Cognitive decline in Parkinson disease

Abstract

Dementia is a frequent problem encountered in advanced stages of Parkinson disease (PD). In recent years, research has focused on the pre-dementia stages of cognitive impairment in PD, including mild cognitive impairment (MCI). Several longitudinal studies have shown that MCI is a harbinger of dementia in PD, although the course is variable, and stabilization of cognition - or even reversal to normal cognition - is not uncommon. In addition to limbic and cortical spread of Lewy pathology, several other mechanisms are likely to contribute to cognitive decline in PD, and a variety of biomarker studies, some using novel structural and functional imaging techniques, have documented in vivo brain changes associated with cognitive impairment. The evidence consistently suggests that low cerebrospinal fluid levels of amyloid-β₄₂, a marker of comorbid Alzheimer disease (AD), predict future cognitive decline and dementia in PD. Emerging genetic evidence indicates that in addition to the APOE*ε4 allele (an established risk factor for AD), GBA mutations and SCNA mutations and triplications are associated with cognitive decline in PD, whereas the findings are mixed for MAPT polymorphisms. Cognitive enhancing medications have some effect in PD dementia, but no convincing evidence that progression from MCI to dementia can be delayed or prevented is available, although cognitive training has shown promising results.

Figure 1. Amyloid-β PET scans in Parkinson disease dementia

Axial slices from two patients with Parkinson disease dementia, showing a | absence and b | presence of amyloid-β binding. ¹¹C-PiB, ¹¹C-labelled Pittsburgh compound B.

Figure 2. Overview of risk factors for Parkinson disease dementia

Three different categories of risk factors for Parkinson disease dementia (PDD) — clinical, molecular, and structural/functional imaging — are illustrated. Factors with evidence from longitudinal studies are shaded pink, and factors with evidence from cross-sectional studies are shaded grey. Interrelationships between factor categories (bidirectional arrows) and temporal relationships between cross-sectional factors and PDD (unidirectional arrows) remain unclear. MCI, mild cognitive impairment; MEG, magnetoencephalogram.