The purpose was to investigate some aspects of epidemiology, risk factors and treatment with ECT in advanced Parkinson’s disease (PD). In study I, we performed a descriptive epidemiologic population-based survey in the Central Health Care District in Östergötland in south-east Sweden, with a population of almost 150,000 inhabitants 1989. The case finding was accomplished in three ways: 1. Collection of all prescriptions for Parkinson’s disease. 2. Search in medical files. 3. Checking with all nursing homes in the area. The crude prevalence was found to be 115 per 100,000 inhabitants. When we used the European Standard Population as a tool for easy comparisons of PD prevalence between different areas and time periods 76 PD-cases per 100,000 inhabitants were found. The corresponding incidences were 11.0 (crude) and 7.9 (age standardised) per 100,000 person-years. Mean age at onset was 65.6. A low prevalence and a high age at onset suggested that e.g. environmental factors could influence the occurrence of PD, and the results implies that only few such factors were present in the investigated area. The findings led to study II, a case-control study which investigated the possible impact of nutritional and environmental risk factors for idiopathic Parkinson’s disease (IP), including 113 cases and 263 control subjects. Dietary, drinking, and smoking habits, as well as previous occupation, were requested in a structured questionnaire. No increased risk was found for any of the nutrients. A reduced risk was found for coffee, wine, and spirits but also for broiled meat, smoked ham or meat, eggs, French loaf or white bread, and tomatoes. These findings could indicate an antioxidant effect. Frequency of preceding and present smoking was reduced in IP patients. Possible mechanisms are discussed. Various occupational groups and exposures were analysed and increased risks of IP in men were found for agricultural work, pesticide exposure, male carpenters, and in female cleaners. In advanced PD there is a need for further therapeutic improvements, and electroconvulsive therapy (ECT) is one insufficiently explored and evaluated method. In study III ECT 16 non-depressed, nondemented PD patients with advanced disease were treated with ECT. In all patients an antiparkinsonian effect of ECT was seen, lasting between a few days and 18 months. Five patients, all with signs of blood brain barrier damage, developed transitory mental confusion after ECT. The results indicated that ECT could cause increased dopaminergic activity, which led us to study IV. Single photon emission computed tomography (SPECT) with the cocaine analogue [123I]-β-CIT was used in order to visualise dopaminergic neurones in the brain. Six patients with PD were examined before and after a series of ECT, and in three cases SPECT was also repeated after one year. The side-to-side difference in the radiotracer uptake was found to be significantly lower in striatum located contralaterally to the part of the body with most pronounced symptomatology. No significant change in uptake of [123I]-β-CIT was seen after ECT, although all patients improved and the most pronounced improvement was seen in patients with less advanced PD. Study V points at two new positive observations with maintenance ECT (MECT). i.e. repeated ECT treatment of PD. One patient had either severe mental side effects on higher L-dopa doses or intolerable parkinsonian symptoms on lower doses. MECT implied marked improvement in parkinsonian symptoms without mental side effects. Another PD patient, who also had a mental depression, showed slight improvement of motor symptoms on a series of ECT. When treated with MECT further antiparkinsonian effects were seen. / On the day of the public defence the status of the article IV was: Submitted; articel V was: Accepted for publication after revision.

