The treatment of PD remains underpinned by levodopa and other dopamine replacement therapies (DRT). Although DRT and in particular levodopa has the ability to improve the motor symptoms of PD, motor complications still bedevil the treatment strategies in PD. In addition, new challenges have emerged. PD is now recognized as a multisystem, multineurotransmitter dysfunction‐related heterogeneous disorder.
Biomarker‐driven evidence suggests that PD is a complex disease that could present with nondopaminergic syndromes.2 Characteristics of these patients with nonmotor subtypes have been recently described. Therefore, in many, the generic prescribing of DRT may not be sufficient, and we need to be aware of the “one size does not fit all” concept regarding treatment.
Consideration of specific personal needs and the clinical phenotype of patients before prescribing is the basis of personalized medicine. The definition of personalized medicine is variable, and the American Medical Association has defined this as “health care that is informed by each person's unique clinical, genetic, and environmental information.”
Personalized medicine is an important consideration for “single multifactorial” pathology‐driven conditions and may require the use of “cocktail therapies.” This concept is now particularly relevant for PD given the multiple pathology culminating in a complex motor and nonmotor disorder.
In PD, for example, treatment needs to be prescribed based on the susceptibility of specific subtypes of PD to side effects (subtype‐specific treatment) or consideration of lifestyle, genetic framework, personality, and pharmacogenetics. This concept of personalized medicine in PD is relatively new, and the defining enablers of this strategy are shown in Figure1.
We accept that there may be substantial overlap between some components such as genetics versus pharmacogenetics or aging with comorbidity. However, true individualization of treatment needs to take into account these factors separately. Personalized medicine can also comprise of various substrategies ranging from a holistic concept to precision medicine based on genomics. In this article, we consider the various concepts that may help development of functionally effective personalized medicine in PD.
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aspergerian
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Emerging concepts suggest that a multitude of pathology ranging from misfolding of alpha-synuclein to neuroinflammation, mitochondrial dysfunction, and neurotransmitter driven alteration of brain neuronal networks lead to a syndrome that is commonly known as Parkinson's disease. The complex underlying pathology which may involve degeneration of non-dopaminergic pathways leads to the expression of a range of non-motor symptoms from the prodromal stage of Parkinson's to the palliative stage. Non-motor clinical subtypes, cognitive and non-cognitive, have now been proposed paving the way for possible subtype specific and non-motor treatments, a key unmet need currently.
Natural history of these subtypes remains unclear and need to be defined. In addition to in vivo biomarkers which suggest variable involvement of the cholinergic and noradrenergic patterns of the Parkinson syndrome, abnormal alpha-synuclein accumulation have now been demonstrated in the gut, pancreas, heart, salivary glands, and skin suggesting that Parkinson's is a multi-organ disorder.
The Parkinson's phenotype is thus not just a dopaminergic motor syndrome, but a dysfunctional multi-neurotransmitter pathway driven central and peripheral nervous system disorder that possibly ought to be considered a syndrome and not a disease.
Personalized medicine is the way forward. If a treatment "works" for me, it works for me. This fact does not change if the treatment doesn't work for you. Every dose and every experience can be seen as data for a n of 1 trial that is you.
Consider the usual way of doing clinical trials: n is large, data is sparse, some patients do well, but some do badly, is that because of the cohort having different genotypes, or phenotypes, or because of the state of their Parkinson's or just because of luck with the timing of the tests? We take the average and look at the spread of the results and often judge the results as not significant, even though some people have had a good experience.
Consider the personalized medicine approach in which PwP are monitored many times a second, and this data is used to assess the efficacy of their treatments. We assess the efficacy of the treatment on an individual basis: some patients will thrive on a particular treatment and so it will be continued, some will do badly on a particular treatment so it will be discontinued.
Since one never knows for sure whether a treatment "works" for you for all time, or whether it just appears to work (for instance, bad side effects kick in after 5 years), you will still want to learn about the experiences of others.
The introduction of many different types of computing power make this possible.
Management of gait and balance impairments in PD represents a clinically unmet need as postural deficits are largely dopamine replacement therapy resistant and gait problems ultimately become resistant to dopaminergic replacement therapy. Recognition of the unique role of PPN cholinergic neurons and their thalamopetal projections in postural control and fall risk provides an opportunity to develop new therapeutic approaches for PD patients with these motor problems. As degeneration of PPN cholinergic neurons varies among PD patients [17], we suggest a personalized medicine approach to select hypocholinergic PD subjects for targeted cholinergic augmentation therapy.
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