Mechanisms of aluminium neurotoxicity in oxidative stress-induced ...

INTRODUCTION
(Olanow et al. 2004). Most likely, LB seem to be symptomatic in PD pathogenesis, not
causative (Wakabayashi et al. 2007).
The six-stage system: a novel neuropathological concept of neurodegeneration
Recently, Braak and colleagues established a staging procedure based on the
distribution of LB and LN (Braak et al. 2003, Braak et al. 2006). According to the
pathological changes observed during the cross-sectional study originally performed on
autopsy cases, the authors proposed that the formation of proteinaceous intraneuronal
LB and LN follows a topographically predictable sequence in six stages with ascending
progression from medullary and olfactory nuclei to the cortex (Figure 13). In early
stages 1 and 2, patients are pre-symptomatic. LB pathology first appears in the dorsal
motor nucleus of the vagal nerve and is confined to the medulla oblongata, pontine
tegmentum and anterior olfactory structures. As the disease advances, in stages 3 and 4,
pathological changes appear in the SN and in other areas of the basal midbrain and
forebrain. Motor symptoms become clinically manifest during this phase. Finally the
final stages 5 and 6 are frequently associated with cognitive impairment as the
neocortex becomes involved (Figure 14).
Many groups give strong support to this neuropathological concept which states
that neurodegeneration in PD starts in non-DAergic areas, notably the enteric nervous
system and then rises via spinal cord and brainstem to nigral and subsequent cortical
neurons (Abbott et al. 2001, Przuntek et al. 2004, Abbotth et al 2005, Ross et al. 2005,
Ross et al. 2006). Nevertheless, it has also been brought into question as some
neuropathological studies showed brains with important neurodegeneration and α-
synuclein pathology in the SNpc and higher brain structures but lacking medullary
involvement (Parkinnen et al. 2003, Jellinger 2004, Parkinnen et al. 2005, Attems and
Jellinger 2008, Dickson et al. 2008, Kalaitzakis et al. 2008a, 2008b, Parkinnen et al.
2008).
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