Bleak though the scene of its treatment may be now, the future seems to be of some hope for those suffering from, or prone to, Parkinson’s Disease (PD).
The neurodegenerative condition, which has left the scientific community scrambling for answers since its first written medical description in 1817 by James Parkinson, remains little understood despite studies of large cohorts of PD-affected across the globe.
PD is characterised by a drop in levels of dopamine, a neurotransmitter that plays an important role in smooth and controlled movements, and the body’s reward and motivation mechanism. While it isn’t clear why this happens, researchers have narrowed down that the onset of Parkinson’s occurs only when 60-80% of the brain’s dopamine-producing cells are lost.
Even today, the medication levodopa, that has been in circulation for over five decades, is the leading contender to treat PD. It works by being converted to dopamine in the brain, as dopamine itself cannot pass through the blood-brain-barrier (BBB). However, with long-term use, the side effects of using levodopa are often worse than the symptoms of the disease itself. It causes dyskinesia (uncontrolled and involuntary movement) in 50% of the individuals using the drug for periods between five to ten years.
To get around this, since the mid-1990s an evolving form of Deep Brain Stimulation (DBS) has come to the aid of those affected by the long-term effect of levodopa. But this treatment is far too expensive for most of the affected people. Moreover, the operation does not promise a future without Parkinson’s Disease-related complications.
Dr Pramod Pal, head of neurology at the National Institute of Mental Health and Neurosciences (NIMHANS ), Bengaluru, reckons that all this could change in the coming years, and gene-testing could be the answer.
“While we have been working towards managing the symptoms of Parkinson’s Disease and making it less debilitating, we have remained in pursuit of preventing Parkinson’s Disease. In that regard, I think gene-testing is the way forward, at least when it comes to the Indian demographic,” he emphasises.
“We must realise that we need India-centric treatment or research. One of the problems is that our epidemiological studies are not at the forefront,” he adds.
Dr Pal says that anywhere between eight percent and 15 percent of PD cases in India have a history of the condition in the family.
According to the latest estimates, over nine million people suffer from PD worldwide, with India accounting for 0.6 percent (six lakh). But this percentage is growing by the day. More pertinently, the condition has expressed itself differently among Indian diasporas, including an unusual number of young-onset cases.
Moreover, if a genetic test to detect Parkinson’s Disease risk becomes available, individuals would be able to be screened far earlier and more effective and gentler treatments to increase their levels of dopamine could be administered.
Early onset in Indians
“We have a unique problem in India, because family history is hard to come by,” Dr Pal explains. “Since there is little or no data to suggest that the bloodline showed any symptoms, we can only assume that they had some form of Parkinsonism. But we have seen that if the child has abnormal genes from the father and the mother, the odds of their getting Parkinson’s Disease at a later stage are high. These conditions are called Autosomal Recessive Disorders. And therefore, you should prevent marriage between blood relatives. Also, if a mother is carrying a mutation in early stages, you can see whether the child has that mutation or not, and at that point abortion is also an option.”
“Since we have better data and a growing awareness now, we should be able to deliver better diagnostics and treatment in the future,” he adds.
Dr Murali Mohan, a leading neurosurgeon in Bengaluru, seconds Dr Pal’s assessment. “We have noticed that a lot of young-onset PD cases have a genetic trail. It may skip a generation, but if we thoroughly look at the patient’s history, we notice a link,” he says.
As for young-onset cases, Dr Pal notes, “Over one third of the Parkinson’s Disease cases in country are young-onset cases. That is not what the West is dealing with. And with young-onset cases, we are dealing with a host of psychiatric problems like impulse control disorders.
So, they develop gambling, alcohol addiction or hypersexuality. Generally, the overall population in India is younger. So that could be playing a part, but we feel it could be because of the genetic architecture of the population.”
“I must admit that we could have a referral bias,” he adds.
While some of these observations address potential causes for India’s struggle with the condition, they do not explain the spike in worldwide PD numbers. “Gene-environment interaction is something worth looking into,” Dr Pal stresses.
Pollution a cause?
Besides awareness and an ageing world population, the role pollutants have played in altering the architecture and response of genes in the human system is barely understood. For instance, a study published in JAMA Neurology last year noted that exposure to nitrogen dioxide increased the odds of developing PD by 40 percent.
When people are exposed to toxic pollutants in the soil, water or air, some of them cannot get the toxins out of their bodies, again because of their genes, notes Dr Pal.
Infectious diseases could also play a role in affecting the substantia nigra, a vital area in the mid-brain, which in turn reduce dopamine production and lead to either Parkinson’s Disease or Parkinsonism. That is why, according to Dr Pal, neurologists across the world are keenly studying how covid-19 affects PD.
These inferences are a result of ongoing studies across the globe. As for tangible developments, Deep Brain Stimulation or DBS has shown good results in inducing symptom-mitigating parameters, helping the affected people to switch easily from periods of difficult mobility or ‘off’ episodes – to improved movement or an ‘on’ status.
Also, a more stable version of another medication, apomorphine, has come to their rescue even as researchers are developing newer ways to deliver levodopa.
“DBS is not an option for everyone, not only because it is an expensive procedure, but also because of several other criteria (psychiatric problems and co-morbidities, etc.) But the future is where we don’t have to do any programming from outside. The software running the lead itself recognises all the changes and adapts itself. For those who can’t afford DBS, there are other ways of introducing levodopa into the system,” he says.
“People affected by PD also face problems of absorption of the medication in the gut. To bypass this issue, newer versions and non-oral techniques to administer levodopa are available,” says Dr Pal.
One such method puts the drug directly in the intestine, but the technique is very expensive and not being done in India yet. An inhaled form of levodopa is also yet to enter India. A patch is under development.
Towards gentler methods and tests
As for technology, the future, he says, lies in Transcranial Magnetic Stimulation, advancements in electrophysiology and MRI studies. Biomarkers, Dr Pal notes, is another promising area. “We are not far from being able to detect Parkinson’s Disease by testing saliva samples or even through skin biopsies,” he says.
Dr Murali Mohan says, “Until the late 1990s, we were still using a very crude form of surgery to alleviate some of the symptoms of PD. Lesioning (using heat to numb problem areas in the brain) was used, but it was very primitive. Lesioning is still used in certain instances, but it is not as effective as DBS.”
In his view, DBS, more than being an effective surgery, helps to reduce the effects of levodopa. And it could significantly benefit those who have been on the drug for a long period.
“As for advancements, we have gotten better at navigating the surgery in operation theatres. There is sophistication when it comes to electrodes and materials used in general. As for a cure, we are yet to find one, but awareness is the key,” says Dr Murali Mohan.
The role of awareness in minimising the effects of PD cannot over overstated. The known evil of levodopa toxicity with prolonged use of the drug is encouraging experts to suggest alternative therapies that boost dopamine production naturally in the body.
These techniques can include something as simple as exercising, getting enough sleep, eating more protein, and taking probiotics. Other less conventional techniques that research is showing helps boost dopamine release in the brain is listening to different music and wearing bright coloured clothes, which in a person suffering from PD can help manage the dosage of levodopa they need to take daily.