Plenary 5:| Volume 163, ISSUE 1-2, P38, September 01, 2011

Biomarkers, Mechanisms, and Treatment of Autonomic Failure in Parkinson Disease and Related Disorders

      Parkinson disease (PD) in one of the most common chronic neurodegenerative diseases of the elderly, and it is likely that as populations age PD will become even more prevalent and more of a public health burden. The movement disorder in PD is characterized by and likely results from severe depletion of dopaminergic neurons of the nigrostriatal system. By the time PD manifests clinically, most of the nigrostriatal dopaminergic neurons are already lost. Identifying laboratory measures—biomarkers—of the disease process is therefore crucial for advances in treatment and prevention. PD is often attended by signs or symptoms of impaired autonomic regulation of the circulation. This lecture comprehensively reviews and updates the field of autonomic cardiovascular abnormalities in PD and related disorders. About 3040% of PD patients have orthostatic hypotension (OH). PD+OH is consistently associated with failure of both the cardiovagal and sympathoneural limbs of the arterial baroreflex, regardless of levodopa treatment. Most PD patients without OH have more subtle baroreflex abnormalities. Plasma levels of the sympathetic neurotransmitter norepinephrine (NE) and of dihydroxyphenylglycol, the main neuronal metabolite of NE, are lower in PD+OH than in PD without OH, indicating a relatively smaller overall complement of sympathetic nerves in PD+OH; however, patients with pure autonomic failure (PAF) have even lower NE and dihydroxyphenylglycol levels than do PD+OH patients, suggesting more extensive extra-cardiac noradrenergic denervation in PAF than in PD+OH. All patients with PD+OH have markedly reduced sympathetic noradrenergic innervation of the left ventricular myocardium. The cardiac neuroimaging findings in PD+OH contrast with those in multiple system atrophy (MSA), which can be difficult to distinguish from PD+OH, in that MSA usually entails intact sympathetic innervation of the heart. In PD patients with localized myocardial denervation there is earlier or more prominent involvement of the inferolateral wall than of the anterobasal septum, consistent with a retrograde, centripetal pathogenetic process. Cardiac sympathetic denervation occurs independently of striatal dopaminergic denervation across individual PD patients. Therefore, although cardiac sympathetic denervation invariably progresses over time in PD and can come on years before the motor disorder, the denervation can also be a late finding. Other non-motor manifestations such as olfactory dysfunction in PD are more closely associated with cardiac noradrenergic than with striatal dopaminergic denervation. PD and PAF feature not only decreased neuronal catecholamine uptake but also accelerated intra-neuronal catecholamine loss, which seems to reflect decreased vesicular uptake via the vesicular monoamine transporter. MSA patients have normal values for these parameters. In summary, baroreflex failure and cardiac and extra-cardiac noradrenergic denervation characterize OH in PD. These abnormalities occur independently of striatal dopamine depletion. Cardiovascular autonomic variables may provide biomarkers of pre-motor PD in some patients. Understanding mechanisms of cardiac sympathetic dysfunction and denervation in PD may also help elucidate bases of central catecholaminergic lesions in a variety of neurodegenerative diseases. In particular, Lewy body forms of alpha-synucleinopathy seem to be associated with decreased vesicular sequestration of cytosolic catecholamines, and since cytosolic catecholamines are toxic, decreased vesicular recycling may be part of a final pathogenetic pathway in the catecholaminergic denervation that characterizes these diseases.
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