Background The last decade has witnessed a renaissance of functional stereotactic neurosurgery in the treatment of patients with movement disorders, especially advanced Parkinson’s disease (PD), essential tremor (ET) and dystonia. Ablative lesions such as thalamotomy and pallidotomy have been gradually replaced by the technique of chronic deep brain stimulation (DBS) applied to targets in the basal ganglia and thalamus, and assumed to be more lenient to the brain than stereotactic radiofrequency lesions. Since the aim of functional neurosurgery is to alleviate symptoms of these chronic, progressive, non-fatal diseases, and to improve life quality of the patients, it is imperative that the surgical procedures remain safe and do not result in complications mitigating any anticipated positive effect of the surgery on the symptoms of the disease. Aim The aim of this thesis is to evaluate, compare and analyse the safety of various surgical procedures used to treat patients with movement disorders, and to document side effects and complications both peri operatively and in a long term follow-up. Further to compare the effects of pallidotomy and pallidal DBS, and to evaluate the longterm efficacy of Vim-DBS. Method 256 consecutive surgical procedures, 129 DBS and 127 stereotactic lesions, were reviewed with respect to complications in 197 treated patients. In a series of 119 patients operated on with DBS during a 10 year period, the occurrence of hardware related complications (infection, breakage, erosion etc) was documented and analysed. Additionally, the interference of external magnetic field with the stimulation was documented. In one patient operated on with subthalamic nucleus DBS, a highly unusual and unexpected psychiatric side effect was carefully analysed. In 5 patients operated on with both methods (lesion and DBS) on each hemisphere, respectively, the effect and side effects of each method were compared. The long term effect and side effects of thalamic DBS was analysed in a series of patients with ET followed for 7 years. Results There were no deaths and few severe neurological complications in this material. Unilateral ablative lesions in the pallidum were well tolerated by patients with advanced PD, while for tremor, thalamic DBS was much safer than thalamotomy, even if its effect on certain aspects of tremor could show some decrease of efficacy over time. Some of the side effects of lesioning are transient while most but not all side effects of DBS are reversible. Hardware-related complications were not uncommon especially in the early “learning curve” period, and the DBS technique, being a life-long therapy, will necessitate a life long follow up of patients. Provided safety protocols are followed and provided patient’s and carer’s education and awareness, external electromagnetic interference should not constitute a risk for patients with DBS. PD patients undergoing STN DBS should be carefully selected to avoid psychiatric or cognitive side effects, due to this brain target´s proximity to, and involvment in, non-motor associative and limbic circuitry. Conclusions In terms of mortality and morbidity, modern stereotactic neurosurgery for movement disorders, both ablation and DBS, is a safe procedure even in advanced stages of disease. Symptoms of PD, ET and dystonia can be alleviated mainly with DBS and even unilaterally with pallidal lesions, at the expense of, in most cases, minor side-effects.

Although neurotransplantation of primary fetal cells into the striatum of patients with Parkinson’s disease (PD) has been reported to be effective, poor clinical outcome and severe side effects lower clinical long-term results. A major drawback of cell replacement therapies in PD is the low cell survival and lacking regeneration of the neuronal circuitries due to the ectopic transplantation of cells into the host striatum. More anatomic and functional integration could potentially be reached by an orthotopic cell transplantation into their natural position within the rostral mesencephalon at the site of the Substantia nigra, where dopaminergic cells get lost in PD. The aim of the thesis was to provide the scientific basis for the use of injectable bioscaffols containing chemo-attractants promoting cell survival, differentiation and axo-dendritic outgrowth of dopaminergic cells. With the so called “bridging” transplantation technology an artificial axon pathway between the substantia nigra and the striatum with targeted nigro-striatal re-innervation should be generated. Thereby, the central dopaminergic nigro-striatal pathway would be reconstructed enabling a fully integration of grafted neurons into the basal ganglia circuitries. The main focus of the thesis was to explore the influence of bioscaffolds on cell survival and morphology of dopaminergic neurons in vitro. The investigations included isolation of primary fetal mesencephalic cells and fetal mesencephalic neural stem cells (NSCs) from embryonic (E14) mouse brain and their culture on ECM compounds and starPEG-heparin hydrogels. Initial characterizations of the gels showed separate as well as simultaneous immobilization and release of growth factors demonstrating that hydrogels could serve as an efficient storage and delivery system for growth factors. The axo-dendritic outgrowth of dopaminergic cells including primary branching, total branching and neurite elongation; cell survival studies; cell type analysis and cell migration were analyzed by immunostaining. Both cell sources showed distinct growth properties depending on the stiffness of the gel material and the presence of biomolecules with increased cell survival by the presence of RGD and FGF-2 in the hydrogel independent of network characteristic. Moreover, the presence of RGD on hydrogels was found to initiate differentiation of NSCs, whereas FGF-2 bound to hydrogels was shown to promote the viability of undifferentiated cells. Additionally, survival and axo-dendritic outgrowth of dopaminergic cells were observed to be affected by the gel properties: RGD or FGF-2 modification of hydrogels with intermediate network density showed the best results for dopaminergic growth. With the addition of GDNF to hydrogels the total amount of cells decreased strongly by an equal quantity of dead cells compared to FGF-2 bound hydrogels. Furthermore, differential effects were found for the survival of different brain cells depending on the growth factor which is loaded. GDNF was found to increase the survival of astrocytes, whereas FGF-2 bound to gels stimulated the viability of oligodendrocyte precursor cells. No differential effects were found for the survival of NSCs and mature neuronal cells on GDNF or FGF-2 bound gels. By showing the penetration of primary fetal mesencephalic cells expressing MMPs as endogenous endopeptidases into MMP-cleavable hydrogels, the potential biodegradability of the starPEG-heparin hydrogels was demonstrated. Together the findings provide the in vitro proof-of-principle data for combining dopaminergic neurons or predopaminergic NSCs with biomaterials for reconstructing the central dopaminergic nigro-striatal pathway by the “bridging” transplantation strategy as an alternative transplantation approach in PD. Further studies should focus on three-dimensional cell culture studies using starPEG-heparin hydrogels with cleavable peptide sequences and their functionalization with gradients of axon guidance molecules to selectively promote dopaminergic outgrowth.

