Cognitive decline and brain amyloid-β accumulation across 3 years in adults with Down syndrome

Abstract

Adults with Down syndrome (DS) have a high incidence of Alzheimer’s disease (AD), providing a unique opportunity to explore the early, preclinical stages of AD neuropathology. We examined change in brain amyloid-β accumulation via the PET tracer [11C] Pittsburgh compound B (PiB) across two data collection cycles, spaced 3 years apart, and decline in cognitive functioning in 58 adults with DS without clinical AD. PiB retention increased in the anterior cingulate gyrus, precuneus cortex, parietal cortex and anterior ventral striatum. Across the two cycles, 14 (27.5%) participants were consistently PiB+, 31 (60.8%) were consistently PiB−, and 6 (11.7%) converted from PiB− at Cycle 1 to PiB+ at Cycle 2. Increased global amyloid-β was related to decline in verbal episodic memory, visual episodic memory, executive functioning, and fine motor processing speed. Participants who were consistently PiB+ demonstrated worsening of episodic memory, whereas participants who were consistently PiB− evidenced stable or improved performance. Amyloid-β accumulation may be a contributor to or biomarker of declining cognitive functioning in preclinical AD in DS.

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

“…Decreases in glucose metabolism and GM volume were evident in DS individuals with an elevated Aβ burden compared to those without an elevated Aβ burden, and patterns extended spatially after the onset of dementia. Most importantly, our findings indicate deviation in the early AD pathophysiology in DS as compared to sporadic AD (e.g., striatum dominant Aβ accumulation in DS [26–28, 53, 54, 57]), yet these divergent early pathways result in the same pattern of change in downstream biomarkers of neurodegeneration. The lack of glucose hypometabolism in the striatum despite a striatum-dominant pattern of Aβ accumulation has also been observed in ADAD [16].…”

“…Our group has previously investigated the associations between specific cognitive abilities and Aβ burden [53, 54]. In 63 non-demented adults with DS (30–53 years), there were associations with PiB SUVR and verbal memory, visual memory, visuospatial construction, attention, and executive functioning after adjustment for mental age, but only with visual memory after adjustment for mental and chronological age [53].…”

“…In 63 non-demented adults with DS (30–53 years), there were associations with PiB SUVR and verbal memory, visual memory, visuospatial construction, attention, and executive functioning after adjustment for mental age, but only with visual memory after adjustment for mental and chronological age [53]. Furthermore, a longitudinal follow up of 53 of those adults with DS after approximately 3 years demonstrated a significant association of global PiB increase and subtle declines in verbal memory, visual memory, visuospatial construction, and fine motor processing speed adjusting for chronological age [54]. …”

“…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).…”

“…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]. …”