymorphism of SNCA has been associated with PD. We performed this study to investigate the relationship between rs894278 and PD status on resting-state brain activity, by analyzing the amplitude of low-frequency fluctuation (ALFF). A total of 81 PD patients and 64 healthy controls were recruited. Disease severity and PD stage were evaluated in PD patients using the unified Parkinson’s disease rating scale (UPDRS) and the Hoehn and Yahr (HY) scale, while the cognitive function of all participants was assessed using the mini-mental state examination (MMSE). All participants were genotyped for the rs894278 SNP and underwent a resting state functional magnetic resonance imaging scan. We found that the ALFF values of PD patients in the lingual gyrus and left caudate were lower than those of HCs; and the ALFF values for the right fusiform of participants with G allele were lower than those of participants without G allele. And we further revealed higher ALFF values in bilateral fusiform in rs894278-G carriers than in rs894278-G non-carriers in the PD group and lower ALFF values in bilateral fusiform in rs894278-G carriers than in rs894278-G non-carriers in the HC group. Our findings show that rs894278 and PD status interactively affect the brain activity of PD patients and HCs, and changes in the brain connectomes may play a key role in the pathogenesis of PD. Thus, our work sheds light on the mechanism underlying PD pathogenesis

Ruhenetzwerke von Parkinsonpatienten – Effekte der Dopamintherapie

Die Motivation der hier vorliegenden Studie war es, Ruhenetzwerke von Parkinsonpatienten mit der Elektroenzephalographie (EEG) auf einer globalen Hirnnetzwerkebene zu analysieren. Als übergreifendes Ziel der Arbeit galt der vertiefte Einblick in pathophysiologische Mechanismen und Effekte der dopaminergen Therapie. Dabei wurden im Einzelnen folgende Hypothesen untersucht: 1) Die Extraktion von Ruhenetzwerken in einem globalen Analyseansatz ohne a priori Annahmen wurde bislang für magnetenzephalographische (MEG) Daten demonstriert. Es wurde angenommen, dass sich dieser Ansatz auch auf EEG Daten übertragen lässt und robuste Ergebnisse generieren würde. 2) Das Verständnis von Morbus Parkinson geht über eine reine Bewegungsstörung weit hinaus. Als Ausdruck einer solchen globalen Neurodegeneration waren daher pathologische Netzwerkveränderungen im Vergleich von Patienten und Gesunden zu erwarten, die sich nicht nur auf motorische Netzwerke beschränken würden. 3) Die dopaminerge Therapie stellt unverändert den zentralen Baustein der Behandlung der Parkinsonerkrankung dar. Als Ausdruck der resultierenden klinischen Besserung waren auch auf der Netzwerkebene spezifische Therapieeffekte zu erwarten. Inwiefern dies durch Restitution physiologischer Netzwerkmuster oder Etablierung einer alternativen Netzwerkstruktur erfolgen würde, sollte näher untersucht werden. ad 1) In der Literatur mit funktioneller Magnetresonanztomographie (fMRT) gut untersuchte und als etabliert geltende Ruhenetzwerke konnten auch in den EEG Daten identifiziert werden. Dabei wurde die eigentliche Netzwerkextraktion mittels einer Independent Component Analysis (ICA) durch Lösung des inversen Problems im Quellenraum lokalisiert. So konnte neben der im EEG grundsätzlich guten zeitlichen Auflösung auch die räumliche Auflösung optimiert werden. ad 2) Bei den näher untersuchten Ruhenetzwerken ließen sich spezifische räumliche und frequenzbezogene Veränderungen feststellen, welche in die bestehende Forschungsliteratur eingegliedert werden konnten und gleichzeitig das Verständnis dieser Veränderungen erweiterten. Insbesondere für den Bereich von motorischen Arealen zeigte sich ein präzises pathologisches Korrelat im b-Frequenzband, was erneut die Schlüsselrolle von b-Oszillationen betonte. Desweiteren zeigten sich Veränderungen des Default Mode Network (DMN) und des visuellen Netzwerks mit aktuell unklarer klinischer Relevanz. ad 3) Im Bereich der motorischen Kortexareale zeigte das supplementär motorische Areal (SMA) im Sinne einer Restitution auf nahezu physiologische räumliche Netzwerkparameter unmittelbare Effekte der medikamentösen Therapie. Dies war im Einklang mit einer wachsenden Evidenz vor allem aus der fMRT Literatur. Als neuer Aspekt ergab sich nun der offenbar spezifische Effekt im g-Frequenzband

