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Evidence for a close bidirectional link between the brain and the gut has led to a paradigm shift in neurology, especially in the case of Parkinson disease (PD), in which gastrointestinal dysfunction is a prominent feature. Over the past decade, numerous high-quality preclinical and clinical publications have shed light on the highly complex relationship between the gut and the brain in PD, providing potential for the development of new biomarkers and therapeutics. With the advent of high-throughput sequencing, the role of the gut microbiome has been specifically highlighted. Here, we provide a critical review of the literature on the microbiome–gut–brain axis in PD and present perspectives that will be useful for clinical practice. We begin with an overview of the gut–brain axis in PD, including the potential roles and interrelationships of the vagus nerve, α-synuclein in the enteric nervous system, altered intestinal permeability and inflammation, and gut microbes and their metabolic activities. The sections that follow synthesize the proposed roles of gut-related factors in the development and progression of, in responses to PD treatment, and as therapeutic targets. Finally, we summarize current knowledge gaps and challenges and delineate future directions for the field.The prominence of gastrointestinal dysfunction among the non-motor features of Parkinson disease (PD) indicates a close bidirectional link between the brain and the gut. This Review discusses the proposed roles of gut-related factors in PD development, progression and treatment responses, and as therapeutic targets.

With the hope that disease-modifying treatments could target the molecular basis of Parkinson's disease, even before the onset of symptoms, we propose a biologically based classification. Our classification acknowledges the complexity and heterogeneity of the disease by use of a three-component system (SynNeurGe): presence or absence of pathological α-synuclein (S) in tissues or CSF; evidence of underlying neurodegeneration (N) defined by neuroimaging procedures; and documentation of pathogenic gene variants (G) that cause or strongly predispose to Parkinson's disease. These three components are linked to a clinical component (C), defined either by a single high-specificity clinical feature or by multiple lower-specificity clinical features. The use of a biological classification will enable advances in both basic and clinical research, and move the field closer to the precision medicine required to develop disease-modifying therapies. We emphasise the initial application of these criteria exclusively for research. We acknowledge its ethical implications, its limitations, and the need for prospective validation in future studies.

Debate is ongoing regarding when, why, and how to initiate pharmacotherapy for Parkinson's disease. Early initiation of dopaminergic therapies does not convey disease-modifying effects but does reduce disability. Concerns about the development of motor complications arising from the early initiation of levodopa, which led to misconceived levodopa-sparing strategies, have been largely mitigated by the outcomes of the PD MED and Levodopa in Early Parkinson's Disease (LEAP) studies. The LEAP study also showed the potential for early improvement in quality of life, even when disability is negligible. Until more effective methods of providing stable dopamine concentrations are developed, current evidence supports the use of levodopa as initial symptomatic treatment in most patients with Parkinson's disease, starting with low doses and titrating to therapeutic threshold. Monoamine oxidase-B inhibitors and dopamine agonists can be reserved as potential adjunct treatments later in the disease course. Future research will need to establish effective disease-modifying treatments, address whether patients’ quality of life is substantially improved with early initiation of treatment rather than a wait and watch strategy, and establish whether new levodopa formulations will delay onset of dyskinesia.

Progressive supranuclear palsy (PSP), previously believed to be a common cause of atypical parkinsonism, is now recognised as a range of motor and behavioural syndromes that are associated with a characteristic 4-repeat tau neuropathology. New research criteria that recognise early presentations of PSP and operationalise diagnosis of the full spectrum of clinical phenotypes have been reported. The Movement Disorders Society PSP diagnostic criteria include syndromes with few or mild symptoms that are suggestive of underlying PSP pathology and could provide an opportunity for earlier therapeutic interventions in the future. These criteria also include definitions for variant PSP syndromes with different patterns of movement, language, or behavioural features than have been conclusively associated with PSP pathology. Data from new diagnostic biomarkers can be combined with the clinical features of disease to increase the specificity of the new criteria for underlying PSP pathology. Because PSP is associated with tau protein abnormalities, there is growing interest in clinical trials of new tau-directed therapies. These therapies are hypothesised to have disease-modifying effects by reducing the concentration of toxic forms of tau in the brain or by compensating for loss of tau function. Since tau pathology is also central to Alzheimer's disease and chronic traumatic encephalopathy, a successful tau therapeutic for PSP might inform treatment of other neurodegenerative diseases.

1·8 billion people of diverse ethnicities and cultures live in the Western Pacific Region. The increasing longevity of populations in this region is a major contributor to the exponential increase in Parkinson's disease prevalence worldwide. Differences exist between Parkinson's disease in the Western Pacific Region and in Europe and North America that might provide important insights into our understanding of the disease and approaches to management. For example, some genetic factors (such as LRRK2 mutations or variants) differ, environmental exposures might play differential roles in modulating the risk of Parkinson's disease, and fewer dyskinesias are reported, with some differences in the profile of non-motor symptoms and comorbidities. Gaps in awareness of the disease and inequitable access to treatments pose challenges. Further improvements in infrastructure, clinical governance, and services, and concerted collaborative efforts in training and research, including greater representation of the Western Pacific Region in clinical trials, will improve care of patients with Parkinson's disease in this region and beyond.

Neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease represent a crucial and exponentially increasing challenge to health care systems throughout the world. There is an urgent need for effective treatments that will both delay their onset and slow their inexorable progression. Many obstacles stand in the way of realizing these goals. It is expected that future advances will have a major impact on how and when the diagnosis will be made. It is hoped that these will eventually make it possible to initiate effective disease-modifying therapies long before the neurodegenerative process becomes established and symptomatic.

A randomized, double-blind, placebo-controlled, 52-week study (no. NCT03068468) evaluated gosuranemab, an anti-tau monoclonal antibody, in the treatment of progressive supranuclear palsy (PSP). In total, 486 participants dosed were assigned to either gosuranemab ( n  = 321) or placebo ( n  = 165). Efficacy was not demonstrated on adjusted mean change of PSP Rating Scale score at week 52 between gosuranemab and placebo (10.4 versus 10.6, P  = 0.85, primary endpoint), or at secondary endpoints, resulting in discontinuation of the open-label, long-term extension. Unbound N-terminal tau in cerebrospinal fluid decreased by 98% with gosuranemab and increased by 11% with placebo ( P  < 0.0001). Incidences of adverse events and deaths were similar between groups. This well-powered study suggests that N-terminal tau neutralization does not translate into clinical efficacy. In the phase 2 PASSPORT study, treatment with the anti-tau antibody gosuranemab did not show clinical benefit in participants with supranuclear palsy, suggesting that N-terminal tau neutralization does not translate into clinical efficacy.

The fundamental role that alpha-synuclein (aSyn) plays in the pathogenesis of neurodegenerative synucleinopathies, including Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy, is a well-accepted fact. A wealth of experimental evidence has linked this relatively small but ubiquitously expressed protein to a plethora of cytopathologic mechanisms and suggests that aSyn may be capable of seeding the progressive spread of synucleinopathy throughout the brain. Beyond the synucleinopathies, the abnormal deposition of aSyn is frequently seen in a variety of other neurodegenerative proteinopathies including Alzheimer’s disease. In spite of the fact that the frequency of concomitant aSyn pathology in these disorders is such that it can be considered the rule rather than the exception, the potential role that aSyn may have in these disorders has received relatively little attention. In this article we postulate that aSyn may in fact be a key protein in driving the pathogenic processes in neurodegenerative comorbidities. In addition to reviewing the frequency of concomitant deposition of aSyn in the neurodegenerative proteinopathies, we also consider our current understanding of the interaction of aSyn with other neurodegenerative disease-associated proteins, including tau, TDP-43, amyloid-β and prion protein, in the context of neuropathologic studies describing the anatomical sites of potential concomitant pathology. We conclude that a growing body of evidence, encompassing neuropathology studies in human brain, animal models of concomitant proteinopathies and studies employing sophisticated methods of probing protein-protein interaction, cumulatively suggest that aSyn is well positioned to exert a strong influence on the pathogenesis of the neurodegenerative comorbidities. We hope to stimulate research in this emerging field and consider that future studies exploring the contribution of aSyn to the pathogenic processes in neurodegenerative comorbidities may provide critical information pertaining to diagnosis and the development of vital disease modifying treatments for these devastating diseases.

Published diagnostic criteria for functional (psychogenic) movement disorders (FMDs) include psychiatric symptoms and some historical variables to affect the threshold between categories of diagnostic certainty. Clinically probable and possible categories, however, do not suffice to rule in FMD or rule out complex organic movement disorders and therefore are of little practical help. In contrast, a handful of unequivocal and reliably incongruent or inconsistent clinical features in each functional movement phenotype, when present, allow a clinically definite diagnosis of FMD, regardless of any psychiatric symptom. We suggest that the use of phenotype-specific clinically definite FMD diagnostic criteria will increase inter-rater reliability and minimize false-positive diagnostic errors. This process involves the ascertainment of core (mandatory) examination features instead of supportive but insufficiently sensitive historical, psychiatric, and inconsistent examination features.

Neurogenic orthostatic hypotension and supine hypertension are common manifestations of cardiovascular dysautonomia in Parkinson's disease and related synucleinopathies. Because these disorders are haemodynamic opposites, improvement in one might be achieved at the expense of worsening of the other. Thus, management decisions necessitate assessment of the individual risks for patients with coexistent neurogenic orthostatic hypotension and supine hypertension. Whereas neurogenic orthostatic hypotension poses risks for falls and can be associated with cognitive impairment in the short term, chronic supine hypertension can be associated with stroke and myocardial infarction in the long term. Because few clinical trial data exist for outcomes in patients with coexistent neurogenic orthostatic hypotension and supine hypertension, clinicians need to balance, on the basis of comorbidities and disease staging, the potential immediate benefits of treatment for neurogenic orthostatic hypotension and the long-term risks of supine hypertension treatment in each patient. Future research needs to focus on ascertaining a safe degree of supine hypertension when treating neurogenic orthostatic hypotension; the effectiveness of nocturnal antihypertensive therapy in patients with coexistent neurogenic orthostatic hypotension and supine hypertension; and the prevalence, scope, and therapeutic requirements for managing neurogenic orthostatic hypotension that manifests with falls or cognitive impairment, but without postural lightheadedness or near syncope.