Pathophysiology
 | This article may be too technical for most readers to understand.(December 2025) |
Parkinson's disease dementia may have a mechanistic basis in neuroinflammation and alpha-synuclein aggregation [11] [12] involving the spreading of misfolded alpha-synuclein aggregates. [11] After initiation of neuroinflammation, IL-1β cytokines and CD4+ T-cells are hypothesized to activate to amplify the pro-inflammatory response of neurons that promotes neuronal dysfunction resulting in dementia. [11]
One hypothesis is that harmful environmental factors, such as toxins, infections, and poor lifestyle-factors, have been linked to triggering oxidative stress, inflammation, and selective vulnerability of dopaminergic neurons, which can lead to senescence, a state of permanent non-proliferation, or complete cell death. [11] Through senescence of neurons, alpha-synuclein pathology spreads, which amplifies inflammation, which leads to cognitive decline in PDD patients. [11] [13] It has been proposed that when Lewy body disease is in an advanced stage where alpha-synuclein pathology spreads and neuronal degeneration appears, PDD may develop. [13] In this hypothesis, a primary pathway toward progression of PDD is described to begin at the olfactory and limbic regions, which will cause parkinsonian motor symptoms and slowly progress to PDD. [13] Alpha-synuclein aggregation can begin in the olfactory bulb and travel to the limbic system. [11] [12] [13] A "brain-first" model and "body-first" model of the progression of PDD have been proposed to describe routes of alpha-synuclein pathology. [11] [12] [13] The "body-first" model of PDD connects enzymatic GBA mutations and ingestion of external toxicants, like contaminated food or water, to the spreading of alpha-synuclein pathology via the vagus nerve and sympathetic pathways to the brainstem and peripheral organs from the enteric nervous system. [12] [13] The "brain-first" model that induces slower progression of PDD connects LRRK2 mutations and inhaled external toxicants, like airborne pesticides and pollutants, to the spread of neuronal senescence and alpha-synuclein pathology from limbic regions to the brainstem and the substantia nigra. [11] [12] [13]
External environmental factors have been linked to inducing glial dysfunction and senescence. [11] When glial cells encounter a harmful environmental factor, they express a pro-inflammatory response and oxidative stress. [11] Air pollution as a harmful environmental factor has been linked to increased alpha-synuclein pathology, which promotes neuroinflammation. [12] Infections, such as periodontitis, as a harmful environmental factor can trigger an immune response and promote neuroinflammation. [14] Bacterial infections lead to IL-1β cytokine release, which can produce oxidative stress that promotes neuroinflammation. [14] The promotion and occurrence of neuroinflammation has been important in predicting possible neurodegenerativity. [14]