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This chapter provides an update about cardiovascular aspects of Parkinson disease (PD), with the following topics: (1) Orthostatic hypotension (OH) as an early finding in PD; (2) neurocirculatory abnormalities in PD+OH independent of levodopa treatment; (3) cardiac and extracardiac noradrenergic denervation in PD+OH; (4) progressive loss of cardiac sympathetic innervation in PD without OH.

Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder that affects adults. It is characterised by autonomic failure affecting many systems; cardiovascular, urinary, sexual, gastrointestinal and sudomotor, amongst others. In addition there are motor deficits, resulting in both parkinsonian and/or cerebellar features. This review will outline the clinical features, investigations and management of MSA, with a particular emphasis on autonomic failure.

Sleep disturbances are frequent in Parkinson disease. These disorders can be broadly categorized into those that involve nocturnal sleep and excessive daytime sleepiness. The disorders that are often observed during the night in PD include sleep fragmentation that may be due to recurrent PD symptoms, sleep apnea, Restless Leg Syndrome/periodic limb movements and REM sleep behavior disorder. Excessive daytime sleepiness is also a common occurrence in PD. EDS can arise from several etiologies, and patients may have more than one etiology responsible. The causes of EDS include nocturnal sleep disorder with sleep deprivation and resulting daytime somnolence, the effect of drugs used to treat PD, and possibly neurodegeneration of central sleep/wake areas. Appropriate diagnosis of the sleep disturbance affecting a PD patient can lead to specific treatments that can consolidate nocturnal sleep and enhance daytime alertness.

Patients with Parkinson’s disease experience prominent difficulties in maintaining sleep, painful night-time abnormal movements, and daytime sleepiness, sometimes culminating in sleep attacks. Recent insights into the pathophysiology of sleep disorders in PD points to a complex interaction between movement disorders, side-effects of dopamine agents and lesions in sleep-wake regulating systems. Treatment with dopamine agonists provides a twice higher risk of daytime sudden sleep episodes than levodopa, with no difference between ergotic and non ergotic compounds. Insomnia can be improved by a better control of night-time disability, restless legs syndrome and dystonia using subthalamic nucleus stimulation or night-time levodopa. A specific REM sleep disorder contributes to REM sleep behavior disorder and also to hallucinations (suggesting they could be awake dreams) and excessive daytime sleepiness. The management of sleep and alertness problems requires to analyze their potential causes, to monitor night-time and daytime sleep, and to subtly adjust psychotropic and dopaminergic treatment.

This brief review deals with pathological aspects of dementia associated with Parkinson’s disease (PDD). PDD has been variably linked with cortical Lewy body topography and density. α-Synuclein and Alzheimer-type pathology frequently co-exist, suggesting that a combination of pathology related to protein dysmetabolism, possibly with synergistic protein-protein interaction, underpins the cognitive impairment in PDD. Dementia may therefore ensue when a “toxic threshold” is reached, irrespective of the combination of pathologies involved in reaching that threshold. The nature of this putative protein-protein interaction needs to be further elucidated, and also whether there are specific clinical correlates of the pathological substrate. Serum and cerebrospinal fluid proteins or imaging techniques may be useful in future as biomarkers to identify the relative contribution of Lewy-related and Alzheimer-type pathology in a given case of PDD and to inform the rational use of drugs that can reduce α-synuclein aggregation and β-amyloid production.

Inflammation in the brain has been recognized to play an increasingly important role in the pathogenesis of several neurodegenerative disorders, including Parkinson’s disease and Alzheimer’s disease. Inflammation- mediated neurodegeneration involves activation of the brain’s resident immune cells, the microglia, which produce proinflammatory and neurotoxic factors including cytokines, reactive oxygen species (ROS), nitric oxide, and eicosanoids that directly or indirectly cause neurodegeneration. In this study, we report that IL-10, an immunosuppressive cytokine, reduced the inflammation-mediated degeneration of dopaminergic (DA) neurons through the inhibition of microglial activation. Pretreatment of rat mesencephalic neuron-glia cultures with IL-10 significantly attenuated the lipopolysaccharide (LPS) induced DA neuronal degeneration. The neuroprotective effect of IL-10 was attributed to inhibition of LPS-stimulated microglial activation. IL-10 significantly inhibited the microglial production of tumor necrosis factor α (TNF-α), nitric oxide, ROS and superoxide free radicals after LPS stimulation.

