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A common symptom of Idiopathic Parkinson’s disease (IPD) is decreased trunk and balance control. These deficits in patients with IPD are not treatable, and their underlying mechanisms are not well understood. Additionally, it is not known to what extent decreased trunk control contributes to postural instability in patients with IPD. Previous work by Martin (1965) observed that patients with post-encephalitatic Parkinson’s disease would fall in the direction of the tilt when perturbed while seated. In order to better understand the underlying causes of these observed trunk deficits and attempt to replicate Martins findings, this study investigated postural corrective movement of the trunk while seated in patients with IPD and age-matched healthy controls. Participants’ range of motion (ROM) was tested actively and passively while lying supine, following which, bilateral electromyography (EMG) (rectus abdominis (RA), external oblique (EO), and erector spinae (EST9, L3)) and 3-D kinematic measures were recorded while participants were seated on a modified chair and received unexpected perturbations, 7° at 40°/sec, in four different directions (forward, backward, left, and right). EMG responses were normalized to participant’s maximum voluntary contractions. We observed patients with IPD to have decreased active and passive ROM only in the frontal plane relative to controls. Patterning of muscle responses to rotational perturbations did not vary between groups in any direction, except backward, and trends toward significantly greater EST9 activity were observed during backward and left tilts in patients with IPD. Despite this both patients with IPD and controls were able to make appropriate trunk corrective movements opposite the direction of the tilt. However, two patients, who were most severely affected, did make incorrect trunk movements in the direction of the tilt during left and right tilting perturbations which, upon visual inspection, appear to be due to improperly modulated and timed muscle responses. Thus, our data counters the findings of Martin, and suggests the trunk is posturally stable in IPD. Therefore, balance instabilities during stance are likely due to improper responses of the lower limbs. However, as disease severity increases, the contributing influence of an improperly responding trunk may add to their postural deficits. / Education, Faculty of / Kinesiology, School of / Graduate

This thesis aimed to improve our understanding of prognosis in Parkinson's disease (PD) in terms of two imporatant outcomes: death and dependency. 88 studies were included in a systematic review of mortality in PD. Inception studies (recruiting patients at diagnosis) provided more consistent results than non-inception studies, with 50% higher mortality that in people without PD. Survival declined, on average, by 5% per year, but hospital-based studies consistently reported higher survival than community-based studies. 23 studies were included in a systematic review of activity limitation (difficulty with activities of daily living) and progression to dependency (the need for help with basic activities of daily living). Heterogeneity prevented quantitative analysis. Recommendations for future studies were developed. The rest of the thesis consists of analyses of the PINE study, a community-based, incident cohort of PD in North-East Scotland with 198 patients followed for up to 12 years. The mortality rate in PD was 8 per 100-person-years and was increased 1.5-fold compared to poulation mortality. Survival probabilities were lower than most previously reported. The rates of development of sustained dependency and "death or sustained dependency" were 14 and 16 per 100-person-years, respectively, in those independent at diagnosis. Older age, male gender, worse bradykinesia, more severe axial signs relative to limb signs, and higher co-morbidity (witih effect only early in the disease course) were independent baseline predictors of mortality in multivariable Cox regression. Increasing age, more smoking, worse bradykinesia, more axial signs relative to limb signs, and poorer cognitive function were independent baseline prognostic factors for both increased dependency and "death or dependency". These prognostic factors were combined into prognostic models for the three outcomes using Weibull parametric survival modelling and were internally vali There are several potential important uses for these models, in clinical practice and in research, subject to external validation.