The main goal of this research is to provide a novel bioanalytical approach to better understand α-synuclein (AS) aggregation linked to Parkinson’s disease (PD) and characterize the implications of contributing factors such as the presence of metal ions and potential therapeutics that would inhibit or reverse AS fibrillation. Current bioanalytical techniques have reported the fibrillation process of AS however, the detection of prefibrillar formation or the nucleation phase of AS has yet to be characterized. This research aimed to address this issue and monitor the primary stages of AS fibrillation from natively soluble monomer to fibrillar aggregates. The electrochemical measurement of these processes utilized the intrinsic electroactivity of 4 tyrosine (Tyr) residues in AS observed at ~0.6 V (vs. Ag/AgCl) to monitor its early fibrillation kinetics. The research presented here provided valuable evidence of the conformational changes attributed to prefibrillar forms of AS.

The main goal of this research is to provide a novel bioanalytical approach to better understand α-synuclein (AS) aggregation linked to Parkinson’s disease (PD) and characterize the implications of contributing factors such as the presence of metal ions and potential therapeutics that would inhibit or reverse AS fibrillation. Current bioanalytical techniques have reported the fibrillation process of AS however, the detection of prefibrillar formation or the nucleation phase of AS has yet to be characterized. This research aimed to address this issue and monitor the primary stages of AS fibrillation from natively soluble monomer to fibrillar aggregates. The electrochemical measurement of these processes utilized the intrinsic electroactivity of 4 tyrosine (Tyr) residues in AS observed at ~0.6 V (vs. Ag/AgCl) to monitor its early fibrillation kinetics. The research presented here provided valuable evidence of the conformational changes attributed to prefibrillar forms of AS.

The purpose of this study was to investigate whether locomotor training, in the form of treadmill training, could ameliorate neurochemical changes and behavioural deficits in the 6-hydroxydopamine (6-OHDA) rat model of Parkinsons disease. It has been recently demonstrated that rehabilitative forelimb motor training can attenuate dopamine loss and some deficits in forelimb movements in this animal model. In addition, brief locomotor treadmill training has been shown to attenuate forelimb deficits in 6-OHDA treated rats. However, it is not known whether locomotor training could result in an amelioration of locomotor deficits in these animals. Rats were lesioned with 6-OHDA injected intracerebrally. Lesioned rats were randomly assigned to one of 3 groups: early treadmill trained, late treadmill trained and untrained. Animals in the treadmill groups were trained to trot on a moving treadmill for 2 x 20 minute sessions daily for 30 days, beginning either 24 hours or 7 days after 6-OHDA injection. Untrained animals were exposed to a stationary treadmill for the same time periods. All animals were assessed on their abilities to perform several behavioural tasks designed to test locomotor and forelimb movement abilities prior to 6-OHDA injection and again at 3 and 6 weeks post-injection. These tests included measurement of ground reaction forces during overground locomotion, paw placements during a ladder crossing task, forelimb useage during exploratory behaviour and ability to initiate forelimb stepping movements. In addition, assessments of dopamine depletion in the striatum were carried out first in vivo, by measuring apomorphine-induced rotations at 2 weeks post 6-OHDA injection, and subsequently by post-mortem analysis of dopamine levels in the striatum using HPLC at the conclusion of the study. Treadmill training resulted in attenuation of dopamine depletion compared to non-treadmill trained animals, as measured by both apomorphine injection and HPLC. However, treadmill training produced no difference in behavioural deficits on a variety of tests compared to untrained animals. In some cases, early treadmill trained animals tended to display more severe behavioural deficits compared to untrained animals. Late treadmill training had a similar but smaller effect compared to early treadmill training. We conclude that treadmill training does not ameliorate locomotor deficits, in the 6-OHDA model of Parkinsons disease, even though this same training results in attenuation of dopamine loss in the striatum.