We investigated whether the cytokines produced in activated microglia in the substantia nigra (SN) and putamen in sporadic Parkinson’s disease (PD) are neuroprotective or neurotoxic. In autopsy brains of PD, the number of MHC class II (CR3/43)-positive activated microglia, which were also ICAM-1 (CD 54)-, LFA-1 (CD 11a)-, TNF-alpha-, and IL-6-positive, increased in the SN and putamen during progress of PD. At the early stage activated microglia were mainly associated with tyrosine hydroxylase (TH)-positive neurites in the putamen, and at the advanced stage with damaged TH-positive neurons in the SN. The activated microglia in PD were observed not only in the nigro-striatal region, but also in various brain regions such as the hippocampus and cerebral cortex. We examined the distribution of activated microglia and the expression of cytokines and neurotrophins in the hippocampus of PD and Lewy body disease (LBD). The levels of IL-6 and TNF-alpha mRNAs increased both in PD and LBD, but those of BDNF mRNA and protein drastically decreased specifically in LBD, in which neuronal loss was observed not only in the nigrostriatum but also in the hippocampus. The results suggest activated microglia in the hippocampus to be probably neuroprotective in PD, but those to be neurotoxic in LBD. As an evidence supporting this hypothesis, two subsets of microglia were isolated from mouse brain by cell sorting: one subset with high production of reactive oxygen species (ROS) and the other with no production of ROS. When co-cultured with neuronal cells, one microglia clone with high ROS production was neurotoxic, but another clone with no ROS production neuroprotective. On the other hand, Sawada with coworkers found that a neuroprotective microglial clone in a culture experiment converted to a toxic microglial clone by transduction of the HIV-1 Nef protein with increasing NADPH oxidase activity. Taken together, all these results suggest that activated microglia may change in vivo from neuroprotective to neurotoxic subtsets as degeneration of dopamine neurons in the SN progresses in PD. We conclude that the cytokines from activated microglia in the SN and putamen may be initially neuroprotective, but may later become neurotoxic during the progress of PD. Toxic change of activated microglia may also occur in Alzheimer’s disease and other neurodegenerative diseases in which inflammatory process is found.

High frequency stimulation (HFS) has become the main alternative to medical treatment, due to its reversibility, adaptability, and low morbidity. Initiated in the thalamus (Vim) for the control of tremor, HFS has been applied to the Pallidum (GPi), and then to the subthalamic nucleus (STN), suggested by experiments in MPTP monkeys. STNHFS is highly efficient on tremor, rigidity and bradykinesia and is now widely applied. Criteria for success are correct patient selection and precise electrode placement. The best outcome predictor is the response to Levodopa. The mechanisms of action might associate inhibition of cell firing, jamming of neuronal message and exhaustion of synaptic neurotransmitter release. The inhibition of glutamate STN release could be neuroprotective on nigral cells. Animal experiments support this hypothesis, not contradicted by the long term follow up of patients. Neuroprotection might have considerable impact on the management of PD patient and warrants clinical trials.

Approximately 30,000 patients have been treated throughout the world with deep brain stimulation for Parkinson’s disease and other conditions. With accumulating experience, there has been an appreciation of the important benefits of this procedure, including the alleviation of disability and improvement in the quality of life. We have also become aware of some limitations of DBS surgery. Among the important issues that remain to be resolved are the timing of surgery, whether early or late in the course of the disease, and the best target for the individual patient, including a reassessment of the relative merits of globus pallidus versus subthalamic nucleus surgery. A better understanding of the symptoms that are resistant to both levodopa therapy and DBS surgery is also required.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson’s disease (PD) patients augments STN-driven excitation of the internal globus pallidus (GPi). However, other DBS-induced changes are largely unknown. Here we report the biochemical effects of STN-DBS in two basal ganglia stations (putamen — PUT — and GPi) and in a thalamic relay nucleus, the anteroventral thalamus (VA). In six advanced PD patients undergoing surgery, microdialysis samples were collected from GPi, PUT and VA before, during and after one hour of STN-DBS. cGMP was measured in the GPi and PUT as an index of glutamatergic transmission, whereas GABA was measured in the VA. During clinically effective STN-DBS, we found a significant decrease in GABA extracellular concentrations in the VA (−25%). Simultaneously, cGMP extracellular concentrations were enhanced in the PUT (+200%) and GPi (+481%). DBS differentially affects fibers crossing the STN area: it activates the STN-GPi pathway while inhibiting the GPi-VA one. These findings support a thalamic dis-inhibition, as the main responsible for the clinical effect of STN-DBS. This, in turn, re-establishes a more physiological level of PUT activity.