This review highlights important recent publications in the area of neuroscience and heart-brain medicine. Abnormalities of regulation of the circulation by catecholamine systems figure as a general theme of the topics highlighted. These topics, which are reviewed in turn below, are (1) mechanisms of cardiac sympathetic denervation in Parkinson disease (PD), (2) cytoplasmic monoamine metabolites as autotoxins, and (3) the validity of power spectral analysis of heart rate variability to indicate cardiac sympathetic tone.
MECHANISMS OF CARDIAC SYMPATHETIC DENERVATION IN PARKINSON DISEASE
The movement disorder component of PD is well recognized as resulting from loss of dopaminergic neurons in the nigrostriatal system of the brain. The finding of low myocardial 6-[18F]fluorodopamine–derived radioactivity by positron emission tomography provided the first neuroimaging evidence for loss of catecholaminergic neurons outside the brain in PD.1 Many reports using 123I-metaiodobenzylguanidine scanning have concurred with this finding. Beginning in the early 2000s, post-mortem neuropathologic studies demonstrated virtually absent immunoreactivity for tyrosine hydroxylase, the rate-limiting enzyme in norepinephrine biosynthesis, in epicardial nerves in PD.2,3 These results provided clues to the mechanism of autonomic dysfunction in PD, a prominent nonmotor manifestation of the disease.
Some individuals who die without clinical parkinsonism have Lewy bodies detected pathologically. Growing evidence shows that incidental Lewy body disease represents early, presymptomatic PD.8 Orimo’s group therefore studied cardiac tissues and paravertebral sympathetic ganglia from patients with incidental Lewy body disease.9 Postmortem tissues were likewise obtained from comparison subjects with multiple system atrophy and from control subjects. Immunohistochemical analyses were performed using antibodies against tyrosine hydroxylase, phosphorylated neurofilament as a marker of axons, and phosphorylated alpha-synuclein as a marker of abnormal alpha-synuclein deposits. Key findings from this study9 were as follows:
- Alpha-synuclein aggregates in the epicardial nerve fibers were closely related to the disappearance of THir axons.
- In incidental Lewy body disease with preserved THir axons, alpha-synuclein aggregates were consistently more abundant in the epicardial nerves than in the paravertebral sympathetic ganglia (Figure 2).
- Distally dominant accumulation of alpha-synuclein aggregates was reversed in incidental Lewy body disease with decreased THir axons and in PD, because both conditions involve fewer alpha-synuclein aggregates in axons and more abundant aggregates in the paravertebral sympathetic ganglia (Figure 2).
Thus, accumulation of alpha-synuclein aggregates in distal cardiac sympathetic axons precedes aggregation in neuronal somata or ganglionic neurites, heralding centripetal degeneration of cardiac sympathetic nerves in PD. This chronological and dynamic relationship between alpha-synuclein aggregation and distally dominant degeneration of cardiac noradrenergic nerves may represent the pathological mechanism behind a common degenerative process in PD.
In conclusion, cardiac noradrenergic denervation in Lewy body diseases, even in early stages, accounts for reduced cardiac uptake of 123I-metaiodobenzylguanidine and 6-[18F]fluorodopamine in PD. Alpha-synuclein aggregation appears to be intimately involved in the cardiac noradrenergic denervation that attends Lewy body diseases. The pathogenetic process seems to proceed in a centripetal, retrograde direction.