Parkinson’s Disease: A Detective Story

The Activator: a spring-loaded thumper. Is this “chiropractic”? Does it really “balance the alignment of the lumbar spine and sacrum”?

I didn’t intend to review Jon Palfreman’s book Brain Storms: The Race to Unlock the Mysteries of Parkinson’s Disease, but after reading it I decided it was too good not to share. Palfreman is an award-winning science journalist who has Parkinson’s himself. He has done a bang-up job of describing Parkinson’s disease, its impact on patients, and how science is working to understand and treat it.

Parkinson first described the disease in 1817. It is characterized by shaking, rigidity, slowness of movement, and difficulty with walking. There is a decrease in dopamine in the basal ganglia in the brain. One million Americans have Parkinson’s disease. The incidence increases with age; by age 80 one in fifty people are affected.

Some very strange phenomena have been observed. Parkinson’s disease is less common among smokers and coffee drinkers. When a patient becomes frozen and unable to take the next step, if you draw a line on the floor they will step over the line and walk on. Patients who can’t walk can run, ride a bike, or ice-skate. Some patients appear to have strong responses to placebos, with reversal of symptoms for long periods. Exposure to vibration seems to decrease symptoms; in the late 1800s patients were treated with vibrating chairs until controlled studies showed they didn’t work.


One of the most effective drugs, L-dopa, almost didn’t happen. The first studies showed it didn’t work, but they used small doses. Fortunately, a few scientists persisted and eventually achieved dramatic results by giving a thousand times as much and adding carbidopa to enhance the effect. It changed Parkinson’s disease from a relentless devastating progression to a chronic disease with a gradual decline. But there were serious side effects. We needed better treatments, and we needed to find the cause of the disease.

Practical tricks

Patients have discovered a number of practical tricks to bypass the basal ganglia, like shifting their weight sideways to allow them to go forward. A strenuous exercise program is quite effective: it doesn’t slow the progression of the disease, but it slows the progression of the disability.

Brain surgery

In 1952 a surgeon made a serendipitous mistake. While performing a procedure called a pedunculotomy, his hand slipped and he severed the artery that supplied the basal ganglia. When the patient woke up, his Parkinson’s symptoms were gone! This discovery led to an effective operation that removed part of the thalamus. Other surgical treatments were developed, including implanting an electronic device for deep brain stimulation and implanting fetal cells.

Fetal cell grafts were initially promising, but RCTs with sham surgery showed they didn’t work, and the surgery carries serious risks. Some researchers continue to support it because there’s no doubt that it worked dramatically for two patients; they argue that it works if you do it right, and the different negative studies merely show that there are lots of ways to do it wrong.

Dopamine neurons

Could Parkinson’s be a natural consequence of aging? We lose dopamine neurons as we age; once 70% of them are gone, the symptoms of Parkinson’s kick in. If we all lived to 120 we might all develop Parkinson’s. Animals don’t get it, probably because they have shorter life spans and because they have proportionally more dopamine neurons than humans.

Researchers are looking for a way to protect or revive dopamine neurons. One treatment involves infusing a protective protein directly into the brain by catheter using high pressure. Another approach is gene therapy. Palfreman describes the vicissitudes and the difficulties of that research.

Paradigm shift

We are seeing a paradigm shift. The focus on Parkinson’s as a dopamine disorder was overly simplistic. It appears that dopamine-related symptoms are only the tip of a complex clinical iceberg with many symptoms that have nothing to do with movement, from constipation to sleep disorders, from double vision to dementia. This has been difficult to tease out, because some of these same symptoms are common with aging. Dementia may eventually affect up to 80% of Parkinson’s patients. The major risk factor for dementia is age, so paradoxically the longer we can keep patients alive, the more of them will become demented.


He quotes a patient’s thoughts on hope that are profound and applicable to other medical conditions like cancer.

…not a naïve hope that I will, by some miracle, have my former self restored, but hope that tomorrow, and the day after, can still be days from which a measure of joy and meaning can be derived.

I applaud that kind of realistic hope and deplore the false hopes that are raised by CAM and quackery.

Environmental or genetic causes?

Years before his diagnosis, the author had produced a Nova documentary titled “The Case of the Frozen Shoulder” about six young drug abusers in San Jose, California who developed the symptoms of Parkinson’s disease after injecting a bad batch of heroin contaminated with a neurotoxic contaminant called MPTP. So we know Parkinson’s can have an environmental cause, but no such cause has been linked to the majority of cases.

Genetic causes were initially dismissed. The fascinating detective story of how a genetic cause was identified is perhaps the best part of the book. It all hinged on a single clinician’s memory. A Parkinson’s patient happened to mention that her ancestors came from a small village in Italy, and the doctor remembered that a family member of another patient had mentioned the same village. He contacted a doctor in that part of Italy and by clever and dogged sleuthing they eventually determined that those two patients were seventh cousins and were two of the 574 descendants of a couple who married in 1700 and that 61 of the recent descendants also had Parkinson’s. They obtained blood samples from family members in both Italy and the US, but they didn’t have the technical skills to take the next step. Years later, researchers at the NIH asked for their blood samples and used linkage studies to roughly localize an area on chromosome 4. By sheer good fortune, one of the researchers was highly familiar with chromosome 4. Also by sheer good luck, an open-access computerized database listed the gene that had mutated. It was called SNCA, and its normal role is to make an obscure brain protein called alpha-synuclein. Researchers had identified that protein in the plaques of Alzheimer’s patients and had put the gene sequences into the database as a public service. It turns out that the characteristic Lewy bodies of Parkinson’s disease consist mainly of alpha-synuclein. This led to promising new avenues of research. Other kindreds were identified that lacked the mutation but that had too many copies of the gene. So far a total of 18 potentially genetic forms of Parkinson’s have turned up.

Cutting edge research

The prospects are exciting: it might be possible to block Alzheimer’s, Parkinson’s, ALS, and a number of other related diseases with a single drug directed at alpha-synuclein. In another development, it appeared that misfolded proteins might play a role, contagiously causing the misfolding of other proteins as in prion diseases like kuru and mad cow disease. The plot thickened when autopsies in Sun City showed that many patients diagnosed with Parkinson’s didn’t actually have the disease. Researchers are looking for biomarkers that may eventually allow early diagnosis and treatment of the disease years before the characteristic symptoms develop. They are investigating so-called “placebo responders.” They are studying the M13 virus, a bacteriophage that acts like a magic elixir with near-miraculous results in rodent studies but that is just now entering human studies. The future looks bright.

I strongly recommend Palfreman’s book

This book is an engaging detective story with edge-of-the-seat excitement that keeps the reader eager to learn what the scientists are going to discover in the next chapter. It’s a good way to learn about a devastating disease that may someday affect you or your family. And it’s a good way to learn how scientific research works, how it progresses by fits and starts, through serendipity and error as well as through well-designed studies. Highly recommended.

This article was originally published in the Science-Based Medicine Blog.

Dr. Hall is a contributing editor to both Skeptic magazine and the Skeptical Inquirer. She is a weekly contributor to the Science-Based Medicine Blog and is one of its editors. She has also contributed to Quackwatch and to a number of other respected journals and publications. She is the author of Women Aren’t Supposed to Fly: The Memoirs of a Female Flight Surgeon and co-author of the textbook, Consumer Health: A Guide to Intelligent Decisions.

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