Parkinson's disease is the second most prevalent neurological condition following Alzheimer's disease. Those with the condition typically experience movement difficulties, cognitive deficits, comorbid affective disorders, and sleep difficulties.
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Due to the progressive nature of the disease and the deliberating effects of the symptoms, researchers continue to investigate its etiology actively. New research has successfully identified neuropathological changes that precede the onset of symptoms by 20 years.
Identifying Early Symptoms in Parkinson's Disease
Researchers at King's College London have successfully identified the earliest neurological markers of Parkinson's disease (PD) that can predict the likelihood of someone developing the condition 20 years before they present with any symptoms.
It is hoped that by studying the early stages of PD, appropriate treatments can be devised to help slow down the progression of the disease, which has been a great difficultly for many researchers.
So far, research has successfully identified an association with PD and decreased dopamine levels in the substantia nigra. As a result of this, many treatment options aim to relieve symptoms by increasing dopamine levels in the brain. However, no cure currently exists for the disease.
The study, published last year in journal Lancet Neurology, has identified alterations within the serotonergic neurotransmitter systems in the brain in the very early stages of PD.
Changes in The Serotonin Systems
The researchers scanned the brain of 14 individuals aged between 20 and 40 who had an atypical genetic mutation that drastically increases their risk of developing idiopathic PD by the time they reach their late forties or fifties.
Specifically, the sample were carriers of the dominant A53T point mutation for the α-synuclein (SNCA) gene. The mutation derives from a small number of villages in northern Greece and in those who have emigrated to Italy.
Based on previous research within this population, the team hypothesized that such carriers have irregularities within their serotonin neurotransmitter systems. This pathology present before a PD diagnosis was thought to be linked to the onset of the disease.
Half of the participants at the time of the research had been diagnosed with PD, while the other half were not currently presenting with symptoms.
The 14 participants underwent a set of assessments and brain imaging and their data compared against 65 individuals with confirmed idiopathic PD and 25 healthy controls.
When analyzing the results, the team found that the genetic mutation carriers had significantly lower levels of serotonin which is typically involved in movement, cognition, and mood.
This pathology was evident prior to any presentation of movement difficulties or changes in the dopamine system.
Implications
The team's research contrasts with what is currently understood about the onset of the disease. However, the promising results could lead to the development of screening tools that could identify those most at risk and lead the way for novel treatment.
For example, Professor Marios Politis, the Chief Investigator of the researchers noted, "Our results suggest that early detection of changes in the serotonin system could open doors to the development of new therapies to slow, and ultimately prevent [the] progression of Parkinson's disease."
However, before this can be achieved, the results would need to be replicated in larger sample sizes and more affordable scanning technology produced.
What is Parkinson's?
Parkinson's is a progressive neurogenerative disease. Those with PD experience the following main signs and symptoms:
- A resting tremor characterized as involuntary shaking of the limbs which typically originate in the arm or hand.
- Rigidity characterized as tension and stiffness of the muscles.
- Bradykinesia defined as slowness of movement.
A range of additional physical and psychological symptoms may also be experienced. These include constipation, anosmia, erectile dysfunction, mild cognitive impairment, and anxiety and depression.
There is a long latency between the loss of dopamine and the onset of the symptoms. As a result, some of the symptoms may not present until approximately 70-80% of the dopamine neurons have been lost.
Considering this, researchers have highlighted the importance of identifying individuals in the intermediate stages of the disease in order to develop neuroprotective strategies of treatment.
Biomarkers of Parkinson's
The neuropathological hallmarks of Parkinson's disease include the presence of Lewy bodies containing a protein called α-synuclein in the brain and the depigmentation of dopamine. It is not currently well understood what triggers some of these hallmarks to arise.
However, several genetic mutations have been shown to be associated, including GBA1, VPS35, α-syn, PINK1, and LRRK2 mutations.
A range of other biomarkers has also been identified including orexin, MHPG, and ApoA1.
Orexin
Orexin is a type of neuropeptide hormone found in the hypothalamus. Its primary function is to regulate bodily functions, including those involved with sleep and cardiovascular function. Research has shown that those with PD have lower amounts of orexin-A which has a negative relationship with PD severity.
3-methoxy-4-hydroxyphenylglycol (MHPG)
MGPG has shown promise as a biomarker. It can help practitioners differentiate between neurodegenerative conditions such as PD, dementia with Lewy bodies, Alzheimer's disease by analyzing its concentration in the serum, and cerebrospinal fluid.
ApoA1
Apolipoprotein (ApoA1) in addition to apoE, a similar apolipoprotein, transport lipids in the brain. Research has shown that those with PD often have lower concentrations of apoaA1 in the cerebrospinal fluid and can, therefore, be used as a biomarker for the disease.
Sources
- Wilson, H., Dervenoulas, G., Pagano, G., Koros, C., Yousaf, T., Picillo, M., Polychronis, S., Simitsi, A., Giordano, B., Chappell, Z. and Corcoran, B., 2019. Serotonergic pathology and disease burden in the premotor and motor phase of A53T α-synuclein parkinsonism: a cross-sectional study. The Lancet Neurology, 18(8), pp.748-759. https://doi.org/10.1016/S1474-4422(19)30140-1
- El-Agnaf, O.M., Salem, S.A., Paleologou, K.E., Curran, M.D., Gibson, M.J., Court, J.A., Schlossmacher, M.G. and Allsop, D., 2006. Detection of oligomeric forms of α-synuclein protein in human plasma as a potential biomarker for Parkinson’s disease. The FASEB Journal, 20(3), pp.419-425.
- Berendse, H.W., Booij, J., Francot, C.M., Bergmans, P.L., Hijman, R., Stoof, J.C., and Wolters, E.C., 2001. Subclinical dopaminergic dysfunction in asymptomatic Parkinson's disease patients' relatives with a decreased sense of smell. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society, 50(1), pp.34-41.
- NHS (2019). Parkinson’s disease: symptoms. https://www.nhs.uk/conditions/parkinsons-disease/symptoms/
- Wang, E.S., Sun, Y., Guo, J.G., Gao, X., Hu, J.W., Zhou, L., Hu, J., and Jiang, C.C., 2010. Tetranectin and apolipoprotein A‐I in cerebrospinal fluid as potential biomarkers for Parkinson’s disease. Acta neurologica scandinavica, 122(5), pp.350-359.
- Vermeiren, Y. and De Deyn, P.P., 2017. Targeting the norepinephrinergic system in Parkinson's disease and related disorders: the locus coeruleus story. Neurochemistry international, 102, pp.22-32.
- Imperatore, R., Palomba, L., and Cristino, L., 2017. Role of orexin-A in hypertension and obesity. Current hypertension reports, 19(4), p.34.
- Emamzadeh, F.N., and Surguchov, A., 2018. Parkinson’s disease: biomarkers, treatment, and risk factors. Frontiers in neuroscience, 12, p.612.
Further Reading
Research uncovers new mechanism in protein aggregation linked to Parkinson's disease