Page 67 - AN-2-1

Advanced Neurologyurology
Advanced Ne Alpha-synuclein, depression and neurodegeneration

is typical of AlzD, has been reported in patients with PD according to a review of six meta-analyses, syndromal
and related syndromes, in which it appears to correlate depression is associated with a 1.5-fold increase in rates of
with cognitive impairment [13,14] . Similarly, alpha-synuclein subsequent AlzD . The exact mechanism underlying these
[35]
(α-synuclein), which is specifically associated with PD, associations is unknown, but various mechanisms have
has been found to be elevated in the cerebrospinal fluid of been suggested to account for these links. These include
patients with AlzD and may be linked to the severity of immune-inflammatory dysfunction, dysfunction related to
cognitive deterioration . At a molecular level, α-synuclein monoaminergic pathways, altered microglial or astrocytic
[15]
appears to increase the production of β-amyloid from functioning, and shared risk factors, such as stress or
amyloid precursor protein (APP), and this effect may environmental toxins. There is a significant degree of overlap
be mediated through the induction of beta-secretase, an between these proposals; for instance, air pollution or stress
enzyme that converts APP into β-amyloid . can cause altered immune-inflammatory activity, which
[16]
Both PD and AlzD are associated with neuropsychiatric can lead to alteration in microglial activity, in turn causing
manifestations, particularly symptoms of depression and neural inflammation and cell damage [36-40] . At a molecular
anxiety [17-19] . In PD, depressive symptoms are associated with level, there is now significant translational and clinical
more severe cognitive and motor coordination deficits [20,21] , evidence suggesting that α-synuclein may also play a role
and fluctuations in mood and anxiety are associated in this association. In animal models, increased expression
with motor fluctuations , thus suggesting a shared of α-synuclein is associated with depressive- and anxiety-
[22]
pathophysiological link between these symptoms. Symptoms like behaviors, and treatments that reverse depression are
of anxiety and depression are also common in patients with associated with reduced α-synuclein aggregation [41-43] .
AlzD and may reflect neurodegenerative changes in their Similarly, chronic exposure to corticosterone, mimicking
cortical and limbic brain regions; however, such symptoms the biochemical effects of chronic stress, worsened the
tend to be more severe in the early stages of the disease but neural and behavioral changes in a mouse model of
[44]
decrease in severity as cognitive deficits worsen . α-synucleinopathy . Studies in human patients with
[23]
depression without features of PD or AlzD have shown
The chronic and progressive nature of both these increased serum α-synuclein and α-synuclein expression, as
disorders and the lack of effective disease-modifying indicated by increased messenger RNA (mRNA) levels [45-47] .
treatment in patients with well-established motor In addition, a study has found an indirect association
or cognitive symptoms of either disorder have led between the cerebrospinal fluid levels of α-synuclein
researchers and clinicians to consider the possibility and cognitive impairment in patients with depression .
[48]
of early intervention in both PD and AlzD [24,25] . For Variations in the expression of SNCA gene, which encodes
such an approach to be effective, it would require early α-synuclein, have also been associated with the response to
identification of specific biomarkers of disease risk and antidepressants in elderly individuals with depression .
[49]
progression [26,27] , early or “prodromal” symptoms that are It is therefore plausible that alterations in the expression
associated with progression to marked neurodegeneration, of α-synuclein may represent a common pathway linking
and overt cognitive or motor symptoms [25,28] , or both.
depression with the subsequent risk of PD or AlzD. The
Recent research has drawn attention to a link between aim of the current study was to examine the plausibility of
certain psychiatric disorders, particularly depression, this association through the analysis of epidemiological,
anxiety disorders, and post-traumatic stress disorder, population genetic, and environmental risk factor data.
and the subsequent emergence of either PD or various The objectives of this study were as follows:
subtypes of dementia, including AlzD [29,30] . Among these
psychiatric disorders, the most consistent and significant (i) To examine the cross-sectional and longitudinal
associations have been reported for depression . In a associations between the prevalence of depression,
[31]
study of patients with severe depression without signs of AlzD and PD over a certain period (1990 – 2019)
parkinsonism, 6.5% of them developed PD over a nine- using data from the global burden of disease study;
year follow-up . A meta-analysis of eleven studies has (ii) To examine the relationship between population-level
[32]
found that depression is associated with at least a two-fold variations in specific polymorphisms of SNCA gene
increase in risk of subsequent Parkinsonism regardless of and the prevalence of these disorders, both cross-
age; the results remained significant even after adjusting sectionally and longitudinally;
for potential confounders . Likewise, a meta-analysis of (iii) To examine whether these associations remain
[33]
longitudinal studies has found a significant association significant after correction for two established
between depression and the subsequent risk of AlzD, with environmental risk factors for AlzD and PD: air
stronger effects observed in severe- or late-life depression ; pollution and pesticide exposure.
[34]

Volume 2 Issue 1 (2023) 2 https://doi.org/10.36922/an.326