The purpose of this thesis is to investigate the reaction to a purely unexpected slip during gait termination and subsequent experiences stopping on the slippery surface in participants who are young and healthy, older and healthy and who have Parkinson’s disease while on traditional dopamine-replacement medication. Gait termination requires control of the forward momentum of the body’s centre of mass (COM). This forward momentum must be dissipated and the COM held within a newly formed base of support. The challenge of stopping on a slippery surface involves maintaining stability while transitioning from steady-state locomotion to steady-state stance. Experience with a slippery surface changes postural and gait characteristics to diminish the perturbing effect of the slip. The magnitude of the slip response diminishes quickly as the movement becomes more efficient. Our investigations revealed a typical slip response to a purely unexpected slip during gait termination including a lowering of the COM, an increased muscular response to support the body, a shortened step and an arm raise. Knowledge of and experience with the slippery surface quickly changed the slip response to reduce the perturbing effect of the slip and also to increase the efficiency of the response while smoothly transitioning from steady-state locomotion to gait termination. Parkinson’s disease impairs balance control, the ability to switch between motor tasks and also to stop within two steps. The need for a voluntary change in motor programs along with difficulty stopping and increased instability makes gait termination a potentially difficult task for someone with Parkinson’s disease (PD). The participants with PD used a slower, safer strategy to stop on non-slippery surfaces to compensate for their instability compared to age-matched controls. When a slip was first introduced during gait termination, the participants with PD continued to be less stable in the plane of progression than the control group. Despite the instability, the PD group was still able to integrate a balance-correcting response into a voluntary gait termination program. The ability to generate adaptive strategies to integrate the balance-correcting response into a voluntary gait termination program over multiple trials does not appear to be affected by PD; both the control group and PD group showed behavioural modifications according to repeated exposures to the slippery surface. Although participants with PD seemed slightly less stable and walked slower, their behavioural adaptations were similar to the control group.

It is difficult to think of any activity that does not require some degree of turning. Despite the prevalence of turning in daily activities and the challenge it poses to mobility-impaired individuals such as those with Parkinson’s disease, there is far less known about the multi-segmental control of turning than the control of standing and straight walking especially in elderly individuals and patient populations. The purpose of this thesis was to examine the coordination of body segment reorientation in healthy older adults and people with Parkinson’s disease (PD) during on-the-spot turns when standing and turns initiated when walking. The coordination of body segments was examined for small and large magnitude turns in both populations. PD participants were examined when “off” and “on” dopamine-replacement medication to determine the effects of medication on multi-segmental coordination when turning. The effect of walking velocity on the multi-segmental coordination of turning also was examined in healthy elderly participants for three different walking velocities. This research revealed differences in coordination patterns for standing versus walking turns and for healthy older adults versus persons with PD. Healthy older adults reorient their head, shoulder, and pelvis in unison, followed by mediolateral foot displacement, during standing turns. This coordination pattern was observed for both small and large turns. By contrast, turns initiated by healthy older adults while walking displayed a top-down temporal sequence similar to that reported for healthy young adults, i.e., the head turns first, followed by the shoulder and pelvis, and finally mediolateral displacement of the foot. This is a robust behavior which was not affected by the magnitude of the turn or walking velocity. PD participants (“off” and “on” medication) displayed temporal coordination patterns similar to age-matched healthy older adults for both standing and walking turns. However, PD participants (“off” and “on” medication) differed from healthy older adults with respect to the velocity and magnitude of reorientation of body segments, i.e., spatial parameters of coordination. The peak angular velocity of each body segment was significantly smaller for PD participants than the healthy older adults during both standing and walking turns; this was observed for both small and large magnitude turns. The magnitude of reorientation of each body segment was measured at the onset of mediolateral foot displacement; this measure revealed significantly smaller head and shoulder rotations for PD participants versus healthy older adults during standing turns, but not walking turns. Medication had no significant effect on the temporal or spatial parameters of body segment coordination during standing and walking turns. Medication increased the magnitude of head turn during the 90° standing turns; however, the magnitude of head turn remained smaller than that of healthy older adults. Multi-segmental coordination patterns differ for turns performed when standing (on-the-spot turn) versus when walking. The temporal parameters of these coordination patterns are not influenced by the magnitude of the turn or the velocity of walking and remain intact in Parkinson’s disease. Parkinson’s disease modifies the spatial parameters of coordination; reducing the velocity and early magnitude of reorientation of each body segment. These spatial parameters are not affected by dopaminergic medication.

