Epidemiological studies have shown lower age-related prevalence of Parkinson's disease in South Asians, with the rate of prevalence being around 52.7 per 100,000 as compared to a higher prevalence rate observed in populations with European origin, 108-257 per 100,000. Additionally, several studies have seen a higher prevalence of in women which contrasts with global data that observes an overall higher prevalence seen in men. Compared to most of the rest of the world, the South Asian countries (including India, Pakistan, Nepal, Bhutan, Maldives, Afghanistan, Sri Lanka, and Bangladesh) seem to be on the lower end of PD prevalence. However, this is not to say that PD is not of concern in these countries. Over the past couple of years, the rate of Parkinson's has gone up in South Asia meaning that it is of high importance to study this pathological disease in these populations.
Background
Parkinson's disease (PD) is a chronic neurodegenerative disorder caused by the progressive degeneration of dopamine-producing neurons in the substantia nigra, a structure located in the midbrain essential for reward and movement. The rapid deterioration of these dopaminergic neurons leads to both motor and non-motor complications. Being that they are quite visible, the motor symptoms are usually used as a preliminary basis for the diagnosis of PD, particularly deterioration of voluntary movements along with muscular rigidity. Tremor, postural instability, dystonia, and speech disturbances are among the most common motor symptoms in PD cases and are heavily researched in an effort to develop efficient methods of management. Conversely, the non-motor symptoms, including cognitive decline, depression, and sleep disturbances, are not as rigorously studied. Many of these complications develop prior to motor symptoms as early as 10 years before a formal diagnosis and tend to become comparatively more cumbersome as the disease advances. Although, in general, the exact cause of PD is unknown, it is likely that both genetics and environment are contributing factors. Along with around 90 genetic risk variants which account for 16-36% of non-monogenic PD, additional variables such as being a non-smoker can influence the risk a given person has for developing PD.
Pathology
Substantial loss of melanized dopaminergic neurons in the substantia nigra pars compacta (SNpc) is a major characteristic of PD pathogenesis. Many studies have shown that differential prevalence of PD between ethnic groups is due to differences in the number of melanized neurons in the substantia nigra. Most Indians, compared to populations with European origin, have around 40% lower in number of melanized nigral neurons, however, they also tend not to lose these neurons with age. Although Indians do have a lower SNpc volume, this population tends to have a higher neuronal density as well as number of neurons which is hypothesized to be the reason for a lower incidence rate of PD, but this needs to be expanded upon.
Another hallmark of PD pathology is the development of Lewy bodies (LBs) in dopaminergic neurons which are protein aggregates that impair neuronal function. A major component of the structure of these LBs is α-synuclein which becomes phosphorylated followed by aggregation in pathological conditions. Under normal conditions, α-synuclein remains mostly unfolded with some parts of the protein folded into α-helical structures, however, in PD, it assumes a β-sheet amyloid structure which is highly susceptible to aggregation. Due to dietary differences, South Asians tend to consume higher levels of curcumin, a strong anti-oxidant and anti-inflammatory agent, which has been observed to attentuate α-synuclein aggregation. However, variation in LB and α-synuclein pathologies in the South Asian population is heavily under studied and needs to be further elucidated.
Ethnic research limitations Similar to many other diseases, genetic risk factors for PD have been and still are investigated through genome-wide association studies (GWAS). Although the GWAS database has revolutionized genetic studies, they are not an accurate representation of the global population's genetic diversity as most of the samples in these datasets are from populations with European backgrounds. Specifically in Parkinson's, most implicated genes that have been associated with both familial and monogenic forms of PD are prevalent in persons of European descent. Additionally, many of the newly found risk variants screened through GWAS that have been associated with around 25% of the disease heritability are mainly from studies that included only individuals of European ancestry. A lack of diversity in PD research limits the relevance of these findings towards populations of other ethnicities.
Diagnosis Diagnosis for Parkinson's is based on a defined criteria and is usually, as mentioned, based on the first motor symptoms. This includes slowness of initiating voluntary movements and bradykinesia along with one more symptom including tremor or muscular rigidity. Any symptoms that could indicate other diseases, such as parkinsonian syndrome, have to be excluded in the screening process as they have different pathological effects compared to PD. Additionally, there needs to be at least three criteria present such as unilateral onset, persistent asymmetry affecting the onset side more, and a positive response towards treatment with levodopa.
Epidemiological differences in PD cases are affected by average knowledge of Parkinson's among populations. Due to a lack of symptom awareness, Parkinson's is oftentimes under-reported in South Asian populations. A study looking into PD knowledge in Asia found that there was not as much awareness regarding non-motor symptoms in the Indian population as compared to East Asian populations. Additionally, Indians were not aware that tremor is not a required symptom to be diagnosed with Parkinson's disease. It is also noted that South Asians, especially the Indian subcontinent has been having younger age of onset of Parkinson's disease as compared to global average. This gap is predicted as high as a decade earlier which is reflected in various recent publications. Because diagnosis partly relies on self-reporting symptoms, this gap in knowledge can make it difficult to get an accurate representation of the variation within the South Asian population as well as become a barrier toward understanding how this disease manifests differently.
