Mubasher A. Qamar

Non-oral dopaminergic therapies for Parkinson’s disease: current treatments and the future

Dysfunction of the gastrointestinal tract has now been recognized to affect all stages of Parkinson’s disease (PD). The consequences lead to problems with absorption of oral medication, erratic treatment response, as well as silent aspiration, which is one of the key risk factors in developing pneumonia. The issue is further complicated by other gut abnormalities, such as small intestinal bacterial overgrowth (SIBO) and an altered gut microbiota, which occur in PD with variable frequency. Clinically, these gastrointestinal abnormalities might be associated with symptoms such as nausea, early-morning “off”, and frequent motor and non-motor fluctuations. Therefore, non-oral therapies that avoid the gastrointestinal system seem a rational option to overcome the problems of oral therapies in PD. Hence, several non-oral strategies have now been actively investigated and developed. The transdermal rotigotine patch, infusion therapies with apomorphine, intrajejunal levodopa, and the apomorphine pen strategy are currently in clinical use with a few others in development. In this review, we discuss and summarize the most recent developments in this field with a focus on non-oral dopaminergic strategies (excluding surgical interventions such as deep brain stimulation) in development or to be licensed for management of PD.

The efficacy of apomorphine – A non-motor perspective

Non-motor features have a great impact on progression and quality of life in individuals with Parkinsons disease. Current treatments for PD are limited and apomorphine is one of the advanced therapies available with advantageous effects on motor complications. Several studies have suggested that apomorphine has potential benefits in PD patients beyond its established role in the treatment of motor fluctuations and levodopa-induced dyskinesia. This review examines the efficacy of apomorphine in the treatment of non-motor symptoms (NMS), describing recent studies that highlight its possible effect on cognition. Despite a limited number of studies, the available evidence shows that apomorphine has an overall beneficial effect on NMS of PD patients, including neuropsychiatric symptoms, sleep disturbances, pain, urinary dysfunction, and impulse control disorders. If the effects of apomorphine on amyloid deposition are confirmed in the future, its place in the armamentarium of PD treatment could see a shift towards younger and non-demented PD patients.

Presynaptic dopaminergic terminal imaging and non-motor symptoms assessment of Parkinson’s disease: evidence for dopaminergic basis?

Parkinson’s disease (PD) is now considered to be a multisystemic disorder consequent on multineuropeptide dysfunction including dopaminergic, serotonergic, cholinergic, and noradrenergic systems. This multipeptide dysfunction leads to expression of a range of non-motor symptoms now known to be integral to the concept of PD and preceding the diagnosis of motor PD. Some non-motor symptoms in PD may have a dopaminergic basis and in this review, we investigate the evidence for this based on imaging techniques using dopamine-based radioligands. To discuss non-motor symptoms we follow the classification as outlined by the validated PD non-motor symptoms scale.

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.

Multidisciplinary Care in Parkinson's Disease.

Parkinsons disease (PD) is now known to be a multisystemic and multipeptide neurodegenerative disorder, whereby patients have an array of symptoms both motor and nonmotor. Nonmotor features of PD have been shown to arise almost 15-20 years prior to motor symptoms and, as such, are also a key determinant to the quality of life of a patient. Therefore, there is increasing evidence that a PD patients management must encompass a multidisciplinary approach to effectively manage and treat the patients PD and also their individual symptoms. Therefore, the notion that a PD nurse specialist and a neurologist are the only key players, is no longer the case. Rather, the involvement of speech and language therapist, physiotherapists, palliative care, and others is vital for a patients recovery and their effective management. Here we discuss a few professions who should ideally be present for each PD patient.

Biomarkers of Parkinson's Disease

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.