...and much more than motor symptoms.

A colleague handed me this paper, not just as an interesting aspect of Parkinson's, but as somewhat supportive paper for the role of serotonin in depression. I have said before that I think the serotonin theory of depression (as depicted in Zoloft commercials) is probably wrong, but my views are actually a bit more nuanced than that. The serotonin theory is probably wrong, but not because it is wrong, rather, it is oversimplified. I think that low serotonin levels on their own probably don't cause depression, but it looks like there may still be a role for serotonin in depressive symptoms, and this paper seems to agree. Science, it's always more complicated than you think at first.

Politis et al. "Serotonin Neuron Loss and Nonmotor Symptoms Continue in Parkinson’s Patients Treated with Dopamine Grafts" Sci Trans Med, 2012.

Parkinson's is something that no one wants to get. It's a degenerative disorder of the nervous system, which results in a wide variety of symptoms. Most people think of Parkinson's and picture a shuffling gait, severe hand tremor, slowness of movement and rigidity. But there are other symptoms as well, include depression, hallucinations, fatigue, sleep disturbances, and cognitive deficits as the disease progresses.

And when most people think of potential causes for Parkinson's, they think of a deficit in dopamine, the neurotransmitter that I usually think of with regard to reward and reinforcement, but which is extremely important in motor systems as well. In Parkinson's patients, you see a striking loss of dopamine neurons in motor areas like the substantia nigra (it's easy to see because the melanin in the substantia nigra, which is latin for "black substance" dyes the cells black, and when those cells die, the stubstantia nigra becomes a lot less substantia and nigra). But again, it's not just dopamine in the substantia nigra, there are other systems involved and differences in signaling that also play a role as the disease progresses.

But what most people are interested in repairing first is the highly debilitating motor deficit. Treatment has focused very heavily on restoring dopamine and motor function. For example, the first line treatment is Levadopa, or L-DOPA, a precursor to dopamine which the brain can then use to make dopamine, and which can restore motor function beautifully:

(I have to say the perky music in this video is really pretty horrid, but the effect of the L-DOPA is very visible)

But this doesn't work forever. Eventually the brain stops responding to dopamine supplementation. Then treatments move to brain stimulation or other methods, many of which also eventually fail. So we are constantly trying to find new treatments to restore function.

One of these new treatments is actually one using stem cells. You can insert a graft of fetal stem cells which express dopamine into the striatum of the brain. When these grafts work (unfortunately, in a lot of cases they do not work, get rejected, or produce bad motor symptoms on their own), they can restore dopamine function to normal levels. The patients can move again, walk again, function normally, and the effects can persist for over a decade (at least, they have persisted for over a decade so far).

But are these patients WELL? The motor symptoms are better, but what about other aspects? The authors of this study looked at four of the successful stem cell treated patients to see how their symptoms in motor and nonmotor areas compared to controls and other Parkinson's patients.

What they found was that in motor symptoms, the patients were definitely improved, all of them no longer required medication. Not only that, their measures of dopamine (as measured by positron emission tomography using radiolabeling of l-dopa to look at amino acid decorboxylase, which gives an indirect measure of dopamine) were comparable to controls.

This is a really nice finding and demonstrates that the stem cell graft, when it works, can really do an excellent job at restoring dopamine function.

The figure above shows the PET scans. On the far left is a normal control, second from left is a Parkinson's untreated patient, and the three on the right are the three stem cell treated patients. You can see that the dopaminergic function measure looks completely normal in comparison. The patients also scored very well on all measures of motor function.

...but they weren't WELL. When the authors looked at measures of the other symptoms, they found that all the patients showed issues, with bowel or sexual dysfunction, mood problems and hallucinations, or sleep issues. And it couldn't be the dopamine, because dopamine function was restored to normal.

No, it's not the dopamine, but it could be the serotonin.

While measures of dopamine were normal, measures of serotonin in the stem cell receiving patients were lower even than in untreated patients.

And the decreases in serotonin function extended all over the brain. Norepinephrine function, however, was normal.

The serotonin here kind of makes sense. The disruptions the patients have been experiencing (the fatigue, the bowel and sexual issues, moodiness) are all things linked with serotonin function. And Parkinson's does progress to the serotonin symptom and destroy the serotonin cells in the raphe.

But what this tells us is that it is no longer enough to target the dopamine related symptoms of Parkinson's alone. It's a start, but it's not the best treatment. The authors propose doing multiple grafts of dopamine and serotonin cells, and I think for less severe symptoms there might be reason to combine L-DOPA with an SSRI or something else to increase serotonin function while possible. Clearly, more studies need to be done on how to help these nonmotor symptoms of Parkinson's. Because restored motor activity is wonderful and incredibly important, but it doesn't necessary mean a cure.

Politis M, Wu K, Loane C, Quinn NP, Brooks DJ, Oertel WH, Björklund A, Lindvall O, & Piccini P (2012). Serotonin neuron loss and nonmotor symptoms continue in Parkinson's patients treated with dopamine grafts. Science translational medicine, 4 (128) PMID: 22491951