Laterality of Motor Symptom Onset, Disease Progression, and Cognition in Parkinson's Disease

The current study examined whether laterality of initial motor symptom onset (left-sided onset vs. right-sided onset) in Parkinson's disease (PD) would predict the pattern and/or severity of cognitive deficits measured at various stages of disease progression. We evaluated the relationship between initial motor presenting symptoms obtained at the time of PD diagnosis and current cognitive profiles across three different patient groups (early unilateral, late unilateral, late bilateral stages of PD). Findings lend some support for study hypotheses regarding a lateralization of cognitive deficits based on initial laterality of motor symptoms. That is, right-sided motor symptom onset in PD was associated with diminished performance on left hemisphere cognitive measures, but the data did not reveal a significant relationship between left-sided motor symptom onset and impairment on right hemisphere measures. The current study also revealed cognitive deficits consistent with hypothesized effects of disease progression, such that cognitive changes during the unilateral stages of PD seem restricted to executive dysfunction, whereas bilateral disease in PD (with greater than 5 years disease duration) is associated with more widespread cognitive decline

Voice tremor in Parkinson's disease (PD) :identification, characterisation and relationship with speech, voice and disease variables

Phd ThesisVoice tremor is associated with Parkinson’s disease (PD), however little is known about the precise characteristics of PD voice tremor, optimum methods of evaluation or possible relationships with other speech, voice, and disease variables. The question of possible differences between voice tremor in people with PD (pwPD) and neurologically healthy ageing people has not been addressed. Thirty pwPD ‘off-medication’ and twenty eight age-sex matched neurologically healthy controls were evaluated for voice tremor features using acoustic measurement, auditory perceptual voice rating, and nasendoscopic vocal tract examination. Speech intelligibility, severity of voice impairment, voice disability and disease variables (duration, disability, motor symptom severity, phenotype) were measured and examined for relationship with acoustic voice tremor measures. Results showed that pwPD were more likely to show greater auditory perceived voice instability and a greater magnitude of frequency and amplitude tremor in comparison to controls, however without statistical significance. PwPD had a higher rate of amplitude tremor than controls (p<0.05). Judged from ‘silent’ video recordings of nasendoscopic examination, pwPD had a greater amount of tremor in the palate, tongue, and global larynx (vertical dimension) than controls during rest breathing, sustained /s/, /a/ and /i/ (p<0.05). Acoustic voice tremor did not relate significantly to other speech and voice variables. PwPD had a significantly higher voice disability than controls (p<0.05), though this was independent of voice tremor. The magnitude of frequency tremor was positively associated with disease duration (p<0.05). A lower rate of amplitude tremor was associated with an increase in motor symptoms severity (p<0.05). Acoustic voice tremor did not relate in any significant way to PD disability or phenotype. ii PD voice tremor is characterised by auditory perceived instability and tremor, a mean amplitude tremor of 4.94 Hz, and tremor in vocal tract structures. Acoustic analysis and nasendoscopy proved valuable adjunctive tools for characterising voice tremor. Voice tremor is not present in all people with PD, but does appear to increase with disease duration. However pwPD examined here represent a relatively mild group with relatively short disease duration. Further work will look at people with more severe disease symptomatology and longer duration

Epidemiology of Parkinson's Disease: The Rotterdam Study

At present, Parkinson's disease (PO), after Alzheimer's disease, is generally considered to be the most frequent progressive neurodegenerative disease in the elderly. Due to the growing proportion of elderly in many populations, more and more persons will be affected by this disabling disease which constitutes a large burden to man and society. Since the publication of James Parkinson's essay, almost two centuries have elapsed and, in spite of numerous efforts to unravel the nature of the disease, the etiology of PO is still unknown. Yet, the neuropathologic and biochemical changes that cause the signs of the disease seem to be settled, based on knowledge that was mainly accumulated in only the past three decades. Neuropathologically, PO is defined by selective degeneration of pigmented neurons of the pars compacta of the substantia nigra and other brainstem ganglia, with cytoplasmic inclusions, called Lewy bodies, in the surviving neurons as the hallmark. These lesions lead to a deficiency of striatal dopamine. It is now considered that parkinsonian signs only become clinically overt after dopaminergic cell loss of approximately 50% and that at that moment the endogeneous dopamine content is depleted by 80%

Nonpharmacological Interventions for Mild Cognitive Impairment in Parkinson’s Disease

This research examined mild cognitive impairment in Parkinson’s Disease (PD-MCI) and the therapeutic potential of nonpharmacological interventions (e.g., cognitive training and transcranial direct current stimulation) for improving cognition, activities of daily living, and quality of life for people with PD-MCI. The results from this research suggest that cognitive training, tDCS, and cognitive training combined with tDCS may involve stimulation and compensation-focussed strategies that improve cognition, activities of daily living, and quality of life in PD-MCI

