Neuropathologic correlates of amyloid and dopamine transporter imaging in Lewy body disease

Abstract

Objective: To develop imaging biomarkers of diseases in the Lewy body spectrum and to validate these markers against postmortem neuropathologic findings.

Methods: Four cognitively normal participants with Parkinson disease (PD), 4 with PD with cognitive impairments, and 10 with dementia with Lewy bodies underwent amyloid imaging with [11C]Pittsburgh compound B (PiB) and dopamine transporter (DAT) imaging with [11C]Altropane. All 18 had annual neurologic examinations. All cognitively normal participants with PD developed cognitive impairment before death. Neuropathologic examinations assessed and scored Braak Lewy bodies, Thal distribution of amyloid, Consortium to Establish a Registry for Alzheimer's Disease neuritic amyloid plaques, Braak neurofibrillary tangles, and cerebral amyloid angiopathy, as well as total amyloid plaque burden in the superior frontal, superior parietal, occipital, and inferior temporal cortical regions. PET data were expressed as the standardized uptake value ratio with cerebellar reference. Analyses accounted for the interval between imaging and autopsy.

Results: All 18 patients met neuropathologic criteria for Lewy body disease; the DAT concentration was low in each case. All patients with elevated [11C]PiB retention measured in a neocortical aggregate had β-amyloid deposits at autopsy. [11C]PiB retention significantly correlated with neuritic plaque burden and with total plaque burden. [11C]PiB retention also significantly correlated with the severity of both Braak stages of neurofibrillary tangle and Lewy body scores. Neuritic plaque burden was significantly associated with neurofibrillary tangle pathology.

Conclusion: Antemortem [11C]Altropane PET is a sensitive measure of substantia nigra degeneration. [11C]PiB scans accurately reflect cortical amyloid deposits seen at autopsy. These findings support the use of molecular imaging in the evaluation of patients with Lewy body diseases.

Figure 1. Boxplots of [11C]PiB retention as a function of neuritic plaque score and Thal amyloid phase in Lewy body disease

Partial correlations adjusting for the interval between [¹¹C]Pittsburgh compound B (PiB) PET and death: (A) neuritic plaque score (r = 0.62, p = 0.0075) and (B) Thal amyloid phase (r = 0.45, p = 0.07). A typical cut point for [11C]PiB positivity is 1.2. Filled circles indicate dementia with Lewy bodies; open diamonds, Parkinson disease with mild cognitive impairment and Parkinson disease with dementia. SUVR = standardized uptake value ratio.

Figure 2. [11C]PiB retention was significantly correlated with total amyloid deposits in occipital and superior parietal regions

Partial correlations controlling for the interval between PET and autopsy: (A) occipital (r = 0.68, p = 0.0035), (B) superior parietal (r = 0.56, p = 0.025), (C) inferior temporal (r = 0.31, p = 0.3), and (D) superior frontal (r = 0.15, p = 0.6). Filled circles indicate dementia with Lewy bodies; open diamonds, Parkinson disease with mild cognitive impairment and Parkinson disease with dementia. PiB = [¹¹C]Pittsburgh compound B; SUVR = standardized uptake value ratio.

Figure 3. β-Amyloid as detected by [11C]PiB was positively correlated with both neurofibrillary tangles and Lewy bodies

Partial correlations controlling for the interval between PET and autopsy: (A) neurofibrillary tangles (NFT) stage with [¹¹C]Pittsburgh compound B (PiB) (r = 0.73, p = 0.001), (B) Lewy body stage with PiB (r = 0.54, p = 0.025), and (C) Lewy body stage with [11C]Altropane (p = 0.21). Filled circles indicate dementia with Lewy bodies. Open diamonds, Parkinson disease with mild cognitive impairment and Parkinson disease with dementia. DAT = dopamine transporter; SUVR = standard uptake value ratio.