Patients as a scientific resource: comments on receiving the Ahrens award.

On this momentous occasion for me, I thank the extraordinarily devoted people who have worked with me in intramural NIH, my family for their tolerance of my spending so much time on NIH “stuff,” and the patients who have entrusted themselves to me and contributed altruistically to medical research over many years and sometimes even after death; and I thank the Association for Patient-Oriented Research for bestowing upon me this high honor. After reflecting on the past 33 years carrying out patient-oriented research in neurocardiology, autonomic disorders, and catecholamine systems of the body, I would like to convey here that patients are a unique scientific resource. By their symptoms, physical signs, and results of their clinical laboratory tests, they put us on the path to the truth. Our job is to try to make sense of what they teach. In 1657, William Harvey—the founder of modern physiology, who first described the circulation of the blood, and the founder of neurocardiology, who first pointed out the effects of emotions on the heart—wrote eloquently about the extraordinary power of studying patients, specifically patients with rare diseases: “Nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows traces of her workings apart from the beaten path; nor is there any better way to advance the proper practice of medicine than to give our minds to the discovery of the usual law of nature, by the careful investigation of cases of rarer forms of disease. For it has been found in almost all things, that what they contain of use or of application, is hardly perceived unless we are deprived of them, or they become deranged in some way.” Let me present to you some examples of how patient-oriented research led to key discoveries in my career. In the late 1980s, with several colleagues I developed 6-[18F]fluorodopamine (18F-DA) as an imaging agent to visualize sympathetic nerves by positron emission tomography (PET) scanning. 1 The heart contains abundant sympathetic noradrenergic nerves. The first patient I studied with this new technology had a rare disease called pure autonomic failure (PAF). PAF is a form of alpha-synucleinopathy in which deposits of the protein alpha-synuclein are found in the cytoplasm of sympathetic nerves. PAF manifests as severe orthostatic hypotension associated with diffuse sympathetic noradrenergic denervation. As expected, the patient had no detectable myocardial 18F-DA-derived radioactivity. Years later, in an ultimate act of philanthropy, she requested that she be autopsied at the NIH. This was done within hours of her death. Extremely low myocardial norepinephrine confirmed the validity of 18F-DA PET in identifying cardiac sympathetic denervation; and the finding of Lewy bodies in her brainstem confirmed that PAF is a Lewy body disease, in the same family as Parkinson disease (PD). 2 Studying patients with the rare disease, PAF, is likely to elucidate mechanisms and suggest novel treatments of more common diseases, such as PD. For instance, we recently obtained evidence that both PAF and PD involve decreased vesicular uptake of cytosolic catecholamines, and since cytosolic catecholamines are toxic, this might be part of a pathogenetic pathway. If so, then why not develop drugs that increase the effi ciency of vesicular uptake? 18F-DA scanning has proven extraordinarily powerful for the differential diagnosis of PD from multiple system atrophy (MSA). 3 In MSA, the cardiac sympathetic nerves are generally intact, but in PD there is often a remarkable loss of cardiac sympathetic nerves, as in PAF. This concept applied to two rare patients with familial PD from mutation or replication of the gene encoding alpha-synuclein. From the finding that both patients had neuroimaging evidence of cardiac sympathetic denervation, we concluded that synucleinopathy can not only destroy nigrostriatal dopaminergic neurons but also destroy sympathetic noradrenergic neurons and produce not only a movement disorder but also a form of dysautonomia. Two other patients carried a diagnosis of “Parkinson's Plus.” One was Milly Kondracke, wife of the political commentator Morton Kondracke. Mort wrote a book about her, Saving Milly, which was also the title of a made-for-TV movie. Milly struggled with progressive neurodegeneration for about 18 years. Near the end, her speech was so garbled that she had to communicate by computer keyboard. The other patient with Parkinson's Plus was an NIH researcher whose first symptoms included orthostatic lightheadedness from orthostatic hypotension. It has been taught that if orthostatic hypotension comes on early and dominates the clinical picture in the setting of a neurodegenerative disorder, then the patient cannot have PD and may have MSA. MSA usually progresses rapidly, survival averaging about a half-dozen years from the time of diagnosis. Milly Kondracke was thought to have PD because of the slow downhill course but Parkinson's Plus because of her slurred speech, poor airway control, and little improvement with levodopa. The other patient was thought to have MSA because of prominent early orthostatic hypotension but Parkinson's Plus because of a good response to levodopa. Milly Kondracke had normal cardiac sympathetic innervation by 18F-DA scanning. This convinced me she did not have PD. Her “Parkinson's Plus” proved to be from MSA. Her case illustrates that separating PD with orthostatic hypotension from the Parkinsonian form of MSA can be very diffi cult clinically, that MSA patients sometimes can survive for many years, and that cardiac sympathetic neuroimaging can be a valuable differential diagnostic tool to distinguish between the two diseases. In the other patient, clear PD with dementia emerged. Her case illustrates that in PD, orthostatic hypotension can be an early sign. 4 In summary, patient-oriented research is a strength of translational medicine. The combination of relevant new technology, suffi cient mastery of the topic to know what is not yet known, and access to patients with rare but informative disorders sets the stage for potentially important discoveries. Patients are a unique scientific resource, because they point us to the truth. We experience the joy and thrill of “sparkles of insight,” when we realize what they teach.