PET evidence of preclinical cerebellar amyloid plaque deposition in autosomal dominant Alzheimer’s disease-causing Presenilin-1 E280A mutation carriers

https://doi.org/10.1016/j.nicl.2021.102749Get rights and content
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Highlights

  • PET evidence of cerebellar Aβ deposition in unimpaired (CU) PSEN1 E280A kindred.

  • Cerebellar Aβ PET SUVR began to distinguish CU carriers from non-carriers at age 34.

  • Cortical and cerebellar Aβ PET SUVR are positively associated in CU carriers.

  • Cerebellar florbetapir SUVR correlated with lower composite score in CU carriers.

Abstract

Background

In contrast to sporadic Alzheimer’s disease, autosomal dominant Alzheimer’s disease (ADAD) is associated with greater neuropathological evidence of cerebellar amyloid plaque (Aβ) deposition. In this study, we used positron emission tomography (PET) measurements of fibrillar Aβ burden to characterize the presence and age at onset of cerebellar Aβ deposition in cognitively unimpaired (CU) Presenilin-1 (PSEN1) E280A mutation carriers from the world’s largest extended family with ADAD.

Methods

18F florbetapir and 11C Pittsburgh compound B (PiB) PET data from two independent studies – API ADAD Colombia Trial (NCT01998841) and Colombia-Boston (COLBOS) longitudinal biomarker study were included. The tracers were selected independently by the respective sponsors prior to the start of each study and used exclusively throughout. Template-based cerebellar Aβ-SUVR (standard-uptake value ratios) using a known-to-be-spared pons reference region (cerebellar SUVR_pons), to a) compare 28–56-year-old CU carriers and non-carriers; b) estimate the age at which cerebellar SUVR_pons began to differ significantly in carrier and non-carrier groups; and c) characterize in carriers associations with age, cortical SUVR_pons, delayed recall memory, and API ADAD composite score.

Results

Florbetapir and PiB cerebellar SUVR_pons were significantly higher in carriers than non-carriers (p < 0.0001). Cerebellar SUVR_pons began to distinguish carriers from non-carriers at age 34, 10 years before the carriers’ estimated age at mild cognitive impairment onset. Florbetapir and PiB cerebellar SUVR_pons in carriers were positively correlated with age (r = 0.44 & 0.69, p < 0.001), cortical SUVR_pons (r = 0.55 & 0.69, p < 0.001), and negatively correlated with delayed recall memory (r = −0.21 & −0.50, p < 0.05, unadjusted for cortical SUVR_pons) and API ADAD composite (r = −0.25, p < 0.01, unadjusted for cortical SUVR_pons in florbetapir API ADAD cohort).

Conclusion

This PET study provides evidence of cerebellar Aβ plaque deposition in CU carriers starting about a decade before the clinical onset of ADAD. Additional studies are needed to clarify the impact of using a cerebellar versus pons reference region on the power to detect and track ADAD changes, even in preclinical stages of this disorder.

Keywords

Brain imaging
PET
Amyloid
Cerebellum
Pons
Autosomal dominant Alzheimer’s disease

Cited by (0)

1

Drs. VG and FL are co-first authors.

2

Drs. YTQ and EMR are co-senior authors.