Parkinson's Disease

 

                                                       Parkinson's Disease

Parkinson's disease genes, thus representing monogenic Parkinson's disease, whereas 90 ü

genetic risk variants collectively explain 16–36% of the heritable risk of non-monogenic Parkinson's disease. Additional causal associations include having a relative with Parkinson's disease or tremor, constipation, and being a non-smoker, each at least doubling the risk of Parkinson's disease. The diagnosis is clinically based; ancillary testing is reserved for people with an atypical presentation. Current criteria define Parkinson's disease as the presence of bradykinesia combined with either rest tremor, rigidity, or both. However, the clinical presentation is multifaceted and includes many non-motor symptoms. Prognostic counselling is guided by awareness of disease subtypes. Clinically manifest Parkinson's disease is preceded by a potentially long prodromal period. Presently, establishment of prodromal symptoms has no clinical implications other than symptom suppression, although recognition of prodromal parkinsonism will probably have consequences when disease-modifying treatments become available. Treatment goals vary from person to person, emphasising the need for personalised management. There is no reason to postpone symptomatic treatment in people developing disability due to Parkinson's disease. Levodopa is the most common medication used as first-line therapy. Optimal management should start at diagnosis and requires a multidisciplinary team approach, including a growing repertoire of non-pharmacological interventions. At present, no therapy can slow down or arrest the progression of Parkinson's disease, but informed by new insights in genetic causes and mechanisms of neuronal death, several promising strategies are being tested for disease-modifying potential. With the perspective of people with Parkinson's disease as a so-called red thread throughout this Seminar, we will show how personalised management of Parkinson's disease can be optimised. Introduction

Parkinson's disease has a large effect on society. In terms of the number of people affected, this disease is a common condition, with approximately 6·1 million people who had been affected worldwide in 2016.1 For reasons that are not yet fully understood, the incidence and prevalence of this disease have risen rapidly in the past two decades .1, 2, 3 The personal effect of Parkinson's disease is enormous. Unique to a degenerative disease, the disease duration can span decades. The typical presentation includes a slow progression with accumulating disability for affected individuals. Parkinson's disease also has profound consequences for caregivers, most experiencing excessive strain.4 For society, Parkinson's disease conveys a mounting socioeconomic burden.5Various observations suggest that Parkinson's disease might not exist as a single entity. First, many different causes can manifest as a similar appearing clinical syndrome, referred to as parkinsonism.6 Some causes are known, such as the less than ten well established genes that can unequivocally cause parkinsonism when mutated. Second, even when a specific cause is uncovered, the disease frequently manifests highly variable symptoms and patterns of progression. For example, the presentation can vary considerably across individuals with an identical toxic cause for their parkinsonian signs, such as exposure to the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a heroin analogue.7 Third, the wishes, needs, and priorities of each person with Parkinson's disease vary widely. A prominent resting tremor might be hardly noticeable for a labourer accustomed to carrying heavy objects, but a similar tremor intensity could be debilitating for a calligraphist. As such, every person has their own unique Parkinson's disease. Considering all three arguments, an extreme notion would be to say that there are over 6 million different variations of Parkinson's disease in the world.

 

Acknowledging this marked heterogeneity in causes, presentation, and personal preferences has implications for clinical practice. This heterogeneity makes Parkinson's disease an ideal disease for precision medicine in which the various treatments—pharmacotherapy, neurosurgery, and rehabilitation—should be individually tailored to match each person's priorities and needs, and eventually their genetic or other specific biological make-up.8 However, this important development towards personalised precision medicine should not be oversold: people with Parkinson's disease also share common pathophysiological pathways, such as neuroinflammation or mitochondrial dysfunction, so some treatments will probably benefit many seemingly different individuals. Moreover, unique therapies for each person with Parkinson's disease will not be available, but there will probably be particular clusters of people that respond to specific types of treatment. The challenge will be to make these clusters as fine-grained as possible.

 

Four individual histories  exemplify the range of clinical presentations and personal differences in treatment priorities. We use this personal perspective as a figurative red thread throughout this Seminar . We also address the many misconceptions that can affect a Parkinson's disease diagnosis

Panel 1

The Parkinson pandemic

 

The global survey of neurological diseases revealed that the incidence and prevalence of Parkinson's disease has increased rapidly throughout the world.1 Parkinson's disease might even be the fastest growing neurological condition worldwide.1, 2 This rapid global growth of new people living with Parkinson's disease has been compared with many of the characteristics typically observed during a pandemic, except for an infectious cause. The growth can be explained in part by the ageing of the population because the incidence of Parkinson's disease increases with age. However, after correction for age-related factors, Parkinson's disease is projected to continue to rise in incidence, being driven by more factors than ageing.1 Although diagnostic strategies for Parkinson's disease have not changed drastically, improved diagnostic accuracy by experienced clinicians offers a partial explanation.3 However, this more accurate diagnostic process cannot explain why the age-adjusted prevalence of Parkinson's disease is growing faster than other neurological disorders, including diseases such as multiple sclerosis, which has seen substantial advances in diagnostic approaches. Other factors potentially contributing to this rise include prolonged survival and environmental pollution with toxins, such as pesticides (eg, paraquat) or chemicals (eg, trichloroethylene), known to be harmful to Parkinson's disease-related neurons and brain circuits. The larger the societal growth in gross national income, the faster the rise in the incidence of Parkinson's disease,2 perhaps because economic growth is a proxy for industrialisation and environmental pollution

Figure 1. Examples of the various questions that people with Parkinson's disease might have during the consecutive phases of the disease

 

The various disease phases are connected by a figurative red thread, as graphically depicted here. We will use this red thread of personal perspectives to guide us throughout this Seminar and to show how the personalised management of people with Parkinson's disease can be optimised.