Dr. NK Venkataramana, Founder Chairman & Director, Brains Super Speciality Hospital.

Even after centuries relentless research Parkinson’s disease (PD) continues to be elusive in understanding the exact mechanisms and causes by which the disease manifests. However, the incidence and disease burden continues to increase all over the world making it the second most common degenerative disease. It is estimated that nearly 12 million people are going to be affected by 2040. Parkinson's disease primarily affects the movements of the body, making the person slow in all activities, and is associated with shaking of the body called tremors.

Major symptoms involve - Shaking of hand or leg (tremor) at rest, slowness of movement (Bradykinesia), stiffness of limbs and body (rigidity), and stooping posture with imbalance (postural instability). These four are considered the cardinal symptoms of Parkinson's disease. However, many motor and non-motor symptoms will develop as the disease progresses. Though Levodopa was discovered in 1967 and remains the mainstay of treatment even today, several challenges in treatment and disease progression remain formidable challenges. It is estimated with best controlled treatment dyskinesias will develop in an average of 5.8 years of treatment and significant motor fluctuations after 10 years. These two will affect the quality of life significantly.

Hence the need to search for new treatment options has become a dire need. Therefore currently 147 active clinical trials are ongoing. Of which 42% of studies are evaluating novel new therapies and 34 % of studies are focusing on repurposing drugs.

Present understanding of the disease

The disease often manifests as sporadic; though the genetic association has been identified in many more so in young-onset Parkinson's disease. However, the exact mechanism is still not clear. Recent research has shown evidence that there are two types 1. The body first and 2. Brain first depends upon the appearance of Lewi bodies. The disease has three phases 1. The preclinical phase 2. The prodromal phase 3. The clinical phases. According to Braak’s hypothesis, the preclinical phase might last for 10 - 15 years and might offer a good window if it can be diagnosed to halt the progression. This may be very nonspecific and vague so often this phase is missed in clinical practice. Whereas prodromal phase the symptoms are very mild and may have mild tremors where neurodegeneration is progressing rapidly. The clinical phase will have full-blown symptoms with fully established disease.

The body's first type - The disease is supposed to start in the gut. The gut microbiome will undergo a process called “dysbiosis”. These specific bacteria will interact with gut neurons and the signals are carried through the vagus nerve to its nucleus in the brain stem. The Lewi bodies are first detected in the gut, vagus nerve, peripheral nerves, and then in the brain stem first, followed by locus coerelius and later in the rest of the brain. When the entire brain is affected symptoms manifest.

The Brain first - The bacteria or toxins enter through the nose and olfactory nerves and the amygdala will be affected. Later it spreads to the substantia nigra, locus coerelius, and rest of the brain. Body first is slow in progression and can be effective for treatment options. However, dementia and side effects of medication are more common. In the brain, first more autonomic disturbances, sympathetic denervation, parasympathetic denervation, locus coerelius degeneration, and many non- motor symptoms will predominate the illness.

The mainstay of pathology is the accumulation of alpha synnuclein a protein that regulates the size of dopaminergic vesicles in presynaptic membran3 and also the synaptic transmission. The toxic accumulation of this protein will eventually kill the dopamine-secreting cell in the substantia nigra. The resultant inflammation will infect adjacent cells causing further destruction and disease progression. The accumulation of this protein and the inability of the cell to excrete the toxic material seems to be genetically mediated. Whereas the inflammation and subsequent cell damage is immune system mediated.

MEDICAL THERAPY:

Levodopa (supplementation of Dopamine) is the mainstay of medical treatment. This drug is taken orally in multiple doses and relieves all the major symptoms of PD. As the disease progresses, the patients develop drug tolerance, fluctuation in clinical benefit, and side effects. Five discoveries were introduced in recent years

1. Newer drugs were approved between 2017 and 2021. a) Levodopa as inhalation - particularly in the off periods. b) Sublingual Apomorphine for quick and more sustainable action c) Safinamide and Istradefylline to treat motor fluctuations d) Opicapone as supplementary to enhance the duration of action of Levo dopa e) Extended-release Amantadine NMDR antagonist for dyskinesias.

2. Technological improvement - scored levodopa tablets. Has four components that can be taken separately and in tandem for precise adjustments of drug dosage and action.

3. Procedures - A) Focused ultrasound delivered with MRI guidance. The focused ultrasound will produce a precise thermal lesion in the thalamus. Very beneficial for unilateral tremors. Tremor relief is sustained on long-term 5-year follow-up. Improvements in quality of life occur around one year. A non-invasive method of treatment. B) Directional DBS - here the newly designed electrode has 2 rings with a total of 8; contact points. Stimulation can be selective, and directional with multiple options to get the best effect and to avoid adverse effects. The direction of stimulation can be directed in such a way the side effects can be totally reduced or minimized significantly. This will allow more targeted programming. The sensing technology will allow individualized stimulation as well as remote programming.

4. Nondopaminergic pathways - other deficiencies in other systems also seem to influence the benefits of treatment. More focus on identifying such defiant replacements will help.

5. Avoid accumulation of Synnuclei. Recently human monoclonal antibodies have been developed to achieve the purpose. In addition, Disease-modifying agents such as anti- inflammatory agents, modifying gut microbiome, and gene species therapies are being tried. A variety of drugs are evaluated for drug repurposing. Many are used as adjuvants to enhance the therapeutic benefits at the moment.

Cell therapies particularly iPSC clinical trials are ongoing with a lot of hope and promise in Japan, China, Sweden, the UK, and the USA. Results are awaited.

Since the disease is quite complicated a continuous search for newer and better options is needed for sure. More importantly, establishing the diagnosis in the window period before the onset of symptoms provides a great lot of opportunities to prevent, postpone, or stall the progression. However, it needs more meticulous research and validation. Maybe a good biomarker might be of immense help. A combination of all available options is another method to try and use in clinical practice. Supportive measures like a healthy lifestyle, avoidance of toxins, modifying microbial flora of the gut, and environmental improvements are some of the relatively simple and possibly effective solutions that can be tried immediately.

Though treating PD is still a challenge the developments are equally exciting. Hope medical discoveries soon will crack the puzzle offering better solutions for the future.