79,80 Yet, as we have seen, while neuron loss and LB formation are widespread in PD, they are also highly select in targeting only particular cell groups and generally sparing all but a few circumscribed regions of cortex.74,81 This serves to distinguish idiopathic PD from Lewy body dementia (LBD), a much rarer condition in which the neurodegenerative changes are qualitatively indistinguishable from those of PD yet differ sharply in quantitative terms.82-84 In LBD, unlike Inhibitors,research,lifescience,medical PD, there is diffuse and severe cortical involvement, which appears to explain the prominent

cognitive decline that appears early in LBD, but is seldom a feature of PD. Autonomic nervous system Autonomic disturbances in PD are frequent, and varied, due to cell loss and LB pathology involving both preganglionic and postganglionic components of both the sympathetic and parasympathetic nervous systems.85-87 The earliest, pathological changes in PD are in fact, extranigral,

beginning with formation of LBs and loss of cholinergic neurons within the dorsal glossopharyngcus-vagus Inhibitors,research,lifescience,medical complex.37,45 Progressive loss of these preganglionic parasympathetic neurons is Inhibitors,research,lifescience,medical one of the factors contributing to the dysphagia and esophageal dysmotility that occur frequently in PD patients.88,89 Postganglionic parasympathetic cell loss and LB pathology within upper portions of the myenteric plexus account for the esophageal and gastric dysmotility syndromes that, are common accompaniments of PD87; esophageal involvement, when severe, can Inhibitors,research,lifescience,medical be indistinguishable from achalasia.90 Involvement of the colonie myenteric plexus in PD is associated with constipation and more severe forms of colonic inertia,

depending on the magnitude of cell loss.86 One of the most common disturbances in PD is orthostatic hypotension, Inhibitors,research,lifescience,medical presumably resulting from the characteristic loss of preganglionic sympathetic neurons in the intermcdiolateral nucleus of the thoracic spinal cord.91 Destruction of postganglionic neurons within the sympathetic chain results in sympathetic denervation of the heart, as indicated by diminished Silmitasertib cardiac uptake of a tracer that, uses the same neuronal transport mechanism as NA.92 While the clinical effects of cardiac sympathetic denervation are unknown, the diagnostic significance may be considerable.93 Evidence heptaminol of cardiac sympathetic denervation occurs early and often in PD, but not in other forms of parkinsonism, such as multiple system atrophy.94 Etiopathogenesis Although the etiology and pathogenesis of sporadic PD have yet to be established, several predisposing factors and pathogenic pathways have been implicated. Among the latter are oxidative stress associated with mitochondrial dysfunction,95-98 proteolytic stress due to dysfunction of the ubiquitin-proteasome system (UPS),99,100 and local inflammation.