Vol 6 n° 3 - Parkinson's disease
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arkinson’s disease (PD), which afflicts nearly 1% of the population above the age of 60, is a multisystem neurodegenerative disorder in which progressive loss of midbrain   dopamine   (DA)   neurons,   with   resulting dopaminergic deafferentation of the basal ganglia, gives rise to characteristic motor disturbances that include slowing  of  movement,  muscular  rigidity,  and  resting tremor. These signs of motor dysfunction, if lateralized, can be clinically diagnostic of PD.1 They are, however, only a subset of the assorted motor, cognitive, affective, autonomic, and even sensory impairments that result from selective degeneration of different neuron types at multiple levels of the central and peripheral nervous sys- tems.A definitive diagnosis of PD requires pathological confirmation of two invariant features: distinctive intra- neuronal inclusions known as Lewy bodies (LBs) in regions of predilection, and reduced numbers of DA neurons in the substantia nigra pars compacta (SNc). PD is, for the most part, a sporadic disorder. Loose famil- ial clustering, in which the pattern of inheritance is not apparent, occurs in up to 15% of cases. Forms of famil- ial PD in which inheritance follows a mendelian pattern are exceedingly rare, accounting for less than 1% of all PD patients. Among all PD patients, the average age at symptom onset is 60. Except for the rare forms of famil- ial PD with mendelian inheritance, the disease is rare in those under 40 years of age. Thereafter, the prevalence rises rapidly, so that by the end of the seventh decade an S t a t e   o f   t h e   a r t 2 5 9 Biology of Parkinson’s disease: pathogenesis and pathophysiology of a multisystem neurodegenerative disorder Garrett E. Alexander, MD, PhD P Copyright © 2004 LLS SAS.  All rights reserved www.dialogues-cns.org Parkinson’s  disease  (PD)  is  the  second  most  common movement  disorder.  The  characteristic  motor  impair- ments—bradykinesia, rigidity, and resting tremor—result from degenerative loss of midbrain dopamine (DA) neu- rons in the substantia nigra, and are responsive to symp- tomatic treatment with dopaminergic medications and functional neurosurgery. PD is also the second most com- mon neurodegenerative disorder. Viewed from this per- spective, PD is a disorder of multiple functional systems, not simply the motor system, and of multiple neurotrans- mitter systems, not merely that of DA. The characteristic pathology—intraneuronal  Lewy  body  inclusions  and reduced numbers of surviving neurons—is similar in each of the targeted neuron groups, suggesting a common neurodegenerative process. Pathological and experimen- tal studies indicate that oxidative stress, proteolytic stress, and inflammation figure prominently in the pathogene- sis of PD. Yet, whether any of these mechanisms plays a causal role in human PD is unknown, because to date we have no proven neuroprotective therapies that slow or reverse disease progression in patients with PD. We are beginning to understand the pathophysiology of motor dysfunction in PD, but its etiopathogenesis as a neurode- generative disorder remains poorly understood.   © 2004, LLS SAS Dialogues Clin Neurosci. 2004;6:259-280. Keywords: nigra; dopamine; striatum; subthalamic nucleus; Lewy body; oxidative stress; -synuclein; proteasome Author  affiliations: Department of Neurology,  Emory University School of Medicine, Atlanta, Ga, USA Address for correspondence: Garrett E. ;Alexander, MD, PhD, Department of Neurology, WMRB-6000, Emory University School of Medicine, 101 Woodruff Circle, Atlanta, GA 30322, USA (e-mail: medgea@emory.edu)