Brain amyloid and cognition in Lewy body diseases

Abstract

Many patients with PD develop PD with dementia (PDD), a syndrome that overlaps clinically and pathologically with dementia with Lewy bodies (DLB); PDD and DLB differ chiefly in the relative timing of dementia and parkinsonism. Brain amyloid deposition is an early feature of DLB and may account, in part, for its early dementia. We sought to confirm this hypothesis and also to determine whether amyloid accumulation contributes to cognitive impairment and dementia in the broad range of parkinsonian diseases. Twenty-nine cognitively healthy PD, 14 PD subjects with mild cognitive impairment (PD-MCI), 18 with DLB, 12 with PDD, and 85 healthy control subjects (HCS) underwent standardized neurologic and neuropsychological examinations and Pittsburgh compound B (PiB) imaging with PET. Apolipoprotein E (ApoE) genotypes were obtained in many patients. PiB retention was expressed as the distribution volume ratio using a cerebellar tissue reference. PiB retention was significantly higher in DLB than in any of the other diagnostic groups. PiB retention did not differ across PDD, PD-MCI, PD, and HCS. Amyloid burden increased with age and with the presence of the ApoE ε4 allele in all patient groups. Only in the DLB group was amyloid deposition associated with impaired cognition. DLB subjects have higher amyloid burden than subjects with PDD, PD-MCI, PD, or HCS; amyloid deposits are linked to cognitive impairment only in DLB. Early amyloid deposits in DLB relative to PDD may account for their difference in the timing of dementia and parkinsonism.

Figure 1. Distribution of onset of motor and cognitive symptoms across the diagnostic groups

Age at acquisition of PiB PET, age at onset of motor symptoms and age at onset of cognitive symptoms for each diagnostic group are displayed using the box-whiskers convention. Box edges show the inter-quartile range. The vertical line within each box is the median value, and the diamond designates the mean. Box whiskers extend to as much as 1.5 interquartiles above and below the edges. The DLB group had a significantly later onset of motor symptoms than the other groups (p <0.01), whereas all groups associated with cognitive symptoms had similar ages at onset of cognitive impairment.

Figure 2. Amyloid burden varies across the diagnostic groups

Precuneus PiB DVR values are displayed for each of the diagnostic groups, using the box-whiskers convention. Dots (jittered slightly laterally) represent actual values. The red horizontal line within each box is the group median PiB DVR value, and the green horizontal line extending beyond the box is the diagnostic group mean. The horizontal line extending across the entire graph indicates the grand mean. The widths of the boxes are proportional to group sample sizes. Group means were not substantially altered by adjustment for age. The DLB group had higher PiB retention than each of the other groups (p<0.04 for each comparison). The PDD, PD-MCI, PD, and HCS group means were not significantly different from each other.

Figure 3. Topography of amyloid burden in DLB

SPM contrasts of PiB DVR in DLB with other diagnostic groups. Regional PiB retention differences are shown in red. A. Amyloid burden in DLB compared with HCS was significantly higher in the frontal, parietal and superior temporal lobes (p (voxel-level) < 0.001, z = 6.33). B. Compared with the aggregated PD, PD-MCI and PDD groups, DLB had higher PiB retention in both frontal and parietal lobes (p (voxel-level) = 0.025, z = 5.13).

Figure 4. Amyloid burden varies with apolipoprotein E genotype

Box-whisker plots showing PiB retention in each diagnostic group differentiated by the presence (+) or absence (−) of at least one ApoE4 allele. There was a significant main effect of ApoE4 versus PiB retention for the entire cohort (p=0.0001), with the strongest associations in the HCS, PD-MCI, PDD and DLB groups.