The aggregation of α-synuclein in the nervous system leads to a class of neurodegenerative disorders termed α-synucleinopathies. A form of primary degenerative dementia called Lewy body dementia (LBD) often develops in the case these aggregations develop into intracellular inclusions called Lewy bodies (LB) and Lewy neurites (LN). Despite the high frequency of LBD, being the leading cause of dementia following Alzheimer′s disease (AD), there is relatively little information discovered about its pathological pathway or diagnostic criteria. In this report, we attempt to address such shortcomings via utilizing a proteomic approach to identify the proteomic changes following intrastriatal injection of α-synuclein pre-formed fibril (α-syn PFF). Through mass spectrometry, we have identified a total of 179 proteins that were either up- or down-regulated at different time points, with the four proteins — TPP3, RAB10, CAMK2A, and DYNLL1 — displaying the most significant changes throughout the timeframe. Further examining the modulated proteins with network-based enrichment analyses, we have found that 1) the most significantly associated neurodegenerative pathways were Parkinson′s (pV = 3.0e-16) and Huntington′s (pV = 1.9e-15) disease, and 2) the majority of molecular functions specific to the pathology only appeared at later time points. While these results do not expose a conclusive biomarker for LBD, they suggest a potential framework that may be utilized to diagnose and differentiate LBD pathology from other forms of dementia by focusing on the cortical proteomic changes which occur in a later time span.