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The concept of prodromal Parkinson disease (PD) is reviewed. A large body of data indicates that overt, defining clinical manifestations are preceded by long periods of subclinical neurodegeneration and gradually emergent functional abnormalities below thresholds for clinical diagnosis. The general concept of long prodromal periods is consistent with neuropathologic evidence of apparently asymptomatic brain α-synucleinopathy pathologies. The importance of idiopathic (isolated) rapid eye movement (REM) sleep behavior disorder (iRBD) is highlighted. Studies of observational cohorts, iRBD cohorts, genetic cohorts, and pure autonomic failure are reviewed.

The epidemiology of Parkinson disease (PD) is reviewed. PD was identified as a distinct clinical entity in the 19th century, and its pathology was clarified in the first half of the 20th century, but it is likely that it was during and after the mid-20th century that it emerged as a major medical problem. Studies of incidence, prevalence, mortality, and potential risk factors are reviewed. PD is a common age-related disorder with rising worldwide prevalence accompanying population aging. PD is associated with relatively increased mortality compared with appropriate reference populations. Considerable uncertainty exists about specific incidence rates and whether age-adjusted incidence is changing. A number of potential environmental risk factors were identified, but the causal relationship of many putative risk factors to PD incidence is unclear.

The clinical presentation and initial evaluation of patients with possible Parkinson disease (PD) is discussed. Evaluation and diagnosis are based on the clinical construct of dopamine replacement therapy (DRT)-responsive parkinsonism. Careful clinical evaluation with directed history-taking and comprehensive neurologic examination is the foundation of evaluating possible PD. Presenting demographic and clinical features are discussed. The clinical approach to diagnosis, including evaluating histories and key features of the clinical evaluation are reviewed. The major differential diagnosis possibilities are discussed.

In this chapter, the pathology of Parkinson disease (PD) is reviewed. Discussions of PD pathology are dogged by the same problems of definition and metasyndromic heterogeneity that arise in other contexts of PD biology. And although pathologic evaluations are often regarded as “gold standards” for disease definition, the PD pathology literature is characterized by notable ambiguities. The intersection of brain aging and PD-specific pathology is discussed, and the key features of intraneuronal accumulation of α-synuclein–immunoreactive Lewy bodies and related inclusions are identified. The distribution of α-synucleinopathy within the substantia nigra, in other brain regions, and in the peripheral nervous system is discussed. The Braak system for staging PD pathology and its implications for understanding pathogenesis are described.

Pharmacotherapy is the cornerstone of management for Parkinson disease (PD). Pharmacotherapy is the most impactful intervention, and other treatment modalities generally work best in conjunction with judicious pharmacotherapy. Pharmacotherapy is primarily symptomatic dopamine (DA) replacement therapy (DRT) with L-dopa preparations, adjuncts to L-dopa preparations, and/or DA agonists. L-dopa preparations continue to be the best treatment for PD. This chapter reviews the fundamentals of dopaminergic neurotransmission, and L-dopa pharmacokinetics and pharmacodynamics. The potential mechanism of peak dose dyskinesias is reviewed, as are the interactions of disease progression with L-dopa pharmacokinetics and pharmacodynamics.

In this chapter, the natural history and continuing care of patients with Parkinson disease (PD) are reviewed. Progression of PD, measures of progression, subgrouping, and clinically important emergent phenomena are discussed. Patients are most interested in guidance about if and when they are likely to experience significant disability and the likely nature of the disabling features. With this in mind, management at different levels of PD (mild, moderate, and severe) is discussed, including options for end-of-life care.

In this chapter, the pathophysiology associated with degeneration of specific, primary neurotransmitter-defined systems is reviewed. An alternative starting point for investigating Parkinson disease (PD) pathophysiology is considering the normal role(s) of specific brain systems affected in the disease. This approach is complicated by the multisystem nature of PD pathology, but it is likely to continue to be important in studying the consequences of neurodegeneration in specific brain systems. Thus, the normal functions of nigrostriatal dopaminergic signaling are reviewed here, and their correlation with the clinical deficits of Parkinson disease (PD) is discussed. The potential roles of altered habit formation and maintenance secondary to striatal dysfunction are reviewed. The potential roles of cholinergic and serotoninergic projection systems degeneration in driving important clinical features of PD are also discussed.

