Pathological Correlates of Cognitive Decline in Parkinson's Disease: From Molecules to Neural Networks

Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by the death of dopaminergic neurons in the substantia nigra and appearance of protein aggregates (Lewy bodies) consisting predominantly of α-synuclein in neurons. PD is currently recognized as a multisystem disorder characterized by severe motor impairments and various non-motor symptoms. Cognitive decline is one of the most common and worrisome non-motor symptoms. Moderate cognitive impairments (CI) are diagnosed already at the early stages of PD, usually transform into dementia. The main types of CI in PD include executive dysfunction, attention and memory decline, visuospatial impairments, and verbal deficits. According to the published data, the following mechanisms play an essential role demonstrates a crucial importance in the decline of the motor and cognitive functions in PD: (1) changes in the conformational structure of transsynaptic proteins and protein aggregation in presynapses; (2) synaptic transmission impairment; (3) neuroinflammation (pathological activation of the neuroglia); (4) mitochondrial dysfunction and oxidative stress; (5) metabolic disorders (hypometabolism of glucose, dysfunction of glycolipid metabolism; and (6) functional rearrangement of neuronal networks. These changes can lead to the death of dopaminergic cells in the substantia nigra and affect the functioning of other neurotransmitter systems, thus disturbing neuronal networks involved in the transmission of information related to the regulation of motor activity and cognitive functions. Identification of factors causing detrimental changes in PD and methods for their elimination will help in the development of new approaches to the therapy of PD. The goal of this review was to analyze pathological processes that take place in the brain and underlie the onset of cognitive disorders in PD, as well as to describe the impairments of cognitive functions in this disease.