Personalized medicine in Parkinson's disease: Time to be precise

Federal State Budgetary Educational Institution of Higher Education “N.I. Pirogov Russian National Research Medical University” of the Ministry of Healthcare of the Russian Federation, Moscow, Russia National Parkinson Foundation International Centre of Excellence, King’s College London and King’s College Hospital, London, UK Department of Basic and Clinical Neuroscience, The Maurice Wohl Clinical Neuroscience Institute, King’s College London, London, UK National Institute for Health Research South London and Maudsley NHS Foundation Trust and King’s College London, London, UK

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. 1,2 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. 3,4 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. 2 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 Figure 1. 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 (Fig. 2). In this article, we consider the various concepts that may help development of functionally effective personalized medicine in PD.

Genetics and Pharmacogenetics
Personalized medicine could predict the susceptibility for the development of PD in an individual basis, and the genetics of PD is important in this context. Identifying at-risk individuals through known genetic susceptibility markers in the preprodromal stage of PD could help precision medicine delay or stop the development of clinical PD (Fig. 3). 5 Although genome-wide association studies have identified a number of PD loci, these do not explain the main bulk of heritability issues in PD. Monogenic PD is rare; however, early-onset autosomal dominant presentations can identify specific genes (such as mitochondrial genes DJ-1, Phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1)) or gene products (aberrant oligomeric alpha-synuclein aggregates). Potentially, this knowledge would identify mechanisms resulting in the mishandling of alphasynuclein and the formation of aberrant oligomeric aggregates (Fig. 3). Specific therapies can then be developed to counteract these mechanisms.
One example is the increased frequency of PD in heterozygote carriers of the glucocerebrocidase gene (GBA), and approximately 5% to 10% of PD patients have GBA mutations. 6 A GBA mutation is currently the most important genetic predisposing risk factor for PD, particularly in the White population, although there are racial variations. For instance, the GBA genotype at rs6812193 single nucleotide polymorphism is not seen in the Chinese population. 7 There is a reciprocal relationship between glucocerebrocidase (GCase) activity and alpha-synuclein function. 8 Enhancing GCase activity may lead to regulation or even attenuation of the formation of misfolded oligomeric alpha-synuclein. 8 In a mouse model of Gaucher's disease, adeno-associated viral vector delivery of the recombinant GCase into the brain caused modulation of alpha-synuclein deposition and improved memory deficits. 6,9 Precision medicine strategy could also be driven by the alteration of activity of chaperone protein such as Hsp90 involved in recognition of misfolded alpha-synuclein (Fig. 3). Specific histone deacetylase or Hsp90 inhibitors acting as pharmacological chaperones such as ambroxol or isofagomine may therefore be beneficial, and clinical trials are in progress. 6,8 In terms of personalized medicine, a strategy of combined chaperone  and GCase augmentation-based "cocktail" therapy could be useful for GBA-positive carriers who remain at risk of conversion to clinical PD. This method could also be useful in those with sporadic PD and documented reductions in GCase activity (Fig. 3). This is particularly relevant as GBA gene mutation variants have been shown to be associated with a specific cognitive subtype in PD with a rapid cognitive decline progressing to dementia. 9 Similarly, the identification of the carriers of the leucine-rich repeat kinase 2 gene (LRRK2) could be targeted with LRRK2 inhibitors. In rodent models, the LRRK2 inhibitor GNE-7915 enhanced the release of dopamine and also synaptic vesicle mobilization and recycling. 10 Another approach of personalised medicine is pharmacogenetics. Pharmacogenetics implies the influence of inherited genetic differences in drug metabolic pathways which affect individual clinical responses to drugs as well as adverse events. 11,12 In PD, the role of  pharmacogenetics is slowly evolving and some examples include the following: The mutations of the catechol-O-methyl transferase (COMT) gene and response to levodopa based on high-and low-activity alleles, 13 The genetic mutations associated with impulse control disorders (dopamine receptor D3 (DRD3) [AA genotype], glutamate ionotropic receptor NMDA type subunit 2B (GRIN2B) [CC geneotype], HTR2A c.102T allele), 14,15 Dopamine receptor D2 (DRD2) (CA dinucleotide short tandem repeat) polymorphism appearing to show a protective effect on development of levodopainduced dyskinesias in men but not in women. 16 In addition, single nucleotide polymorphisms rs2283265 and rs1076560 of the DRD2 gene have been reported to be significantly associated with a good response to rasagiline in early PD. 17 Possible clinical implications are outlined in Table 1; however, it must be pointed out that there are contradicting studies, and at this moment no definitive recommendations can be provided. 12 Pharmacogenetic strategies could also potentially be useful for excessive daytime sleepiness (COMT polymorphism, DRD2, and DRD4 [both linked to "sleep attacks"]), hypocretin neuropeptide precursor (HCRT) (prepro-hypocretin), and psychosis (dopamine receptor D4 (DRD4), cholecystokinin (CCK), apolipoprotein E (APOE4), angiotensin convertin enzyme (ACE)) in PD, although clinical implications are unclear and controversial. 18,19 Age: Biology, Chronology, and Personalized Medicine Aging is a complex process, and there may be differences between chronological versus biological aging. However, many anti-PD therapeutic strategies define age as a definitive landmark that influences therapy. For instance, in clinical practice dopamine agonists are often not prescribed in "older" PD (defined by Genetic: telomeres and telomere length as a possible biomarker of biological aging Comorbidity: whether present or absent (see Table 3) Imaging biomarkers: magnetic resonance imaging DRT-related adverse events (ICD, dyskinesias) in younger patients Tolerability of DRT (young vs old) DRT, dopamine replacement therapy; ICD, impulse control disorder.

