Invited Article: Nervous system pathology in sporadic Parkinson disease

Sporadic Parkinson disease (PD) is, after Alzheimer disease (AD), the second most frequent neurodegenerative disorder.¹ The pathologic process in PD is progressive and takes years to reach its full extent. It does not affect nonhuman vertebrates or organ systems other than the nervous system, and, apparently, it does not go into remission. Unlike AD, however, the pathology is distributed throughout the entire nervous system—that is, not only the central but also the peripheral and the enteric nervous systems (CNS, PNS, ENS). As a result, PD has come to be acknowledged as more than a monosystemic disorder with preferential obliteration of nigral dopaminergic neurons.^2–8,e1-e3

PARKINSONISM AND SPORADIC PD

In the clinically recognizable, i.e., motor, phase of sporadic PD, most patients display signs of motor dysfunction (hypo- or bradykinesia, cogwheel rigidity, postural instability, resting tremor),^9,e4,e5 but these symptoms also occur in other disorders associated with dopamine loss in the nigrostriatal system.^e6,e7 Familial forms of parkinsonism exist,^3,e8,e9 and the syndrome may also develop as a sequel to intoxication, trauma, vascular alterations, metabolic disease, or infection.^e3,e10-e14 In addition, parkinsonism can develop in tauopathies, including corticobasal degeneration and progressive supranuclear palsy,^e15-e17 or in synucleinopathies, such as multiple system atrophy and Lewy body disease.^{10,11,e18-e20} Lewy body disease has been subdivided further into pure autonomic failure, dementia with Lewy bodies, and sporadic PD.^11,12 The latter two entities are nearly indistinguishable at neuropathologic examination, and there is a growing consensus that, clinically, they are closely related, if not identical.^13–17 Here, we refer only to the Lewy body pathology associated with the synucleinopathy sporadic (or idiopathic) PD, the most widespread form of parkinsonism.^1,8,e25

SPORADIC PD IS LINKED TO PROTEIN MISFOLDING AND THE DEVELOPMENT OF ABNORMAL INTRACELLULAR INCLUSIONS

In PD, typical α-synuclein immunoreactive inclusions (Lewy neurites [LNs], Lewy bodies [LBs]) develop within specific types of projection neurons in all portions of the …