Neuroimaging studies of brain networks in Parkinson’s Disease

Parkinson’s disease (PD) is a common, disabling, neurodegenerative disease characterised by three core motor symptoms: tremor, rigidity and bradykinesia. These symptoms arise from degeneration of dopaminergic (DA) cells in the substantia nigra (SN) and the subsequent loss of dopaminergic terminals within the striatum, and circuits to cortical areas, critical in the control of movement. Other, non-DA systems are now known to be involved in the pathogenesis of PD, defective cognitive functions and side effects of DA medication treatments. Thus, the use of non-invasive in vivo techniques such as magnetic resonance imaging (MRI) has allowed a reliable, albeit in-direct method of assessing alterations in the PD brain. It is now widely considered that motor control is dependent upon the integrated operation of large-scale distributed brain networks. Recent methodological advances in MRI techniques allow both structural and functional connectivity between critical regions of motor control to be investigated and increase our understanding of the impact of PD pathology on motor networks and its subsequent effect on symptomatology. In this thesis, I present three studies that combine both structural and functional MRI techniques to assess the neural PD motor network and to test the general hypothesis that loss of effective motor control in PD arises from disrupted connectivity. I demonstrate in a sizable cross-sectional study that as disease burden increases, effective functioning in key motor areas and functional connectivity between regions in both the active and resting state is initially compromised but does show evidence of compensatory mechanisms. In addition, I show that compensatory mechanisms are likely to possess a neural reserve property rather than permit a period of normal functioning. Next, I present a follow-up study that assessed the active and resting neural motor network longitudinally. This study clearly shows that functional connectivity of the active and resting neural motor network is compromised as the disease progresses with evidence suggesting the initiation of compensatory mechanisms. Finally, structural properties of key regions related to PD pathology (substantia nigra and striatum) have been assessed to elucidate the effect of PD progression on diffusion indices and clinical symptoms. This work identifies the importance of multi-modal assessment of neural networks in PD to evaluate the effect of disease on neural motor control.Open Acces

MOOD SYMPTOMS IN PARKINSON’S DISEASE AND THEIR IMPACT ON A QIGONG EXERCISE’S EFFICACY FOR TREATING SLEEP QUALITY AND GAIT PERFORMANCE