ELECTROPHYSIOLOGY OF BASAL GANGLIA (BG) CIRCUITRY AND DYSTONIA AS A MODEL OF MOTOR CONTROL DYSFUNCTION

The basal ganglia (BG) is a complex set of heavily interconnected nuclei located in the central part of the brain that receives inputs from the several areas of the cortex and projects via the thalamus back to the prefrontal and motor cortical areas. Despite playing a significant part in multiple brain functions, the physiology of the BG and associated disorders like dystonia remain poorly understood. Dystonia is a devastating condition characterized by ineffective, twisting movements, prolonged co-contractions and contorted postures. Evidences suggest that it occurs due to abnormal discharge patterning in BG-thalamocortocal (BGTC) circuitry. The central purpose of this study was to understand the electrophysiology of BGTC circuitry and its role in motor control and dystonia. Toward this goal, an advanced multi-target multi-unit recording and analysis system was utilized, which allows simultaneous collection and analysis of multiple neuronal units from multiple brain nuclei. Over the cause of this work, neuronal data from the globus pallidus (GP), subthalamic nucleus (STN), entopenduncular nucleus (EP), pallidal receiving thalamus (VL) and motor cortex (MC) was collected from normal, lesioned and dystonic rats under awake, head restrained conditions. The results have shown that the neuronal population in BG nuclei (GP, STN and EP) were characterized by a dichotomy of firing patterns in normal rats which remains preserved in dystonic rats. Unlike normals, neurons in dystonic rat exhibit reduced mean firing rate, increased irregularity and burstiness at resting state. The chaotic changes that occurs in BG leads to inadequate hyperpolarization levels within the VL thalamic neurons resulting in a shift from the normal bursting mode to an abnormal tonic firing pattern. During movement, the dystonic EP generates abnormally synchronized and elongated burst duration which further corrupts the VL motor signals. It was finally concluded that the loss of specificity and temporal misalignment between motor neurons leads to corrupted signaling to the muscles resulting in dystonic behavior. Furthermore, this study reveals the importance of EP output in controlling firing modes occurring in the VL thalamus

Neuroimaging biomarkers associated with clinical dysfunction in Parkinson disease

Parkinson disease (PD) is the second most common neurodegenerative disorder in the world, directly affecting 2-3% of the population over the age of 65. People diagnosed with the disorder can experience motor, autonomic, cognitive, sensory and neuropsychiatric symptoms that can significantly impact quality of life. Uncertainty still exists about the pathophysiological mechanisms that underlie a range of clinical features of the disorder, linked to structural as well as functional brain changes. This thesis thus aimed to uncover neuroimaging biomarkers associated with clinical dysfunction in PD. A 'hubs-and-spokes' neural circuit-based approach can contribute to this aim, by analysing the component elements and also the interconnections of important brain networks. This thesis focusses on structures within basal ganglia-thalamocortical neuronal circuits that are linked to a range functions impacted in the disorder, and that are vulnerable to the consequences of PD pathology. This thesis investigated neuronal 'hubs' by studying the morphology of the caudate nucleus, putamen, thalamus and neocortex. The caudate nucleus, putamen and thalamus are all vital subcortical 'hubs' that play important roles in a number of functional domains that are compromised in PD. The neocortex, on the other hand, has a range of 'hubs' spread across it, regions of the brain that are crucial for neuronal signalling and communication. The interconnections, or 'spokes', between these hubs and other brain regions were investigated using seed-based resting-state functional connectivity analyses. Finally, a morphological analysis was used to investigate possible structural changes to the corpus callosum, the major inter-hemispheric white matter tract of the brain, crucial to effective higher-order brain processes. This thesis demonstrates that the caudate nucleus, putamen, thalamus, corpus callosum and neocortex are all atrophied in PD participants with dementia. PD participants also demonstrated a significant correlation between volumes of the caudate nuclei and general cognitive functioning and speed, while putamina volumes were correlated with general motor function. Cognitively unimpaired PD participants demonstrated minimal morphological alterations compared to control participants, however they demonstrated significant increases in functional connectivity of the caudate nucleus, putamen and thalamus with areas across the frontal lobe, and decreases in functional connectivity with parietal and cerebellar regions. PD participants with mild cognitive impairment and dementia show decreased functional connectivity of the thalamus with paracingulate and posterior cingulate cortices, respectively. This thesis contributes a deeper understanding of the relationship between structures of basal ganglia-thalamocortical neuronal circuits, corpus callosal and neocortical morphology, and the clinical dysfunction associated with PD. This thesis suggests that functional connectivity changes are more common in early stages of the disorder, while morphological alterations are more pronounced in advanced disease stages