T I T O V A A N D C H A U D H U R I
chronological age) because of the possibility of side effects; in addition, deep brain stimulation is usually not attempted beyond 65 to 70 years. Such generic strategies do not take into consideration "healthy aging," a longer life span, and differences between biological and chronological aging. Aging-related variables that may influence personalized medicine are outlined in Table 2.
Telomeres are crucial for adjusting cellular response to stress as well as the stimulation of cell growth and work by "capping" chromosomes (Table 2). 20 With the accumulation of "uncapped" or short telomeres, apoptosis and cell death are triggered. Aging is associated with a decline in telomere length that results in a progressive functional reduction of tissue function and causes mortality although studies have suggested that short telomere may not be linked to PD. 20 Clinically, enhancing telomerase functional activity as well as the inhibition of telomerase activity have been explored in cancer therapy, and a telomerase template unit (GRN163L) is currently undergoing clinical trials. 21 Telomerase immortalized midbrain astrocytes has been used in rodent PD models to direct stem cells to dopaminergic cells. 22 Although there was dopaminergic neurogenesis, there was also uncontrolled expansion similar to tumorogenesis.
Personalized medicine concurrent with aging could be supported by magnetic resonance imaging showing focal (medial temporal or global) atrophy or white matter vascular disease, suggesting an increased propensity to cognitive impairment. This should trigger early consideration for cognitive testing and a low threshold for the use of cholinesterase inhibitors in addition to social and home care support.
Some dopamine agonists such as transdermal rotigotine patch are well tolerated in older patients and maybe a suitable and preferable choice, particularly if there are gastrointestinal issues. 23,24 Comorbidities PD is associated with a number of comorbidities that may guide management strategy of PD independent of aging (Table 3). Examples include type 1 diabetes in younger PD versus type 2 in older patients, whereas thyroid dysfunction can cross any age group. Personalized medicine strategies should thus take into account the impact of cerebrovascular and cardiovascular risk factors (some antihypertensives have a dopamine-blocking effect), the influence of diabetes and osteoporosis, a major problem in older female patients with PD.