Parkin gene is associated with the development of autosomal recessive juvenile parkinsonism (Kitada et al., 1998) which is a common form of familial Parkinson’s disease (Klein and Schlossmacher, 2006). Since Parkin has multiple cell protective effects, increasing the expression level of Parkin in the brain might be able to rescue cells in danger, which in turn might prevent or slow down the development of Parkinson’s disease (Ulusoy and Kirik, 2008). In order to increase Parkin expression, it is important to understand the transcriptional mechanisms regulating Parkin expression (Maston et al., 2006). Since human Parkin is very big (~1.4 Mb) (Asakawa et al., 2001), in this study we use the smaller Fugu parkin gene, which is an ortholog of human Parkin (Yu et al., 2005), to search for the transcriptional factors and signaling pathways regulating Parkin expression. We have cloned vertebrate constructs that allow for the monitoring of an entire genomic Fugu parkin gene tagged with a reporter (eGFP or luciferase) in mammalian cells; and have established cellular model for studying the expression. According to the “TRANSFAC” transcription factor database, as well as “TFBIND” and “TFSEARCH” softwares (Wingender et al., 1996; Heinemeyer et al., 1998; Heinemeyer et al., 1999; Tsunoda and Takagi, 1999; Akiyama 1995), potential Nrf2 binding sites are conserved in the promoters of mammalian parkin (including human Parkin and mouse parkin) and in Fugu parkin. In this study, we could not find a link between the presence of the potential Nrf2 binding site(s) in the parkin promoter and the up-regulation of parkin; and we could not find an association between the Nrf2 pathway activation and the induction of parkin under the specific experimental conditions.

The mechanisms by which Leucine-Rich Repeat Kinase-2 (LRRK2) mutations in humans are linked to the risk of Parkinson disease (PD), Crohn’s disease and leprosy remain elusive. We hypothesized a shared role for LRRK2 in immune system functions. I discovered robust LRRK2 expression in mammalian leukocytes, foremost within cells of the innate immune system. For example, human lymph nodes, spleen, and distal ileum exhibited abundant LRRK2-positive macrophages and granulocytes, findings that were confirmed by FACS of cells collected from the same organs of adult mice. Microscopy studies revealed robust LRRK2 reactivity in infiltrating, myeloperoxidase-positive granulocytes and CD68-positive macrophages in inflammatory conditions, such as viral encephalitis, idiopathic radiculitis, terminal ileitis and abscess formation. Analysis of midbrains from idiopathic versus genetic variants of Parkinson disease (PD) revealed rare, anti-LRRK2-positive reactivity that was confined to intravascular leukocytes. Neuronal LRRK2 signals were seen in forebrain regions, consistent with reports in the literature. To explore an immunological role for Lrrk2, we first examined bone marrow-derived macrophages from PD-linked R1441C knock-in mice and wild-type (WT) animals. Following stimulation with bacterial and viral pathogens, Lrrk2 expression was increased in cells from both genotypes. In subsequent in vivo experiments using an established, nasal inoculation model of newborn mice with a virulent microbe, we detected a role for WT Lrrk2 in modifying disease outcomes, such as after reovirus (type-3 Dearing) infection. There, Lrrk2 deficiency conferred increased vulnerability to elevated viral protein levels in the brain and greater mortality rates from encephalitis in mice. In contrast, we observed an initially protective role for the PD-linked G2019S mutant in the same reovirus inoculation model; there, lower viral titers were recorded in the lungs and brain of acutely infected, Lrrk2 knock-in mice at days 3 and 11 post-inoculation (dpi), respectively. Paradoxically, in related survival studies, we observed a significantly higher (rather than the expected reduced) mortality rate during the ensuing weeks in female mice that carried the G2019S Lrrk2 mutation. Related screening for cytokine dysregulation in infected tissues of mutant mice revealed significant changes in select signaling molecules, e.g., MIG and IP10. These collective results suggest a role for mammalian LRRK2 in the innate immune system following the encounter of a virulent pathogen, which is associated with a female sex bias. An early mechanistic clue points at changes in cytokine production by infected tissue, a second at the degradation efficiency of viral proteins. We speculate that LRRK2 alleles function in the regulation of the host’s innate response to invading pathogens, which may help explain its association with three human disorders, each of which is pathogenetically associated with one or more environmental trigger. Future studies will test LRRK2’s function in other infection paradigms, expand on mechanisms underlying genotype-dependent differences in inflammation, and determine the effects of LRRK2’s kinase inhibition in in vivo models.

