Nataliya Titova

Parkinson's: a syndrome rather than a disease?

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 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

Nonmotor Symptoms in Experimental Models of Parkinson's Disease

Nonmotor symptoms of Parkinsons disease (PD) range from neuropsychiatric, cognitive to sleep and sensory disorders and can arise from the disease process as well as from drug treatment. The clinical heterogeneity of nonmotor symptoms of PD is underpinned by a wide range of neuropathological and molecular pathology, affecting almost the entire range of neurotransmitters present in brain and the periphery. Understanding the neurobiology and pathology of nonmotor symptoms is crucial to the effective treatment of PD and currently a key unmet need. This bench-to-bedside translational concept can only be successful if robust animal models of PD charting the genesis and natural history of nonmotor symptoms can be devised. Toxin-based and transgenic rodent and primate models of PD have given us important clues to the underlying basis of motor symptomatology and in addition, can provide a snapshot of some nonmotor aspects of PD, although the data are far from complete. In this chapter, we discuss some of the nonmotor aspects of the available experimental models of PD and how the development of robust animal models to understand and treat nonmotor symptoms needs to become a research priority.

Biomarkers of Parkinson's Disease: An Introduction

The development of biomarkers is of great importance in Parkinsons disease (PD) as it may contribute to confirmation and support of the diagnosis, tracking of progression, and prediction of the natural history of PD. Biomarkers also help in the identification of targets for treatment and measuring the efficacy of interventions. Biomarkers are, therefore, crucial to understanding the pathophysiology of PD, the second commonest neurodegenerative disorder in the world. Modern understanding of PD suggests that it is a multipeptide, multiorgan disorder presenting with a heterogeneous clinical condition, both motor and nonmotor. Biomarkers need to reflect this neuropathological and clinical heterogeneity of PD. In this review, we outline some key advances in the field of clinical, genetic, neuroimaging, and tissue-based biomarkers proposed or used for PD. The individual sections will be covered in relevant chapters and our review is largely a primer aimed to alert readers to the current state of the various biomarkers proposed for PD. In doing so, we have also underlined the important role multimodal rather than single biomarkers could play in our future understanding of PD.

The future of parkinson’s treatment – Personalised and precision medicine

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Advanced Parkinson’s or “complex phase” Parkinson’s disease? Re-evaluation is needed

Holistic management of Parkinson’s disease, now recognised as a combined motor and nonmotor disorder, remains a key unmet need. Such management needs relatively accurate definition of the various stages of Parkinson’s from early untreated to late palliative as each stage calls for personalised therapies. Management also needs to have a robust knowledge of the progression pattern and clinical heterogeneity of the presentation of Parkinson’s which may manifest in a motor dominant or nonmotor dominant manner. The “advanced” stages of Parkinson’s disease qualify for advanced treatments such as with continuous infusion or stereotactic surgery yet the concept of “advanced Parkinson’s disease” (APD) remains controversial in spite of growing knowledge of the natural history of the motor syndrome of PD. Advanced PD is currently largely defined on the basis of consensus opinion and thus with several caveats. Nonmotor aspects of PD may also reflect advancing course of the disorder, so far not reflected in usual scale based assessments which are largely focussed on motor symptoms. In this paper, we discuss the problems with current definitions of “advanced” PD and also propose the term “complex phase” Parkinson’s disease as an alternative which takes into account a multimodal symptoms and biomarker based approach in addition to patient preference.