Personality and Perception of Treatment (Listening to the Patient)
Patient choice and informed decision making is key to the 21st-century management of PD. The main factors related to personality and personalized medicine are listed in Table 4. Successful treatment of PD should consider personality traits that may be a risk factor for the development of impulse control disorders (ICD), dopamine dysregulation syndrome, and levodopaphobia. [28][29][30] Personal and cultural beliefs such as a reliance on complementary or alternative therapies could inherently make the patient less likely to accept conventional DRT. In some patients, rigid perceptions may influence the acceptability of the DRT delivery pattern. As an example, some patients may find nonoral therapies unacceptable. Personalized medicine strategy in these patients should include close liaison with primary and secondary care in addition to detailed explanations of DRT. Those who have had poor compliance with multiple dosing-based previous treatment strategies or are currently noncompliant for DRT, need to be considered for once-a-day therapy.

Lifestyle
Activity levels related to lifestyle choice are important because patients active in sport and profession may prefer once-a-day therapy as opposed to DRT  Personality predisposing to reward seeking behavior and risk factors for ICD, dopamne dysregulation, and punding [28][29][30] Novelty seeking behavior High alcohol consumption History of substance abuse and drug addiction Single status Presence of medical therapy phobia, particularly levodopaphobia Belief in alternative or complementary therapies such as homeopathy Personal and cultural belief of patient and carergiver Past and current history of noncompliance to regular prescribing ICD, impulse control disorder.  taken several times a day (Fig. 4). The delivery pattern of dopaminergic drugs may also be relevant (oral vs nonoral). Concern over the loss of employment and the type of employment could influence personalized medicine. In an employed younger PD patient, one may have to opt for rapid relief of motor and nonmotor symptoms by using appropriate DRT or rescue therapies so that the patient can continue to work. In others engaged in machinery operating or work requiring high levels of alertness, sedating DRT and other therapies need to be avoided.

Pharmacoeconomics
The acceptability of prescribed DRT in PD depends on the affordability and the local reimbursement system. Unfortunately, in many countries expensive anti-PD drugs are either self-funded or need expensive insurance. These pharmacoeconomic issues are important for the success of individualized therapy in PD.

Nonmotor Subtypes of PD and Personalized Medicine
The concept of nonmotor subtypes is based on the biomarker-driven identification of phenotypes comprising of cholinergic, noradrenergic, serotonergic, and mixed neurotransmitter dysfunction underpinned by dopamine deficiency. 1,2 The resulting clinical phenotypes are likely to have nonmotor symptoms ranging from cognitive to sleep (Table 5). 3,4 These findings have also been replicated by cluster analysis of de novo PD cases and individual cohort studies. 31,32 Personalized medicine in these subtypes involves the treatment of specific nonmotor symptoms and consideration of the nonmotor side effects (such as sudden onset of sleep) of dopaminergic drugs. This can be achieved by a multimodal approach with imaging, genetic, pharmacogenetic biomarkers resulting in a subtype-specific treatment strategy (Fig. 5). Proposed strategies are summarized in Table 5. In addition, future imaging may help stratify treatment in patients susceptible to DRT-related side effects. Imaging showing abnormal dopamine turnover or release (eg, in ventral striatum) may imply susceptibility to levodopainduced dyskinesias or ICD and help develop tailored therapy.

Conclusions
Contrary to the common perception that personalized medicine is completely based on a genetic approach, we feel a holistic strategy spanning genes, clinical subtypes, personality, lifestyle, aging, and comorbidities constitute true personalized medicine. Enriching the phenotypic expression of PD with a multimodal clinical-and biomarker-based approach may be the best way to address individualized treatment to achieve better clinical effect (Fig. 5). However, the complex nature of PD coupled with clinical phenotypic heterogeneity presents major challenges for formulating successful personalized medicine. Further research is therefore urgently needed to evaluate the best ways to deliver state-of-the-art personalized medicine in PD.