PET Radioligands Reveal the Basis of Dementia in Parkinson's Disease and Dementia with Lewy Bodies

Abstract

Background: Effective therapies for dementia with Lewy bodies (DLB) and Parkinson's disease (PD) dementia will require accurate diagnosis and an understanding of the contribution of distinct molecular pathologies to these diseases. We seek to use imaging biomarkers to improve diagnostic accuracy and to clarify the contribution of molecular species to cognitive impairment in DLB and PD.

Summary: We have performed cross-sectional and prospective cohort studies in subjects with DLB, PD with normal cognition, PD with mild cognitive impairment and PD with dementia, contrasted with Alzheimer's disease (AD) and healthy control subjects (HCS). Subjects underwent formal neurological examination, detailed neuropsychological assessments, MRI and PET scans with the radioligands altropane (a dopamine transporter, DAT) and Pittsburgh compound B (PiB; β-amyloid). Putamen DAT concentrations were similar in DLB and PD and differentiated them from HCS and AD. Decreased caudate DAT concentration related to functional impairment in DLB but not PD. PiB uptake was greatest in DLB. However, cortical PiB retention was common in PD and predicted cognitive decline. PET imaging of tau aggregates holds promise both to clarify the contribution of tau to cognitive decline in these diseases and to differentiate DLB and PD from the parkinsonian tauopathies.

Key messages: Together, DAT and amyloid PET imaging discriminate DLB from PD and from other disease groups and identify pathological processes that contribute to their course. Multimodal PET imaging has the potential to increase the diagnostic accuracy of DLB and PD in the clinic, improve cohort uniformity for clinical trials, and serve as biomarkers for targeted molecular therapies.

Figure 1

Altropane imaging in DLB and PD. A. Putamen DAT levels differentiate DLB, PDD, and nondemented PD from AD and HCS. Putamen DAT levels in the DLB/PDD group and the nondemented PD group were similar to each other and lower than the putamen DAT levels of AD and HCS (p<0.0001 for each comparison). B. Relative caudate DAT concentration differentiates DLB from nondemented PD. B1. Caudate DAT levels were lower in DLB and nondemented PD than HCS (DLB vs HCS, p<0.0003; PD vs HCS, p<0.0003). B2. Adjusting for putamen DAT concentration and age, caudate DAT concentration in DLB was lower than in nondemented PD (p<0.041). C. Caudate DAT concentration relates to cognitive function in DLB but not in nondemented PD. Adjusting for age, duration of motor symptoms, and putamen DAT concentration, higher CDR-SB was associated with greater reduction in DAT concentration in DLB (R²=0.84, p<0.0001 for model). Note that a similar decline in caudate DAT concentration in nondemented PD was not associated with a similar impairment on the CDR-SB (p=0.0008 for interaction between DAT concentration and diagnosis).

Figure 2

Greater amyloid burden in PD, measured as PiB retention in the precuneus, is associated with a faster transition to a more severe cognitive diagnosis. PD-nl and PD-MCI groups were pooled for this analysis, and transitions from PD with normal cognition to PD-MCI or PDD, and from PD-MCI to PDD were evaluated (p=0.008; Cox regression). The survival probability is shown for precuneus PiB DVR of one standard deviation below (1; green) and above (1.4; blue) the mean (1.2; red).