Pathobiology of Cognitive Impairment in Parkinson Disease: Challenges and Outlooks

Abstract

Cognitive impairment (CI) is a characteristic non-motor feature of Parkinson disease (PD) that poses a severe burden on the patients and caregivers, yet relatively little is known about its pathobiology. Cognitive deficits are evident throughout the course of PD, with around 25% of subtle cognitive decline and mild CI (MCI) at the time of diagnosis and up to 83% of patients developing dementia after 20 years. The heterogeneity of cognitive phenotypes suggests that a common neuropathological process, characterized by progressive degeneration of the dopaminergic striatonigral system and of many other neuronal systems, results not only in structural deficits but also extensive changes of functional neuronal network activities and neurotransmitter dysfunctions. Modern neuroimaging studies revealed multilocular cortical and subcortical atrophies and alterations in intrinsic neuronal connectivities. The decreased functional connectivity (FC) of the default mode network (DMN) in the bilateral prefrontal cortex is affected already before the development of clinical CI and in the absence of structural changes. Longitudinal cognitive decline is associated with frontostriatal and limbic affections, white matter microlesions and changes between multiple functional neuronal networks, including thalamo-insular, frontoparietal and attention networks, the cholinergic forebrain and the noradrenergic system. Superimposed Alzheimer-related (and other concomitant) pathologies due to interactions between α-synuclein, tau-protein and β-amyloid contribute to dementia pathogenesis in both PD and dementia with Lewy bodies (DLB). To further elucidate the interaction of the pathomechanisms responsible for CI in PD, well-designed longitudinal clinico-pathological studies are warranted that are supported by fluid and sophisticated imaging biomarkers as a basis for better early diagnosis and future disease-modifying therapies.

Damage to the Locus Coeruleus Alters the Expression of Key Proteins in Limbic Neurodegeneration

“…Remarkably, the piriform cortex is growingly recognized to be a primary site of neurodegeneration in dementia, and it is affected at the early stages of neurodegeneration when only a mild cognitive impairment is present at the clinical level [ 19 , 74 , 82 , 84 , 121 , 122 , 123 ]. In fact, the early degeneration of the piriform cortex is associated with mild cognitive impairment and odor loss, which is described in the pre-clinical stages of AD and PD [ 53 , 54 , 55 , 80 , 88 , 89 , 90 ]. In the present manuscript, the piriform cortex was recruited by alpha-syn and p-Tau accumulation at 7 days following the administration of DSP4.…”

“…In fact, a loss of NE within the limbic system and the piriform cortex leads to a loss of olfactory perception and recognition, the re-arrangements of neural circuitries, and pathological findings, such as p-Tau deposition within neurons of the piriform cortex. This is reminiscent of what occurs in mild cognitive impairment, dementia, and during limbic involvement of PD [ 53 , 54 , 55 , 56 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 ]. This is key when considering that the piriform cortex is early and markedly affected in AD and PD.…”

“…The effects of a loss of LC-NE innervation are likely to be more relevant in areas where baseline NE innervation is more abundant. This explains why, even in PD, LC loss is key to producing limbic alterations [ 53 , 54 , 55 , 56 ]. Therefore, in the present study, a special emphasis was dedicated to studying limbic regions involved both in AD and PD that receive the highest LC-NE innervation, consisting of allo-cortical areas, such as the hippocampus [ 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 ] and piriform cortex [ 65 , 66 ], compared with dorsal striatum, which receives scattered NE innervation [ 67 ].…”