Lewy pathology accumulates in enlarged corticostriatal synapses in α-synucleinopathies

Abstract

Lewy body diseases, including Parkinson’s disease, Parkinson’s disease dementia, and dementia with Lewy bodies, are neurodegenerative disorders characterized by the accumulation of misfolded α-synuclein in the form of Lewy pathology. A hallmark of these diseases is degeneration of the nigrostriatal pathway, resulting in loss of dopaminergic input to the striatum and consequent motor dysfunction. Lewy pathology is present in many regions outside the substantia nigra, and cortical Lewy pathology is the best correlate of cognitive decline in individuals who develop dementia. In addition, there is a high burden of neuritic Lewy pathology in the putamen, though the neuronal origin of this pathology is unclear. In the current study, we quantified the burden of Lewy pathology in the putamen across the spectrum of Lewy body diseases. Immunohistochemistry was used to quantify the Lewy burden in the putamen, cingulate and frontal cortices of 9 controls and 24 Lewy body disease cases. Even in Parkinson’s disease cases without dementia, we observed a nearly complete striatal dopaminergic denervation among Lewy body disease cases. Consistent with this denervation, most α-synuclein pathology did not colocalize with dopaminergic terminals, but was instead enriched in excitatory terminals. This enrichment in glutamatergic terminals was associated with swollen axons, but not with overall loss of those terminals. These findings suggest that Lewy pathology accumulates at excitatory corticostriatal synapses prior to overt synaptic degeneration and could contribute to cognitive decline in Lewy body diseases.