Typical Parkinson’s Disease (PD) is a complex disease that arises from a combination of factors including genetics, environment, gene-environment interactions, sex and age. How these factors interact has yet to be elucidated. We have previously published roles for PD-linked genes in response to microbial infections in an effort to model gene-environment interactions in PD. Mutations in the GBA1 gene, encoding a protein that confers glucocerebrosidase (GCase) activity, represent the commonest risk factor for PD development. In the present study, we sought to understand the role of murine Gba1 in microbial infection. GCase activity was found to be sex- and organ-dependent in young adult mice carrying the p.D409V mutation. Mice carrying Gba1 p.D409V knock-in mutations did not show altered immune outcomes in response to Influenza virus H1N1, bacterial Salmonella typhimurium, or serial infections of the two. In response to Vesicular Stomatitis Virus (VSV), p.D409V mice survived at a higher rate overall compared to their wild type littermates, while homozygous males survived at a higher rate compared to wild type males in a sex-dependent manner. Heterozygous females had a lower viral load in the lung after VSV infection. GCase activity was found to be altered in VSV-infected p.D409V mice in a sex-and organ-dependent manner. Taken together, this study identifies a possible role for Gba1 in host response to an acute neurotropic infection and highlights the importance of exploring sex-dependent outcomes in Gba1-focused studies.

Thesis (Ph.D.)--Boston University / Parkinson disease (PD) is the second most common neurodegenerative disorder, affecting an estimated 2% of the population above 65 years of age. Although familial forms of PD have been linked to specific mutations responsible for the onset of the disease, the majority of PD cases is still of unknown etiology. PD has been traditionally studied using individual genetic methods, such as linkage analysis, genome-wide association (GWAS), or microarray expression studies. Nevertheless, the intrinsic disease genetic variability, and the unilateral analysis approach of available datasets made the detection of robust gene or pathway signals difficult. Studies of PD that combine a range of systems genetics approaches, and integrate complementary disease-relevant genetic datasets, represent a promising approach for accommodating prior inconsistent, as well as diverse results. To investigate the genetics of idiopathic PD, I performed the largest genome-wide expression study in brain tissue to date. The study was carried out on the 1-color Agilent 60-mer Whole Human Genome Microarray, and included 26 neurologically healthy control and 27 PD samples from the frontal cortex Brodmann 9 area (BA9). The selected brain samples were of high quality (high pH and RNA integrity, no significant signs of Alzheimer disease pathology), and had rich documentation of neuropathological and clinical information available. I analyzed the microarray expression results in combination with genotyping data for PD-associated single nucleotide polymorphisms obtained for the microarray brain samples, and detected a pathway of interest for PD involving the FOXO1 (Forkhead box protein O1) gene. This result was verified in additional publically available expression datasets. I then performed a network-based canonical pathway analysis of PD, combining results from available GWAS, microarray expression, and animal model expression studies. The used analysis framework was a human functional-linkage network (FLN), consisting of genes as nodes, and weighted links indicating the confidence of gene-pair involvement in similar biological processes. I demonstrated the relevance of the used FLN for studying PD. Additionally, I ranked genes and pathways based on the available disease datasets. The frontal cortex BA9 study, and an additional non-PD microarray study were used as the positive and negative controls, respectively, for the obtained results.

Thesis (Ph.D.)--Boston University / Although motor dysfunction in Parkinson's disease (PD) and memory deficits in Alzheimer's disease (AD) are the respective hallmark symptoms, both neurodegenerative disorders are also associated with significant disruptions in visual functioning. In PD, visuospatial function is impaired, particularly in patients with left-side onset of motor symptoms (LPD), reflecting pathology in right hemisphere brain regions, including the parietal lobe. LPD visuospatial performance is characterized by perceptual distortions, suggesting that lower-level visual processing may contribute to abnormal performance. In AD and PD, reduced contrast sensitivity and other visual difficulties have the potential to impact everyday functioning. The relation of PD visuospatial problems, and AD and PD contrast sensitivity deficits to higher-order impairments is understudied. The present experiments examined visual and visuospatial difficulties in these groups and evaluated an intervention to improve everyday visual function. Experiment I assessed performance on a line bisection task in PD. Participants included non-demented patients (10 LPD, 10 with right-side motor onset [RPD]) and 11 normal control adults (NC). Performance was related to data from measures of retinal structure (Optical Coherence Tomography) and function (Frequency Doubling Technology; FDT) across the eye. Correlations of structure and function were found for all groups. LPD showed predicted downward bisection bias in some sections of the left visual field. Expected rightward bisection bias in LPD was not consistently seen using this presentation method. For RPD, in some sectors, worse FDT sensitivity correlated with upward line bisection bias, as predicted. Experiment II investigated if performance of a complex, familiar visual search task (bingo) could be enhanced in AD and PD by manipulating the visual components of contrast, size, and visual complexity of task stimuli. Participants were 19 younger adults, 14 AD, 17 PD, and 33 NC. Increased stimulus size and decreased complexity improved performance for all groups. Increasing contrast also benefited the AD patients, presumably by compensating for their contrast sensitivity deficit, which was more severe than in the PD and NC groups. The general finding of improved performance across healthy and afflicted groups suggests the value of visual support as an easy-to-apply intervention to enhance cognitive performance.

