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Parkinson's Disease - Brain Regions and their Dysfunctions



Parkinson's Disease

"Although levodopa continues as the gold standard for efficacy, its chronic use is associated with potentially disabling motor complications. (...) Current dopamine agonists, while producing more constant plasma levels, fail to match levodopa's efficacy. Strategies to treat levodopa-related motor complications are only partially effective, rarely abolishing motor fluctuations or dyskinesias. Best results are currently achieved with invasive strategies via subcutaneous (s.c.) or intraduodenal delivery of apomorphine or levodopa, or deep brain stimulation of the subthalamic nucleus.

Another area of major unmet medical need is related to nondopaminergic and nonmotor symptoms of PD. Targeting transmitter systems beyond the dopamine system is an interesting approach, both for the motor and nonmotor problems of PD. So far, clinical trial evidence regarding 5-HT agonists, glutamate antagonists, adenosine A(2) antagonists and alpha-adrenergic receptor antagonists, has been inconsistent, but trials with cholinesterase inhibitors and atypical antipsychotics to treat dementia and psychosis, have been successful." S

"Subthalamic deep brain stimulation is now well established as a treatment for the dopaminergic motor symptoms of Parkinson's disease. It has little effect on postural instability and "on-state" gait freezing. Animal experiments and early human pilot studies suggest that Pedunculopontine nucleus stimulation may alleviate these phenomenon, consistent with the hypothesis that these disabling symptoms are secondary to degeneration in non-dopaminergic pathways." S

"Frontal lobe dysfunction and other cognitive deficits have been described in Parkinson's disease (PD), which may lead to dementia. Both striatal dopaminergic deficiency and regional or global brain volume loss have been suggested to contribute to cognitive decline in PD. (...) PD patients had impaired cognitive performance in many neuropsychological tests compared to controls, not limited just to frontal lobe function tests. Caudate Fdopa correlated positively with performance in verbal (immediate and delayed) and visual memory. Patients with PD showed atrophy in the hippocampus and the prefrontal cortex and hippocampal atrophy was related to impaired memory. Our findings suggest that striatal dopaminergic depletion and global brain volume loss contribute to cognitive impairment in non-demented PD patients, but dysfunction of extra-striatal dopaminergic or non-dopaminergic systems probably plays a role especially in more generalized cognitive impairment." S
Affected Region Dysfunctions
Basal ganglia "(...) early restoration of basal ganglia physiology will support the compensatory events and delay the irreversible modification of circuitry that characterizes the clinical progression of PD." S

" (...) as disease severity increased, contributions of the basal ganglia to the selection process and their effective connectivity with the medial frontal cortex (MFC) decreased, whereas involvement of the MFC increased. We conclude that the basal ganglia are important for rapidly switching toward novel motor plans even when there is no sequential structure to learn or implement. The enhanced MFC activity may result either from reduced focusing abilities of the basal ganglia or from compensatory processes." S
Caudate nucleus "Reduced striatal levels of all of the key serotonergic markers (neurotransmitter and metabolite, transporter protein, synthesizing enzyme protein) provide strong evidence for a serotonergic disturbance in PD, but with some patients affected much more than others. The more marked caudate reduction suggests that raphe neurons innervating this area are more susceptible to 'damage' than those innervating putamen and that any functional impairment caused by striatal serotonin loss might primarily involve the caudate." S
Nucleus lentiformis "(...) there might be some changes with MRS (magnetic resonance spectroscopy) on the lentiform nucleus during the early stage of idiopathic Parkinsonís disease with unilateral symptom." S
Globus pallidus "Deep brain stimulation is used as therapy for different diseases especially for Parkinsons disease. In articles there is often reported about psychiatric changes and cognitive deficits after electrode implantation. (...) The results of the evaluation are the following: the prevalence of mania (9,6%) and psychosis (5%) with stimulation of the subthalamic nucleus is higher, whereas it is lower with stimulation of the internal globus pallidus and of the thalamus than the prevalence of these psychiatric conditions in the population of adults." S
Putamen "Unlike the preferential loss of dopamine in putamen, the caudate was affected more than putamen by loss of all serotonin markers: serotonin (-66% versus -51%), 5-HIAA (-42% versus -31%), SERT (-56% versus -30%) and TPH (-59% versus -32%). (...) The more marked caudate reduction suggests that raphe neurons innervating this area are more susceptible to 'damage' than those innervating putamen and that any functional impairment caused by striatal serotonin loss might primarily involve the caudate." S
Thalamus "(...) The results of the evaluation are the following: the prevalence of mania (9,6%) and psychosis (5%) with stimulation of the subthalamic nucleus is higher, whereas it is lower with stimulation of the internal globus pallidus and of the thalamus than the prevalence of these psychiatric conditions in the population of adults." S
Subthalamus/ Subthalamic nucleus "High-frequency stimulation (HFS) of the subthalamic nucleus (STN) is a well-established therapy for patients with severe Parkinson's disease (PD), but its mechanism of action is unclear. (...) Our findings suggest that HFS may act by modulating pathological patterns of synchronized oscillations, specifically by reduction of pathological beta activity in PD." S

"The findings suggest that the functional pathways associated with motor disability in PD are linked to the STN (subthalamic nucleus) firing rate." S

"Raprl electrical stimulation (electrical stimulation of contralateral prelemniscal radiations) is safe and efficient to treat patients with the Parkinson's disease symptomatic triad. By use of Raprl stereotactic coordinates, electrodes were placed behind the subthalamic nucleus." S

"The use of the RN (red nucleus) as an internal fiducial marker for targeting the optimal region of STN stimulation was reliable and closely approximates the position of the electrode contact that provides the optimal clinical results." S
Metathalamus "Neural pathway for visual information processing involves retina, lateral geniculate body, primary visual cortex, and higher visual cortical areas, all of which have been reported to be disordered either functionally or pathologically in Parkinson disease (PD)." S
Fornix "Our study is the first to find the fornix fiber degeneration in PD patients with EDS (excessive daytime sleepiness). These results indicate that fornix dysfunction may have some correlations with EDS in PD." S
Substantia nigra "The degeneration of neurons in the substantia nigra is associated with Parkinsonís disease." S

"The accuracy of the diagnosis of Parkinson's disease early in the course of the disease remains a clinical challenge. Imaging of dopamine transporters with DatSCAN and SPEC tomography contributes to identifying patients without nigral degeneration and thus helps preventing unnecessary and potentially harmful treatments." S

"High field strength MRI demonstrates lateral substantia nigra pars compacta abnormalities in early Parkinson disease (PD) consistent with increased iron content and corresponding to the known distribution of neuronal loss occurring in this disorder." S

"At least 2 decades have past since the demonstration of a 40-50% deficit in total glutathione (GSH) levels in the substantia nigra in patients with Parkinson's disease (PD). The similar loss of GSH in the nigra in Incidental Lewy body disease, thought to be an early form of PD, indicates that this is one of the earliest derangements to occur in the pre-symptomatic stages of PD." S

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