Significant unresolved problems in Parkinson disease research and clinical practice are discussed briefly.

In this chapter, the pharmacologic management of Parkinson disease (PD) is reviewed. L-dopa preparations are the cornerstone of management in the treatment of PD. The features and limitations of L-dopa preparations are discussed, comparing the benefits and drawbacks of different preparations. Newer formulations are also detailed. Adjunctive agents such as catabolic enzyme inhibitors and dopamine agonists are discussed. The pharmacologic management of important non-dopamine replacement–responsive clinical features is also surveyed.

Parkinson Disease is a comprehensive introduction to the biology and clinical features of Parkinson disease (PD). This book is aimed at clinicians in training, general neurologists seeking a useful guide to PD, and scientists seeking an overview of clinical aspects of PD. Topics covered include nosology of PD, PD epidemiology, pathology and pathophysiology of PD, and theories of PD pathogenesis. Clinical features, including the many non-motor features, natural history of disease progression, clinical pharmacology, and management of PD receive coverage. Important themes are heterogeneity of PD, the multifocal nature of PD pathology, the diversity of clinical features, dopaminergic signaling and the impacts of dopaminergic deficiency, the importance of non-motor features, limitations of existing treatment modalities, and the necessity of approaching PD as a multisystem disorder.

Surgical interventions occupy an important place in the management of Parkinson disease (PD). Prior to the advent of dopamine replacement therapy (DRT), there was considerable interest in lesional surgical interventions for PD. This chapter reviews surgical interventions, primarily deep brain stimulation (DBS) for PD. The rationale and indications for DBS are reviewed, and DBS procedures, outcomes, and complications are discussed. Lesional, cell-based, and gene therapy interventions also are discussed briefly.

In this chapter, Parkinson disease (PD) nosology is discussed through the presentation of a unifying definition of PD. A Linnean-style binomial classification scheme for PD and related disorders also is described.

In this chapter, the nature, variety, and impact of non-motor features of Parkinson disease (PD) are reviewed. Non-motor features, commonly termed non-motor symptoms (NMS), are aspects of PD with great clinical impacts. The high morbidity associated with many non-motor features is emphasized: in both health-related quality of life (QoL) studies and surveys of clinical impacts of PD, non-motor features are identified by patients, caregivers, and clinicians as some of the most troublesome aspects of PD. Cognitive impairments, neuropsychiatric disorders, sleep disorders, pain, fatigue, autonomic disorders, visual disorders, and oral health problems are reviewed.

Hypotheses regarding the pathogenesis of Parkinson disease (PD) are reviewed in this chapter. All proposed mechanisms of neurodegeneration involve disruptions of basic cellular processes, with considerable overlap among and interdigitation of these proposed mechanisms and cellular processes, both in terms of normal functions and potential dysfunctions. PD is an age-related syndrome with incidence focused in and generally rising in the later decades of life, and while many brain regions are affected in PD, there is at least relatively selective neuronal vulnerability to the pathogenic processes causing neuronal dysfunction-degeneration. The relative vulnerability of dopaminergic substantia nigra neurons is reviewed. Major hypotheses including the toxic effects of α-synuclein and its possible prion-like spread, mitochondrial dysfunction, oxidative stress, endolysomal dysfunction, and neuroinflammation are discussed. The role of neuroprotection trials in addressing major hypotheses of pathogenesis is discussed.

In this chapter, the basal ganglia architecture is reviewed; this architecture implies that parallel cortico-basal ganglionic-thalamocortical loops carry functionally specific streams of information through the nodes of the basal ganglia, that a series of standardized computations are performed during nodal information transmission, and that nigrostriatal dopaminergic neurons are responsible for some form of diffuse modulatory input. The “standard model” of basal ganglia pathophysiology can explain both bradykinesia and choreiform movements, and this contributed significantly to its acceptance and further articulation; its shortcomings are also discussed Additional features of basal ganglia architecture are reviewed in the context of Parkinson disease and parkinsonism.