Over two centuries since the discovery of Parkinson’s Disease: Where are we now?
-Aryaditi Jena and Sejal Kakkar
“You are nothing but a pack of neurons.” -Francis Crick
What happens when the structural and functional unit of the nervous system degenerates? It gives rise to a set of devastating conditions, collectively known as neurodegenerative diseases. Neurodegenerative diseases are a heterogeneous group of disorders characterized by the progressive degeneration of the structure and function of the central nervous system or peripheral nervous system. Neurons normally do not reproduce or replace themselves, so when they become damaged, they cannot be replaced by the body. Neurodegenerative diseases are difficult to be cured and debilitating conditions that result in progressive degeneration and/or death of nerve cells. This causes problems with movement (called ataxias) or mental functioning (called dementias). Examples of neurodegenerative diseases include Parkinson’s, Alzheimer’s, and Huntington’s disease.
Parkinson’s disease, abbreviated as PD, was first described by James Parkinson in 1817. Parkinson’s disease was already known in ancient India as “Kampavata.” It is the second most common neurodegenerative disorder. More than 10 million people worldwide are living with Parkinson’s Disease.
The Neuroscience of Parkinson’s Disease:
The cardinal symptoms of PD result mainly from a progressive and profound loss of neuro-melanin containing dopaminergic neurons in the substantia nigra pars compacta of the midbrain. The Parkinsonian pathogenesis is associated with eosinophilic, intracellular proteinaceous inclusions, termed Lewy bodies. Accumulation of these Lewy bodies generates dystrophic Lewy neurites in the brainstem and cortical areas.
The dopaminergic neurons in the midbrain project fibres up into the centre of the brain, to an area called the striatum. Cells in the striatum attempt to inhibit the signals being sent from the overlying motor cortex to the muscles in the body. The role of the released dopamine is to tone down that inhibition – it acts as volume control on the inhibitory signals. Thus, with the loss of dopamine in Parkinson’s, there is less control over the inhibition and the signal from the cortex becomes blocked in the striatum, resulting in slowness and stiffness of movement.
Environmental factors were long thought to be the predominant cause of Parkinsonism. However, recent research, through the study of certain families clearly exhibits a Mendlian inheritance pattern in Parkinsonism due to mutations in certain genes. Several causative genes have been identiﬁed, showing mitochondrial or lysosomal dysfunction, protein aggregation, ubiquitin-proteasome system, and kinase signalling pathways.
The clinical manifestations of Parkinson’s Disease begin to develop gradually. In the initial stages, PD is characterized by a classic tetrad of motor symptoms: low frequency resting tremors, the rigidity of skeletal muscles of face and hands, bradykinesia (slowness in movement), postural instability. Other symptoms include lack of coordination, slurring of speech and gait changes which may start on one side and gradually affect both sides. These symptoms worsen with time. Over the subsequent years, bradykinesia may lead to hypomimia (expressionless face), loss of balance and freezing of movements.
Latest in the Parkinsonian research domain:
Parkinson's disease and melanoma -- a type of skin cancer -- do not appear to have much in common. However, for nearly 50 years, doctors have recognized that Parkinson's disease patients are more likely to develop melanoma than the general population. Now, scientists report a molecular link between the two diseases in the form of protein aggregates known as amyloids.
Several microRNAs in the blood of people with Parkinson’s disease differ from healthy controls, correlate with disease progression, and are associated with hallmarks of the disorder, a large-scale study reported. These findings support the possible use of microRNAs as biomarkers in diagnosing Parkinson’s and in predicting a patient’s prognosis.
At the University of Manchester, researchers used gas chromatography/mass spectrometry to analyze sebum (waxy substance produced by your body's sebaceous or oil glands) and concluded that changes to lipid profiles in the sebum of people with PD can be used as a potential biomarker for clinical diagnosis of the disease. The analysis revealed 10 metabolites, including ceramides and fatty acyls, that differed significantly from the control cohort in both the drug-naive and medicated populations.
Researchers identified new genetic loci associated with Lewy body dementia & provide insights into the genetic architecture of Parkinson’s Disease. GWAS analysis identifies 5 independent risk loci, while genome-wide gene-aggregation tests implicate mutations in the GBA gene. The 5 independent genome-wide significant loci that influence risk for developing LBD: GBA, BIN1, TMEM175, SNCA-AS1, & APOE.
Parkinson’s Disease and the Pandemic:
Previous studies have not clarified whether having PD is associated with higher mortality rates in COVID-19 patients. In a preliminary study titled “Coronavirus Disease 2019 Case Fatality and Parkinson's Disease”, carried out by Qiang Zhang et.al., people with PD were observed to have a higher risk of mortality from COVID-19 than those who did not have PD.
Parkinson’s disease patients who get infected with COVID-19 are more likely to experience severe respiratory issues and post-COVID morbidity. Another additional concern for those with PD is that the coronavirus may trigger a worsening of motor and non-motor symptoms. These mental health challenges are known to be higher for people with PD living under social isolation, higher stress levels and without adequate exercise.
Recently published in the Journal of Parkinson’s Disease, titled, “COVID-19 Vaccination for Persons with Parkinson's Disease: Light at the End of the Tunnel?” tackles the question of getting the COVID-19 vaccine for people with Parkinson’s using a scientific, evidence-based approach. Based on efficacy and safety from Phase III data and considering the risks of COVID-19 in the PD population, the approved vaccines are strongly recommended for patients with Parkinson’s Disease.