Pioneer Award Address: Ignorance isn’t biased: Comments on receiving the Pioneer Award

Beyond a brain disease: Seeing PD as a heart-brain disorder

More than 50 neuroimaging studies since our original report have agreed remarkably consistently on the association between PD and loss of sympathetic nerves in the heart; moreover, postmortem pathology studies have amply confirmed that a profound loss of cardiac sympathetic nerves is characteristic of PD.¹⁶ I have yet to come across a single patient with PD and orthostatic hypotension who has not had cardiac sympathetic denervation, and virtually all patients with PD who do not have orthostatic hypotension seem to have at least partial loss of cardiac sympathetic nerves.

Considering that the source of those nerves is the ganglia, which lie outside the central nervous system, PD must be more than a brain disease and more than a movement disorder. It must also be a disease of the sympathetic nerves in the heart, a form of a dysautonomia, and a heart-brain disorder.

The role of catecholamines: Another discovery born of unbiased ignorance

To appreciate fully the significance of this finding, I must mention my favorite chemical family, the catecholamines, whose chemical structures resemble cats (Figure 2).¹⁷ PD results from a loss of a particular chemical, dopamine, in a particular pathway in the brain; dopa mine is a catecholamine. The other catecholamines in humans are norepinephrine and adrenaline. As noted above, norepinephrine is the chemical messenger of the sympathetic nerves, and adrenaline is the well-known hormone that produces many of the signs of emotional distress.

Almost a half century ago, Hornykiewicz and colleagues made the pivotal discovery that PD features loss of dopamine in the nigrostriatal system in the brain.¹⁸ Given the cardiac sympathetic denervation, PD might be a disease of catecholamine systems both inside and outside the central nervous system—dopamine in the nigrostriatal system, and norepinephrine in the sympathetic nerves of the heart.

Then what of the third catecholamine, adrenaline, in PD? Plasma levels of adrenaline and of its metabolite, metanephrine, are normal in PD, even in patients who have PD and orthostatic hypotension, which involves loss of norepinephrine-producing nerves not only in the heart but in other organs.¹⁹ What is different about the adrenaline-producing cells in the medulla (from the Latin for “marrow”) of the adrenal glands atop each kidney? Why aren’t these catecholamine-producing cells also lost in PD?

I have some ideas in mind but won’t go into them here. The point is that the discovery of normal adrenaline-producing cells in PD, despite loss of cells producing the other catecholamines, was not based on my testing a hypothesis. It was a discovery born of ignorance, and because ignorance isn’t biased, that discovery points to the truth. Whatever the eventual explanation for the specific pattern of catecholamine cell loss in PD, it cannot refute the discovery itself.

HOW DISCOVERIES ARISE: AN APPLIED EXERCISE FOR READERS

Now let’s have you, the reader, make a discovery and induce its significance based on what I have tried to teach so far, that discoveries arise from the application of relevant technology and from insights of the prepared mind. Take a look at the scans in the left panels of Figures 3 and 4. The large red structures in Figure 3, which look like a sad clown’s eyes, correspond to the striatum. The striatum is made up of the putamen, which is like the mascara on the side of the sad clown’s eyes, and the caudate, which is like the beady eyes themselves. In the left panel of Figure 4, the small spots in the midbrain correspond to the substantia nigra, a major site of dopamine-producing neurons in the human brain.

We can see in the right panel of Figure 3 that in PD there is a loss of the ability to store dopamine in the striatum—especially in the putamen, the mascara of the sad clown’s eyes. In the right panel of Figure 4 we see that in the brainstem there is a loss of the dopamine-containing nerve cells in the substantia nigra. These scans therefore demonstrate graphically the nigrostriatal lesion characteristic of PD. There is a loss of the nerve cells in the substantia nigra in the midbrain and a loss of the dopamine-containing terminals in the striatum.

Now take a look at the scans of these areas in a patient with PAF in Figure 5. Remember that PAF involves a loss of sympathetic nerves in the heart, just like in PD, but that PAF does not involve parkinsonism. Look at the sad clown’s eyes. The mascara is there, of course, because the patient does not have parkinsonism. But now look for the spots in the substantia nigra—they are missing, just as in PD.

PAF is a rare disease, and I have only studied several cases with high-resolution PET scanning of the brain, but so far they have all had this unexpected, unpredicted finding of loss of dopaminergic neurons in the substantia nigra.²⁰

What does this pattern mean? If PAF patients have just as much loss of nigral neurons as PD patients do, and if PAF patients do not have parkinsonism, then the movement disorder in PD cannot result from loss of the dopamine neurons in the substantia nigra per se. Instead, the movement disorder in PD seems to come from loss of the dopaminergic terminals in the striatum.

How can PAF patients have normal dopamine terminals in the putamen when the number of dopaminergic cell bodies is severely reduced? Somehow, PAF patients must be able to sprout new terminals, even as they lose the cell bodies. Maybe if we knew how PAF patients do this, we would have a way to treat or even prevent PD.

How do PAF patients maintain normal dopamine terminals as the cell bodies die off? No one knows. Until now, no one thought of asking such a question. No one hypothesized that this discovery would be made, but it was. And because ignorance isn’t biased, we have put our finger on the truth. By keeping in mind what isn’t known, we could see what wasn’t there. Now we can begin to think of what to look for next.