The purpose of this study was to investigate both the non-motor features associated with Parkinson's disease (PD), i.e. anxiety and depression, and these features impact the efficacy of a mild exercise intervention treating sleep dysfunction and other non-motor symptoms, as well as a gait impairment. To determine the prevalence and comorbidity of depression and anxiety symptoms and their relationship with disease progression, a retrospective database analysis was performed using data collected during the routine evaluations of 1221 patients diagnosed with PD performed during the initial visit to a PD clinic. Given the discrepancy in previous estimates of mood symptoms in PD, it was hypothesized that 50% of the population would demonstrate anxiety or depression symptoms and that severity of these symptoms would correlate with overall disease severity. Anxiety and depression symptom severity was measured with respective Beck scales, while disease duration (years since PD diagnosis), Hoehn and Yahr (HY) stage, and Unified Parkinson's Disease Rating Scale (UPDRS) scores assessed modes of disease progression. Anxiety and depression were analyzed in categories of severity, prevalence, and strength of relationship with respect to disease progression markers using correlational analysis and chi-square tests. Results of the database analysis confirm previous findings that anxiety and depression are relevant non-motor symptoms of PD as well as the hypothesis, where more nearly half the sample population was determined to have significant depression while two-thirds reported anxiety symptoms. While the severity of mood symptoms was found to be worse in patients with greater disease progression, this relationship was found to be non-linear. A randomized controlled pilot clinical trial was then completed to assess the impact of mood disorders on the efficacy of a mild exercise intervention- Qigong meditation- on the non-motor symptoms of PD especially sleep quality, fatigue, and cognitive impairment, as well as gait performance. Previous studies have found that mood symptoms negatively affect adherence with interventions for treating symptoms of PD. In a previous pilot study conducted in our research laboratory the practice of Qigong meditation improved sleep, fatigue, cognition, as well as gait performance in PD; however, there was no control group and the sample size was small. We hypothesized that the current pilot study would find significant improvements in the experimental group compared to the control group and in terms of non-motor symptoms, especially sleep quality, and gait performance compared to the control groups, and that mood disorders in participants might decrease efficacy of the intervention. During six weeks of intervention, both a control and experimental group performed the mild/Qigong exercise twice daily in addition to a weekly group session. While both groups performed the same body motions of the exercise, only the experimental group synchronized their breathing, sounds, and meditation with the movements. Non-motor symptoms in PD were assessed using standard evaluations. The effect of mood symptoms on efficacy of the intervention was primarily measured by the rate of compliance demonstrated by study participants reporting a history of anxiety/depression. Based on a thorough examination of potential technologies for measuring gait pattern, A Gaitmat II device was selected and used to quantify gait velocity, stride time, stride and step length. As hypothesized, participants in the experimental group reporting a history of anxiety/depression reported lower overall compliance with the exercise program than fellow participants. Further, patients in the experimental group demonstrated significant improvement in sleep quality compared to the control group while both groups improved gait performance and some autonomic symptoms including urinary and sexual functioning. Fatigue also improved in the experimental group, though not comparatively significant. The study findings suggest the Qigong exercise may be a viable complementary therapy for treating both non-motor symptoms (NMS) and gait impairment of PD, especially sleep dysfunction. Further, mechanisms associated with the practice of Qigong may specifically slow, halt, or even reverse neurological damage associated with PD, given the neurodegenerative association with the PD symptoms improved in the study. Both the database analysis and pilot clinical trial suggest mood disorders are prevalent non-motor symptoms in PD, and that addressing these aspects is integral for providing adequate care to persons with PD and optimize the benefit of alternative therapies such as Qigong exercise in treating non-motor and motor features of the disease

Effectiveness of intensive physiotherapy for gait improvement in stroke: systematic review

Introduction: Stroke is one of the leading causes of functional disability worldwide. Approximately 80% of post-stroke subjects have motor changes. Improvement of gait pattern is one of the main objectives of physiotherapists intervention in these cases. The real challenge in the recovery of gait after stroke is to understand how the remaining neural networks can be modified, to be able to provide response strategies that compensate for the function of the affected structures. There is evidence that intensive training, including physiotherapy, positively influences neuroplasticity, improving mobility, pattern and gait velocity in post-stroke recovery. Objectives: Review and analyze in a systematic way the experimental studies (RCT) that evaluate the effects of Intensive Physiotherapy on gait improvement in poststroke subjects. Methodology: Were only included all RCT performed in humans, without any specific age, that had a clinical diagnosis of stroke at any stage of evolution, with sensorimotor deficits and functional gait changes. The databases used were: Pubmed, PEDro (Physiotherapy Evidence Database) and CENTRAL (Cochrane Center Register of Controlled Trials). Results: After the application of the criteria, there were 4 final studies that were included in the systematic review. 3 of the studies obtained a score of 8 on the PEDro scale and 1 obtained a score of 4. The fact that there is clinical and methodological heterogeneity in the studies evaluated, supports the realization of the current systematic narrative review, without meta-analysis. Discussion: Although the results obtained in the 4 studies are promising, it is important to note that the significant improvements that have been found, should be carefully considered since pilot studies with small samples, such as these, are not designed to test differences between groups, in terms of the effectiveness of the intervention applied. Conclusion: Intensive Physiotherapy seems to be safe and applicable in post-stroke subjects and there are indications that it is effective in improving gait, namely speed, travelled distance and spatiotemporal parameters. However, there is a need to develop more RCTs with larger samples and that evaluate the longterm resultsN/

