Biomarkers

Abstract

Background: Triplication of the amyloid precursor protein in individuals with Down Syndrome (DS) produces an increased risk for the development of Alzheimer's disease (AD). Declining cholinergic integrity plays a role in the cognitive deficits observed in late-onset AD. In the present study, we assess the relationship between basal forebrain volume or [¹⁸F]-FEOBV uptake and cognitive performance in adults with DS.

Method: 188 individuals from the ABC-DS cohort (U01AG051406; U01AG051412; U19AG068054) were assessed cross-sectionally. Basal forebrain volumes were calculated from T1 MRIs using the ScLimbic FreeSurfer pipeline. Ten individuals were recruited as part of a TRC-DS sub-study (25-55 years old) or de novo (18-24 years old), where they underwent MRI imaging and [¹⁸F]-FEOBV PET imaging. Regional [¹⁸F]-FEOBV SUVRs were calculated using PetSurfer. Participants from both studies underwent numerous cognitive assessments. Linear regressions were performed between cognitive performance and regional [¹⁸F]-FEOBV SUVR or basal forebrain volume correcting for intellectual disability.

Result: In the ABC-DS cohort, the Down Syndrome Mental State Exam (DSMSE) total score was positively associated with basal forebrain volume (p<0.05), and total free recall on the cued recall task was positively associated with left basal forebrain volume (p=0.0027). In the TRC-DS sub-study, [¹⁸F]-FEOBV uptake in the right amygdala, right rostral anterior cingulate cortex, and left transverse temporal cortex were positively associated with DSMSE total score (p<0.05). In the cued recall task, [¹⁸F]-FEOBV uptake in the left cuneus and right entorhinal cortexes and the isthmus of the right cingulate cortex was negatively associated with total free recall (p<0.05).

Conclusion: In the ABC-DS cohort, increased cholinergic integrity predicted improved performance on the DSMSE and cued recall task. Regional [¹⁸F]-FEOBV uptake can indicate which areas of cholinergic innervation are important for these different cognitive tasks. Increased regional [¹⁸F]-FEOBV uptake predicted improved performance on the DSMSE, with the object memory and apraxia sub-scores displaying the largest effect sizes. Interestingly, increased [¹⁸F]-FEOBV uptake predicted decreased free recall in the cued recall task. This unexpected result may indicate upregulation of the vesicular acetylcholine transporter in this non-demented DS cohort or may be spurious due to the small cohort. Increased sample size will further elucidate this effect.