Aetiologies underlying neurodegeneration
From the information previously presented, we understand the pathology that is found in PD-D, where it occurs, how it may correlate with clinical symptoms, how it can be correlated with clinical syndromes, and how it progresses; nevertheless the mechanisms that underlie these pathological changes remain unclear. Several theories have been developed to explain why the pathological changes that take place in Lewy body diseases actually occur. At the root of this discussion is the assumption that the aggregation of a-synuclein in LBs is the central neuropathological feature of these diseases, and this is supported by the finding that mutations in the a-synuclein gene lead to parkinsonism, the finding of aggregated a-synuclein with abnormal nitration, phosphorylation, and ubiquitination, the development of neurodegeneration in a-synuclein transgenic animal models, and the aforementioned clinico-pathological correlation studies . The finding that LBs are found in grafted neurons supports this assertion; however, the finding that LRP is present in patients without parkinsonism or cognitive dysfunction
(incidental Lewy body disease) implies at least that LRP may not be the only mechanism underlying neurodegeneration in Lewy body diseases, which is certainly the case in more severe dementing syndromes such as DLB. Furthermore, some have theorized that there is a ‘bystander’ effect occurring when multiple pathologies such as LRP and ARP coexist and possibly augment one another in these disease entities. Recent studies suggest that a combination of Lewy body pathology and ARP rather than Lewy body pathology alone is the most robust pathological correlate of PD-D. Such a combination has been linked with faster progression of dementia, and the rate of progression also correlates with the Ap burden [23, 44]. A combined assessment of a-synuclein, tau, and Ap is a better predictor of the progression of dementia than a-synuclein alone . Clinico-pathological studies using cerebrospinal fluid (CSF) analysis and in vivo positron emission tomography (PET) scanning with the nC-Pittsburgh-B compound shed some light on the role of ARP. CSF levels of tau and Ap have been thoroughly investigated as biomarkers in AD [45, 46], and it is suggested that intra-parenchymal sequestration of Ap results in its relatively reduced levels in CSF. Some studies specifically testing these biomarkers in PD-D revealed reduced CSF Ap levels, and in vivo PET studies assessing amyloid burden showed less severe and less frequent amyloid accumulation in PD-D. It was noted that pre-dementia patients also showed reduced CSF levels of amyloid markers, whereas PD patents without dementia showed higher levels than patients with PD-D .
Others have suggested that the mere accumulation of abnormal proteins is not sufficient to account for the clinical symptoms, and instead an assessment of the neurochemical changes that occur as a result of the degeneration of neurons, particularly monoaminergic neurons, would more accurately represent the underlying pathophysiology. Other changes, including vascular and normal ageing changes, can contribute to the degeneration of these neurons to differing degrees .
If we accept the assumption that a-synuclein pathology is central to the pathophysiology of these diseases, it still remains unclear how exactly that occurs. The possibility of a direct toxic effect of a-synuclein has been proposed, but this remains unproven. Indeed, a-synuclein aggregates may be a by-product of compensatory biological processes that are neuroprotective. Other possible mechanisms underlying degeneration include overproduction of a-synuclein, dysfunction of chaperones and other components of the ubiquitin-proteosome system, inflammation, oxidative stress, excitotoxicity, mitochondrial dysfunction, growth factor deficiencies, prion-like mechanisms of cell injury, or a combination of these .