Nonmotor Parkinson's and Future Directions

Nonmotor symptoms (NMS) of Parkinsons disease (PD) are integral to the condition largely regarded as a motor syndrome. A range of NMS underpin the prodromal stage of Parkinsons and are present with variable frequency, range, and nature across the whole journey of a patient with Parkinsons from the onset of the motor disease to palliative stage. These symptoms also are key determinants of quality of life of the patient as well as the carer. Despite this, recognition management and focused treatment of NMS of PD remain poor. Future would, therefore, need to focus on better definition and management of NMS of PD. This would include development of robust animal models of specific NMS such as cognitive, sleep, and autonomic dysfunctions as well as pain to understand the mechanistic pathways of these symptoms. In turn this will lead to better drug development using a bench to bedside model. Nonmotor clinical subtypes of PD have also been described and, in future, proper biomarkers will consolidate these findings in addition to defining the natural history of the subtypes. Revised versions of established scales and questionnaires will enable the adoption of good clinical practice with recognition of these subtypes in clinic. This will enhance the delivery of true subtype-specific therapies. Drug development should also include nondopaminergic and cell replacement restorative therapies with a nonmotor focus. An additional key area of future research would be the formalizing of true personalized medicine for PD. Personalized medicine pathways should concentrate on the role of exercise, complementary medicine as well as age, body weight, ethnicity on various NMS of PD. Genetics and pharmacogenetic developments in PD will add to the precision of the individualized approach.

Non-motor Parkinson disease: new concepts and personalised management

Most patients with Parkinson disease (PD) have non-motor symptoms (NMS), and on average these can range from four to 19 different symptoms. NMS dominate the prodromal phase of PD and some may serve as clinical biomarkers of PD. NMS can be dopaminergic, non-dopaminergic, of genetic origin or drug induced. Clinical assessment of NMS should include the NMS Questionnaire (completed by patients) for screening, as recommended by the International Parkinson and Movement Disorders Society and other international societies. The total number of NMS in a patient with PD constitutes the NMS burden, which can be graded using validated cut-off scores on the NMS Questionnaire and Scale and can be used as an outcome measure in clinical trials. Despite NMS burden having a major effect on the quality of life of patients and carers, a large European study showed that NMS are often ignored in the clinic. The syndromic nature of PD is underpinned by non-motor subtypes which are likely to be related to specific dysfunction of cholinergic, noradrenergic, serotonergic pathways in the brain, not just the dopaminergic pathways. NMS can be treated by dopaminergic and non-dopaminergic strategies, but further robust studies supported by evidence from animal models are required. The future of modern treatment of PD needs to be supported by the delivery of personalised medicine.

Non-Motor Symptoms Assessed by Non-Motor Symptoms Questionnaire and Non-Motor Symptoms Scale in Parkinson's Disease in Selected Asian Populations

Background: Ethnic variations have been described in medical conditions, such as hypertension, diabetes, and multiple sclerosis. Whether ethnicity plays a role in Parkinsons disease (PD), particularly with regard to non-motor symptoms (NMS), remains unclear. Existing literature is diverse, controversial, and inadequately documented. This review aims to analyse and report the currently available literature on NMS, specifically in Asian PD patients. Summary: We conducted a literature review using PubMed, searching for articles and currently available publications that reference and assess NMS in PD patients living in Asia using the validated NMS Questionnaire (NMS Quest) and NMS Scale (NMSS). In total, 24 articles were included: 12 using the NMS Quest and 12 using the NMSS. Symptoms of constipation, memory impairment, and nocturia were the most frequently self-reported symptoms (NMS Quest) in selected Asian populations, while symptoms within the domains sleep/fatigue, attention/memory, and mood/apathy were most prevalent when applying the health-professional completed NMSS. Key Messages: NMS are generally prevalent and highly burdensome within selected Asian PD populations living in countries included in this review. Our review suggests that NMS-driven phenotypic heterogeneity is present in Asian patients, and compared to Western PD populations there might be variations in assessed NMS.

The Epidemiology of Nonmotor Symptoms in Parkinson's Disease (Cohort and Other Studies)

Nonmotor symptoms (NMS) of Parkinsons disease (PD) were recognized by James Parkinson himself and are now considered to be an integral part of PD. While clinical assessment had focused on prevalence and severity of individual NMS such as dementia and depression, work in the last decade has concentrated on global or holistic assessment of NMS using validated tools such as the NMS questionnaire and NMS scale. These studies from cohorts of varying sizes have allowed comparison of NMS across different disease stages, duration, age, and ethnicity in PD. The data also allow exploration of the concept of the nonlinear relationship of NMS to disease duration of PD and motor stages as well as nonmotor subtypes of PD. In this chapter, these aspects of epidemiological studies of NMS in PD cohorts are described.