Making it count : novel behavioural tasks to quantify symptoms of dementia with Lewy bodies

Dementia with Lewy bodies (DLB) is a neurodegenerative disease and a common cause of dementia in the elderly. The primary pathology of DLB is the mis-folding of the α-synuclein protein, classifying DLB as a synucleinopathy. However, concomitant pathologies are commonly found in post-mortem examination of DLB patients that may complicate diagnosis. Furthermore, DLB is a relatively new disease, first discovered in 1976, while the first official diagnostic criteria released in 1996. Consequently, the diagnostic criteria for DLB have evolved as more is learnt about the clinical and neuropathological profile. Synucleinopathies are also known to be heterogeneous, with no single symptom or biomarker present in all DLB cases. Instead, combinations of common symptoms lead to a diagnosis of probable DLB. Two of the most prominent and debilitating symptoms of DLB are visual hallucinations and cognitive fluctuations. Visual hallucinations (VH) in DLB patients are typically vivid, well-formed percepts and are a major cause of patient and caregiver stress as well as a risk factor for the patient being placed into professional care. Cognitive fluctuations (CF) involve a cycling change in attention and alertness and may occur on a daily or monthly basis, while drops in awareness may last seconds or hours. Currently, the only tools to measure cognitive fluctuations or visual hallucinations are scales or questionnaires that rely on responses from the patient or informant. Furthermore, severity of the symptom is then ranked on an arbitrary ranking system. While this method has advantages in a clinical setting, the subjective nature of the scales combined with the ranking of scores results in a loss of sensitivity. In a research setting, especially imaging or clinical trials, objective measures that are sensitive to changes in symptom severity are highly valued. This allows researchers to assess the relationship between behavioural and fMRI data and clinicians to observe subtle changes in severity. Furthermore, the measures need to be easy to conduct as patients are often severely impaired. The aim of this thesis is to test cognitive function using three paradigms that are novel to DLB patients: Sustained Attention Response Task (SART), the Mental Rotation (MR) task and the Bistable Percept Paradigm (BPP). Overall, this thesis provided the groundwork needed before these three tasks can be utilised in a clinical or research setting. Moreover, as each task was accessible to DLB patients and provided a measure associated with VH or CF, they may prove useful for future neuroimaging/neuropsychological studies

Aberrant Intrinsic Activity and Connectivity in Cognitively Normal Parkinson’s Disease

Disturbances in intrinsic activity during resting-state functional MRI (rsfMRI) are common in Parkinson’s disease (PD), but have largely been studied in a priori defined subnetworks. The cognitive significance of abnormal intrinsic activity is also poorly understood, as are abnormalities that precede the onset of mild cognitive impairment. To address these limitations, we leveraged three different analytic approaches to identify disturbances in rsfMRI metrics in 31 cognitively normal PD patients (PD-CN) and 30 healthy adults. Subjects were screened for mild cognitive impairment using the Movement Disorders Society Task Force Level II criteria. Whole-brain data-driven analytic approaches first analyzed the amplitude of low-frequency intrinsic fluctuations (ALFF) and regional homogeneity (ReHo), a measure of local connectivity amongst functionally similar regions. We then examined if regional disturbances in these metrics altered functional connectivity with other brain regions. We also investigated if abnormal rsfMRI metrics in PD-CN were related to brain atrophy and executive, visual organization, and episodic memory functioning. The results revealed abnormally increased and decreased ALFF and ReHo in PD-CN patients within the default mode network (posterior cingulate, inferior parietal cortex, parahippocampus, entorhinal cortex), sensorimotor cortex (primary motor, pre/post-central gyrus), basal ganglia (putamen, caudate), and posterior cerebellar lobule VII, which mediates cognition. For default mode network regions, we also observed a compound profile of altered ALFF and ReHo. Most regional disturbances in ALFF and ReHo were associated with strengthened long-range interactions in PD-CN, notably with regions in different networks. Stronger long-range functional connectivity in PD-CN was also partly expanded to connections that were outside the networks of the control group. Abnormally increased activity and functional connectivity appeared to have a pathological, rather than compensatory influence on cognitive abilities tested in this study. Receiver operating curve analyses demonstrated excellent sensitivity (≥90%) of rsfMRI variables in distinguishing patients from controls, but poor accuracy for brain volume and cognitive variables. Altogether these results provide new insights into the topology, cognitive relevance, and sensitivity of aberrant intrinsic activity and connectivity that precedes clinically significant cognitive impairment. Longitudinal studies are needed to determine if these neurocognitive associations presage the development of future mild cognitive impairment or dementia

