RT Book, Section A1 Micheli, Federico A1 Cersosimo, Maria G. A1 Wooten, G. Frederick A2 Watts, Ray L. A2 Standaert, David G. A2 Obeso, Jose A. SR Print(0) ID 55792904 T1 Chapter 11. Neurochemistry and Neuropharmacology of Parkinson's Disease T2 Movement Disorders, 3e YR 2012 FD 2012 PB The McGraw-Hill Companies PP New York, NY SN 978-0-07-161312-5 LK neurology.mhmedical.com/content.aspx?aid=55792904 RD 2024/03/28 AB Parkinsonism is a clinical syndrome characterized by tremor at rest, bradykinesia and hypokinesia and cogwheel rigidity. There are many causes or etiologies of parkinsonism, but the most common is Parkinson's disease (PD). PD has long been considered a clinical–pathologic entity defined clinically by parkinsonism and pathologically by depigmentation of the substantia nigra with the appearance of Lewy bodies: eosinophilic, intraneuronal, cytoplasmic inclusion bodies that contain high concentrations of ubiquitinated α-synuclein. Recent discoveries suggest, however, that the clinical phenotype of PD is much more heterogenous than originally conceived and strains the concept of a clinical entity. At the same time, doubt has been raised about the requirement for the presence of Lewy bodies in PD by the apparent absence of these inclusions from the brains of patients with some of the recently described autosomal dominant and recessive genetic mutations causing clinically typical PD. In addition, there is now an impressive body of evidence emerging that identifies a variety of clinical conditions that cluster in patients destined to develop PD before any of the classical features of parkinsonism are present. These include gastrointestinal dysfunction,1 sleep disorders,2 and anosmia.3 Braak and colleagues have suggested that these “premonitory symptoms” are associated with Lewy body pathology in lower brain stem nuclei preceding the development of such pathology in dopaminergic neurons of the substantia nigra.4 Further complicating the simplistic concept of a clinical–pathologic entity is the emerging evidence that many patients with the clinical features of PD will develop freezing and imbalance, depression, apathy, fatigue, psychosis, and dementia in the later clinical stages of their disease.5 These typically late-emerging features are not particularly responsive to dopaminergic therapies and are unlikely to develop as a consequence of the death of dopamine neurons in the nigrostriatal pathway, per se.