The purpose of this thesis is to investigate the reaction to a purely unexpected slip during gait termination and subsequent experiences stopping on the slippery surface in participants who are young and healthy, older and healthy and who have Parkinson’s disease while on traditional dopamine-replacement medication. Gait termination requires control of the forward momentum of the body’s centre of mass (COM). This forward momentum must be dissipated and the COM held within a newly formed base of support. The challenge of stopping on a slippery surface involves maintaining stability while transitioning from steady-state locomotion to steady-state stance. Experience with a slippery surface changes postural and gait characteristics to diminish the perturbing effect of the slip. The magnitude of the slip response diminishes quickly as the movement becomes more efficient. Our investigations revealed a typical slip response to a purely unexpected slip during gait termination including a lowering of the COM, an increased muscular response to support the body, a shortened step and an arm raise. Knowledge of and experience with the slippery surface quickly changed the slip response to reduce the perturbing effect of the slip and also to increase the efficiency of the response while smoothly transitioning from steady-state locomotion to gait termination. Parkinson’s disease impairs balance control, the ability to switch between motor tasks and also to stop within two steps. The need for a voluntary change in motor programs along with difficulty stopping and increased instability makes gait termination a potentially difficult task for someone with Parkinson’s disease (PD). The participants with PD used a slower, safer strategy to stop on non-slippery surfaces to compensate for their instability compared to age-matched controls. When a slip was first introduced during gait termination, the participants with PD continued to be less stable in the plane of progression than the control group. Despite the instability, the PD group was still able to integrate a balance-correcting response into a voluntary gait termination program. The ability to generate adaptive strategies to integrate the balance-correcting response into a voluntary gait termination program over multiple trials does not appear to be affected by PD; both the control group and PD group showed behavioural modifications according to repeated exposures to the slippery surface. Although participants with PD seemed slightly less stable and walked slower, their behavioural adaptations were similar to the control group.

It is difficult to think of any activity that does not require some degree of turning. Despite the prevalence of turning in daily activities and the challenge it poses to mobility-impaired individuals such as those with Parkinson’s disease, there is far less known about the multi-segmental control of turning than the control of standing and straight walking especially in elderly individuals and patient populations. The purpose of this thesis was to examine the coordination of body segment reorientation in healthy older adults and people with Parkinson’s disease (PD) during on-the-spot turns when standing and turns initiated when walking. The coordination of body segments was examined for small and large magnitude turns in both populations. PD participants were examined when “off” and “on” dopamine-replacement medication to determine the effects of medication on multi-segmental coordination when turning. The effect of walking velocity on the multi-segmental coordination of turning also was examined in healthy elderly participants for three different walking velocities. This research revealed differences in coordination patterns for standing versus walking turns and for healthy older adults versus persons with PD. Healthy older adults reorient their head, shoulder, and pelvis in unison, followed by mediolateral foot displacement, during standing turns. This coordination pattern was observed for both small and large turns. By contrast, turns initiated by healthy older adults while walking displayed a top-down temporal sequence similar to that reported for healthy young adults, i.e., the head turns first, followed by the shoulder and pelvis, and finally mediolateral displacement of the foot. This is a robust behavior which was not affected by the magnitude of the turn or walking velocity. PD participants (“off” and “on” medication) displayed temporal coordination patterns similar to age-matched healthy older adults for both standing and walking turns. However, PD participants (“off” and “on” medication) differed from healthy older adults with respect to the velocity and magnitude of reorientation of body segments, i.e., spatial parameters of coordination. The peak angular velocity of each body segment was significantly smaller for PD participants than the healthy older adults during both standing and walking turns; this was observed for both small and large magnitude turns. The magnitude of reorientation of each body segment was measured at the onset of mediolateral foot displacement; this measure revealed significantly smaller head and shoulder rotations for PD participants versus healthy older adults during standing turns, but not walking turns. Medication had no significant effect on the temporal or spatial parameters of body segment coordination during standing and walking turns. Medication increased the magnitude of head turn during the 90° standing turns; however, the magnitude of head turn remained smaller than that of healthy older adults. Multi-segmental coordination patterns differ for turns performed when standing (on-the-spot turn) versus when walking. The temporal parameters of these coordination patterns are not influenced by the magnitude of the turn or the velocity of walking and remain intact in Parkinson’s disease. Parkinson’s disease modifies the spatial parameters of coordination; reducing the velocity and early magnitude of reorientation of each body segment. These spatial parameters are not affected by dopaminergic medication.