System for the diagnosis and monitoring of coronary artery disease, acute coronary syndromes, cardiomyopathy and other cardiac conditions

Cardiac electrical data are received from a patient, manipulated to determine various useful aspects of the ECG signal, and displayed and stored in a useful form using a computer. The computer monitor displays various useful information, and in particular graphically displays various permutations of reduced amplitude zones and kurtosis that increase the rapidity and accuracy of cardiac diagnoses. New criteria for reduced amplitude zones are defined that enhance the sensitivity and specificity for detecting cardiac abnormalities

Neuroimaging of fetal cell therapy in Parkinson’s disease

Parkinson’s disease is the second most common neurodegenerative disease characterised by the elevated formation of α-synuclein-immunopositive intraneuronal proteinaceous inclusions (Lewy pathology) and the progressive loss of neuromelanin-laden dopaminergic cells of the substantia nigra pars compacta, resulting in the loss of striatal dopaminergic terminals and emergence of cardinal motor features including bradykinesia, rigidity, tremor and postural instability. Dopaminomimetic agents provide effective symptomatic relief in the early stages of illness, yet due to the inherently progressive nature of the disease and the induction of debilitating side effects their efficacy is eventually lost. Cellular restorative strategies involving intrastriatal transplantation of human fetal ventral mesencephalic (hfVM) tissue gained traction from the early 1990’s, when several multi-disciplinary teams reported drastic motoric improvements concomitant with graft-derived dopaminergic re-innervation. However, outcomes of double-blind randomised controlled trials and the presentation of novel dyskinetic movements persisting in the “off-state” called for substantial revision of cell delivery strategies. The current thesis utilises positron emission tomography to examine the effects of hfVM implantation under the Transeuro protocol on dopaminergic ([18F]FDOPA, [11C]PE2I) and serotonergic ([11C]DASB) systems in patients with Parkinson’s disease and elucidate the neural underpinnings of its clinical impact. The main findings are; 1) implanted hfVM tissue led to increases in putamenal dopamine synthesis and storage capacity, dopamine and serotonin transporter density as compared to non-transplanted patients; 2) modification to surgical procedures provided inhomogenous and inconsistent re-innervation; 3) hfVM transplantation was associated with clinical improvements in measures of bradykinesia, rigidity and tremor; 4) graft-related changes in posterior putamenal dopamine and serotonin transporter density predicted symptomatic relief of bradykinesia and tremor; 5) heterogeneity of posterior putamenal re-innervation may impact upon potential clinical benefit; 6) graft-induced dyskinesia was associated with greater post-operative increases in dopamine transporter expression in the anterior putamen; 7) there was no evidence that graft-induced dyskinesia was related to serotonergic hyperinnervation. The novel findings presented in this thesis have major implications for cell-based restorative strategies beyond the hfVM era and will likely foster informed [re]consideration of many aspects of therapeutic delivery and trial design. For its ability to provide mechanistic insight in vivo, neuroimaging may continue to play a central role in the optimisation of future interventions.Open Acces