Longitudinal changes in amyloid positron emission tomography and volumetric magnetic resonance imaging in the nondemented Down syndrome population

Abstract

IntroductionDown syndrome (DS) arises from a triplication of chromosome 21, causing overproduction of the amyloid precursor protein and predisposes individuals to early Alzheimer's disease (AD).MethodsFifty-two nondemented adults with DS underwent two cycles of carbon 11-labeled Pittsburgh compound B ([11C]PiB) and T1 weighted magnetic resonance imaging (MRI) scans 3.0 ± 0.6 years apart. Standard uptake value ratio (SUVR) images (50–70 minutes; cerebellar gray matter [GM]) and GM volumes were analyzed in standardized space (Montreal Neurological Institute space).Results85% of PiB(−) subjects remained PiB(−), whereas 15% converted to PiB(+), predominantly in the striatum. None reverted from PiB(+) to PiB(−). Increases in SUVR were distributed globally, but there were no decreases in GM volume. The PiB positivity groups differed in the percent rate of change in SUVR [PiB(−): 0.5%/year, PiB converters: 4.9%/year, and PiB(+): 3.7%/year], but not in GM volume.DiscussionDespite the characteristic striatum-first pattern, the global rate of amyloid accumulation differs by pre-existing amyloid burden and precedes atrophy or dementia in the DS population, similar to general AD progression.

Alzheimer-Like Pattern of Hypometabolism Emerges with Elevated Amyloid-β Burden in Down Syndrome

“…Parametric GM, white matter, and cerebrospinal fluid volume images were estimated using a mixed-model tissue-type segmentation (Matlab2015, SPM12 [46]) and DS specific tissue type prior probability maps were created in a two pass method to account for the unique DS brain morphology (e.g., smaller overall brain with smaller frontal cortex, temporal cortex, and cerebellum [47, 48]). The DS specific prior probability maps have been previously described [28], and population specific brain templates are often created in two passes for atypical populations [49–51]. Intracranial total volume (ITV) was calculated from GM, white matter, and cerebrospinal fluid volumes.…”

“…Region of interest (ROI) specific PiB positivity thresholds were determined by sparse k-means clustering with resampling due to the bimodal distribution of the data, using a previously described process [52] applied to non-atrophy corrected data from the complete DS cohort [27, 28, 53, 54]. A subject was classified as PiB(+) if at least one ROI exceeded its threshold (anterior cingulate: 1.59, frontal cortex: 1.48, parietal cortex: 1.51, precuneus: 1.64, striatum: 1.45, temporal cortex: 1.38).…”

“…ROIs were defined in standardized space from the Wake Forest University pick atlas toolbox (aal human atlas; SPM12; MATLAB2015). The binary masks were dilated (4 mm Gaussian smoothing and thresholding at 0.3) to account for intersubject variability in brain morphology and were closely inspected to ensure proper coverage for each region on each subject, as previously described [27, 28]. …”

“…Analysis of specific cognitive abilities with amyloid burden have been previously published [53, 54], and current analysis was limited to the Peabody Picture Vocabulary Test 4th Edition (PPVT [55]), a measure of receptive language that correlates strongly with IQ scores [56], but not with chronological age. PPVT score, expressed as a mental age, was used as a measure of overall cognitive performance in the DS population [27, 28, 49, 53, 54]. …”

“…Moreover, the longitudinal rate of Aβ accumulation in DS was similar to that in the general population when stratified by amyloid positivity [28]. Preliminary data of tau PET imaging in DS suggests similar binding in the medial temporal cortex [29].…”