Ethnic variation From studies looking at Parkinson's in South Asian populations, ethnic variation has been observed in both motor and non-motor symptomology. These populations seem to be more prone towards experiencing a rigid-akinetic dominant phenotype of this disease as opposed to the tremor-dominant phenotype meaning there is a slowness of movement initiation along with stiffness of muscle tone. The rigid-akinetic phenotype has been linked with a higher risk of both cognitive dysfunction and motor decline. Non-motor symptoms (NMS) have been sparsely studied in South Asian PD patients including a couple of studies looking at the incidence rates of some common NMSs in Pakistan. +Incidence rates of non-motor symptoms between ethnic groupsCountryTotal participantsDrooling (%)Constipation (%)Hyperhidrosis (%)Insomnia (%)Urinary urgency (%)Depression (%)Anxiety (%)Pakistan9737603753625240United States7027301941593836United Kingdom15855421018463742
Contributors to ethnic variation
Genetic
There are many genes that are implicated in PD with each one being differentially prevalent between populations. Initial works on genetics for Parkinson's disease in south Asia were limited. In last few years large scale studies are going on, which are giving more instights into the genetics understanding and variations in South Asian Populations. Along with many others, the following genes have been implicated in PD in South Asian populations with further understanding of Polygenic Risk Scores.
Glucocerebrosidase (GBA) The GBA gene encodes for glucocerebrosidase (GCase) which is a lysosomal enzyme that breaks down glucosylceramide into glucose. In the context of Parkinson's, mutations in GBA occur at a higher frequency than other genes indicated in PD. Although the exact mechanism of mutant GBA and its contributions towards PD has not been elucidated as of yet, there are proposed mechanisms that mutations in this gene might be gain-of-function or loss-of-function. In general, it is likely that mutant GBA accumulates and affects lysosomal function leading to dysregulation of autophagic pathways which is essential for the degradation of α-synuclein in dopaminergic neurons. Only a few studies have examined the prevalence of GBA variants in South Asian populations with most looking at Indian patients. Most of these studies have shown that, compared to populations with European backgrounds, GBA variants are not as common in Indian populations. Among all of the GBA variants, Indian patients carrying the p. Leu444Pro mutant have observed to have an earlier onset of PD as well as a positive family history. However, even then, the frequency of this mutant is quite low which points towards the possibility that the p. Leu444Pro variant, and GBA mutants in general, have a limited role in the pathogenesis of PD in Indian populations.
PARKIN Encoded by the PARK2 gene, the PARKIN protein is a ubiquitin ligase that is indicated in protein processing as well as degradation and is essential for the quality control of proteins. Mutations in PARKIN have led to a loss-of-function resulting in an accumulation of the ligase's substrate causing the degradation of dopaminergic neurons in the substantia nigra. Importantly, these mutations have been the most common cause of autosomal recessive early-onset PD (EOPD) in familial disease with the estimated frequency being 50%. Comparatively, prevalence of mutations in PARKIN, looking at specifically the Indian population, contributing to EOPD was 10% in familial cases and 25% in autosomal recessive cases. The PARK2 gene itself is highly polymorphic with its pathological variants being highly prevalent. The G1239C and G1281A variants, specifically, exist at high frequencies and both interfere with the binding efficiency of PARKIN to its substrate.
Dysregulation of PARK1 and PARK4 caused by mutations in the α-synuclein (SNCA) gene accounts for 1.7-2.7% of familial Parkinson's and 0.3% of spontaneously occurring PD. In South Asian studies, focusing on Indian populations, there were no observed instances of PD patients with mutations in the SNCA gene. In general, it seems to be that populations with Indian descent do not seem to have as much of an incidence of PARKIN mutations as compared to that of other populations; although, these studies can be expanded upon in order to be relevant to other South Asian countries.
LRRK2 Leucine-rich repeat kinase 2 (LRRK2) plays a role in the phosphorylation of Rab GTPases which consequently regulates vesicular trafficking. Dysfunction of the LRRK2 due to a mutation in its gene has been linked with being a genetic risk factor for familial and sporadic forms of PD as well as causing autosomal dominant late onset forms of PD. High activity of pathogenic LRRK2 is associated with dopaminergic neuronal death, defects in protein synthesis, oxidative damage among others. Variants of this kinase, specifically the p.G2019S mutant, are reported to be differentially prevalent among populations, but in most Asian populations, including South Asia, these mutations are reported to be absent. However, in more recent studies that have more comprehensively screened the genome of multiple ethnic populations found four novel LRRK2 variants specific to the Indian population, granted the significance of these mutants have not yet been assessed.