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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., (© 2019 American Academy of Neurology.)

Objectives: To identify in vivo MRI markers that might correlate with cerebral microinfarcts (CMIs) on autopsy in patients with cerebral amyloid angiopathy (CAA)., Methods: We included patients with neuropathologic evidence of CAA on autopsy and available antemortem brain MRI. Clinical characteristics and in vivo MRI markers of CAA-related small vessel disease were recorded, including white matter hyperintensities, cerebral microbleeds, cortical superficial siderosis, and centrum semiovale perivascular spaces. In addition, the presence of intracerebral hemorrhage on MRI was assessed. Evaluation of the presence and number of CMIs was performed in 9 standard histology sections., Results: Of 49 analyzed patients with CAA, CMIs were present in 36.7%. The presence of ≥1 CMIs on autopsy was associated with higher numbers of microbleeds on antemortem MRI (median 8 [interquartile range 2.5-33.0] vs 1 [interquartile range 0-3], p = 0.003) and with the presence of intracerebral hemorrhage (44.4% vs 16.1%, p = 0.03). No associations between CMIs and other in vivo MRI markers of CAA were found. In a multivariable model adjusted for severe CAA pathology, higher numbers of microbleeds were independent predictors of the presence of CMIs on pathology., Conclusions: CMIs are a common finding at autopsy in patients with CAA. The strong association between MRI-observed microbleeds and CMIs at autopsy may suggest a shared underlying pathophysiologic mechanism between these lesions., (© 2016 American Academy of Neurology.)

Objective: Recent genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) identified 9 novel risk loci. Discovery of functional variants within genes at these loci is required to confirm their role in Alzheimer disease (AD). Single nucleotide polymorphisms that influence gene expression (eSNPs) constitute an important class of functional variants. We therefore investigated the influence of the novel LOAD risk loci on human brain gene expression., Methods: We measured gene expression levels in the cerebellum and temporal cortex of autopsied AD subjects and those with other brain pathologies (∼400 total subjects). To determine whether any of the novel LOAD risk variants are eSNPs, we tested their cis-association with expression of 6 nearby LOAD candidate genes detectable in human brain (ABCA7, BIN1, CLU, MS4A4A, MS4A6A, PICALM) and an additional 13 genes ±100 kb of these SNPs. To identify additional eSNPs that influence brain gene expression levels of the novel candidate LOAD genes, we identified SNPs ±100 kb of their location and tested for cis-associations., Results: CLU rs11136000 (p = 7.81 × 10(-4)) and MS4A4A rs2304933/rs2304935 (p = 1.48 × 10(-4)-1.86 × 10(-4)) significantly influence temporal cortex expression levels of these genes. The LOAD-protective CLU and risky MS4A4A locus alleles associate with higher brain levels of these genes. There are other cis-variants that significantly influence brain expression of CLU and ABCA7 (p = 4.01 × 10(-5)-9.09 × 10(-9)), some of which also associate with AD risk (p = 2.64 × 10(-2)-6.25 × 10(-5))., Conclusions: CLU and MS4A4A eSNPs may at least partly explain the LOAD risk association at these loci. CLU and ABCA7 may harbor additional strong eSNPs. These results have implications in the search for functional variants at the novel LOAD risk loci.