Elsevier

The Lancet

Volume 397, Issue 10291, 12–18 June 2021, Pages 2284-2303
The Lancet

Seminar
Parkinson's disease

https://doi.org/10.1016/S0140-6736(21)00218-XGet rights and content

Summary

Parkinson's disease is a recognisable clinical syndrome with a range of causes and clinical presentations. Parkinson's disease represents a fast-growing neurodegenerative condition; the rising prevalence worldwide resembles the many characteristics typically observed during a pandemic, except for an infectious cause. In most populations, 3–5% of Parkinson's disease is explained by genetic causes linked to known Parkinson's disease genes, thus representing monogenic Parkinson's disease, whereas 90 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 (panel 1).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.5

Various 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 (appendix p 14) 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 (figure 1). We also address the many misconceptions that can affect a Parkinson's disease diagnosis (table 1).

Section snippets

Clinical spectrum

The motor features of Parkinson's disease are hard to miss. The video shows the complete motor examination of people with recently identified Parkinson's disease. However, the clinical spectrum also contains many less visible components, including non-motor features, such as cognitive decline, depression, and pain (appendix pp 3–4). These non-motor features contribute substantially to the disability of affected individuals.9 A rating scale can measure this non-motor burden.10

The earliest stages

Epidemiology

Parkinson's disease is an age-related disease, with incidence and prevalence increasing steadily with age.29 However, the misconception that Parkinson's disease exclusively affects older people should be dismissed. The age of onset for almost 25% of affected individuals is younger than 65 years and for 5–10% is younger than 50 years. The term young-onset Parkinson's disease has been introduced when referring to affected individuals with an age of onset younger than 40 years (maybe even younger

Causes and modifying factors

When discussing the causes of Parkinson's disease, three factors are relevant: genetics, environment, and interactions thereof (figure 4). There is a relatively good understanding of causative genes, and a person's entire genome can readily be deciphered, but the assessment of the so-called environmentome (ie, the sum of all potentially causative and protective factors that are present in our environment) is not possible at present. Moreover, unlike a person's genetic make-up, which is largely

Pathophysiology

The pathophysiology of Parkinson's disease appears to result from the complex interplay of aberrant α-synuclein aggregation, dysfunction of mitochondria, lysosomes or vesicle transport, synaptic transport issues, and neuroinflammation.61 These disease mechanisms collectively result in accelerated neuronal death of primarily dopaminergic neurons, but the neuropathology involves multiple other motor and non-motor circuits. Loss of nigrostriatal dopamine cells causes a gradient of striatal

Prognosis

Parkinson's disease is a progressive condition, although the rate of deterioration varies considerably across different individuals.6 Absence of progression excludes a diagnosis of Parkinson's disease, whereas unusually fast rates of progression—with rapid development of factors, such as falls or dementia—suggest an alternative diagnosis.15 Life expectancy is decreased overall, yet most people live long with Parkinson's disease, many even decades. Common causes of death include aspiration

Prodromal phase

A long prodromal period might precede the onset of clinically manifest Parkinson's disease.92 Various prodromal features are listed in the appendix (pp 3–4). Much relevant information is readily available in primary care medical records—mining these can be used to identify at risk individuals.93 The prodromal symptom with the highest risk of subsequent phenoconversion to overt Parkinson's disease is idiopathic REM sleep behaviour disorder, which is by itself rare but quite specific, and can

Initiating treatment in de-novo Parkinson's disease

Parkinson's disease is treatable. Dopaminergic pharmacotherapy is one of four main strategies (figure 5). People with Parkinson's disease might raise important questions when considering initiation of pharmacotherapy. One argument to postpone treatment is the long-held notion that levodopa could be toxic and hasten disease progression by promoting oxidative stress, fuelling levodopa phobia and motivating both physicians and people with Parkinson's disease to postpone treatment. However, the

Non-pharmacological interventions

Many features of Parkinson's disease do not respond adequately to optimal pharmacotherapy. This issue increases with disease progression because neurodegeneration progressively involves non-dopaminergic brain areas. Moreover, dose-limiting side-effects hamper a successful deployment of pharmacotherapy. This recognition fuelled a drive toward an integrated multidisciplinary management approach, with potentially useful contributions by many different disciplines. The evidence base has increased

Future directions for Parkinson's disease research

Despite the progress since the previous Lancet Seminar on Parkinson's disease,61 much remains to be discovered. Stimulated by the most poignant questions that we, as authors, commonly encounter in our clinical practices, we highlight several directions for future research here.

Conclusion

Parkinson's disease has been recognised for over 200 years. Together, the various forms of Parkinson's disease create fast-growing health-care issues with enormous global impact. Fortunately, Parkinson's disease is treatable, particularly when the interventions are delivered with a personalised approach, and by well trained experts.161 Encouraged by the many exciting developments highlighted here, we have hope that treatments and services will continue to evolve, with a tangible effect on

Search strategy and selection criteria

We searched for literature via the Cochrane Library and MEDLINE between Jan 1, 2017, and Dec 30, 2020. We used Medical Subject Headings and free text search term “Parkinson* disease” and restricted our search to the English language. This search resulted in 23 058 articles that were screened on the basis of the title and, partially, by the abstract review. Articles included in our selection of the top 100 Parkinson's disease articles from January, 2017, to December, 2020, were chosen on the

Declaration of interests

BRB serves as the coeditor in chief for the Journal of Parkinson's Disease, serves on the editorial board of Practical Neurology and Digital Biomarkers, has received fees from serving on the scientific advisory board for Biogen and UCB (paid to the institute), has received fees for speaking at conferences from AbbVie, Biogen, UCB, Zambon, Roche, GE Healthcare, and Bial (paid to the institute), and has received research support from the Netherlands Organization for Health Research and

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