Parkinson’s Disease (PD) is a devastating progressive neurodegenerative disorder second only to Alzheimer's disease in prevalence. Progression is insidious and PD symptomology manifests when approximately half of the DA neurons projecting from the substantia nigra pars compacta (SNpc) to the striatum are lost. PD is histologically characterized by the presence of intracytoplasmic inclusions primarily composed of hyper-phosphorylated and ubiquinated α-synuclein (SNCA), known as Lewy Bodies. Conserved LB pathology in α-synuclein and LRRK2 mediated disease suggests a common pathological pathway in disease progression. In order to address the potential disease-relevant nexus between these two proteins, we generated transgenic C. elegans lines co-expressing LRRK2 (pan-neuronal) and α-synuclein (dopaminergic neuron specific). We report increased and progressive DA-ergic neuron loss in nematodes co-expressing disease linked mutant LRRK2 and α-synuclein compared to nematode lines expressing only α-synuclein. Also, guided by previous CLR network analysis, we implicated mis-regulation of proteostasis machinery in disease progression by demonstrating differential effects of LRRK2 co-expressed with α-synuclein on macroautophagy in our nematode lines expressing LGG, a marker for autophagic flux. Our studies show overexpression of G2019S LRRK2 inhibits autophagy and accelerates age-related dopaminergic neuron toxicity whereas overexpression of WT LRRK2 does not. Cooverexpression of a-synuclein caused increased inhibition of autophagy and showed an increase in DA-ergic neuron degeneration. Although we have no concrete evidence of interaction, we suggest that LRRK2 demonstrates an agedependent interaction with a-synuclein, which potentiates degeneration of dopaminergic neurons.

Parkinson’s Disease (PD) is the second most common neurodegenerative disorder and has a rapidly increasing prevalence. It is characterized by motor deficits, primarily resting tremor, rigidity, postural instability, and bradykinesia, associated with the progressive loss of dopaminergic neurons and formation of Lewy bodies. Current pharmacological treatments address mainly the primary motor symptoms of the disease and do not provide protection against further neurodegeneration. Therefore, complementary interventions are examined for their potential role in reducing symptoms, both motor and non-motor, and rate of PD progression. The Mediterranean, ketogenic, and MIND diets are promising interventions that simulate fasting states, thereby inducing adaptive and protective cellular stress responses. The large quantities of foods high in antioxidants, anti-inflammatory effects, and healthy fats recommended by these diet plans may combat PD pathology, particularly neuroinflammation, oxidative stress, and mitochondrial dysfunction. Ketogenic diets, in addition, provide more efficient brain energy sources, in the form of ketone bodies, that may further curb effects of mitochondrial dysfunction. Fats, omega-3 fatty acids in particular, provide significant, clinically relevant neuroprotection from the disease and supplementation is recommended. PD patients, on average, have insufficient serum levels of certain vitamins which may contribute to PD progression. When supplemented in large amounts, these vitamins may have the opposite effect. Certain foods, such as dairy products, red meats, and highly processed foods, are associated with increased risk of PD and may be considered neurodegenerative. Sodas, especially diet sodas, are significantly correlated with more rapid disease progression and increased symptom severity. Physical activity is highly recommended for PD patients for its motor and non-motor benefits and neuroprotective roles. Among the most effective forms of PA are suggested to be aerobic exercise and progressive training programs. Consistent exercise is advised for consistent cognitive benefits and alleviation of other symptoms. The potential benefits of cognitive training for individuals with PD remain to be seen. Further research in all areas is needed to elucidate the most effective complementary interventions in combating PD.