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PET evidence of preclinical cerebellar amyloid plaque deposition in autosomal dominant Alzheimer's disease-causing Presenilin-1 E280A mutation carriers.
Neuroimage Clin. 2021; 31:102749.NC

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.

Links

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Authors+Show Affiliations

Ghisays V
Banner Alzheimer's Institute, Phoenix, AZ, USA; Arizona Alzheimer's Consortium, Phoenix, AZ, USA.
Lopera F
Neurosciences Group of Antioquia, Universidad de Antioquia, Medellín, Colombia.
Goradia DD
Banner Alzheimer's Institute, Phoenix, AZ, USA; Arizona Alzheimer's Consortium, Phoenix, AZ, USA.
Protas HD
Banner Alzheimer's Institute, Phoenix, AZ, USA; Arizona Alzheimer's Consortium, Phoenix, AZ, USA.
Malek-Ahmadi MH
Banner Alzheimer's Institute, Phoenix, AZ, USA; Arizona Alzheimer's Consortium, Phoenix, AZ, USA.
Chen Y
Banner Alzheimer's Institute, Phoenix, AZ, USA; Arizona Alzheimer's Consortium, Phoenix, AZ, USA.
Devadas V
Banner Alzheimer's Institute, Phoenix, AZ, USA; Arizona Alzheimer's Consortium, Phoenix, AZ, USA.
Luo J
Banner Alzheimer's Institute, Phoenix, AZ, USA; Arizona Alzheimer's Consortium, Phoenix, AZ, USA.
Lee W
Banner Alzheimer's Institute, Phoenix, AZ, USA; Arizona Alzheimer's Consortium, Phoenix, AZ, USA.
Baena A
Neurosciences Group of Antioquia, Universidad de Antioquia, Medellín, Colombia.
Bocanegra Y
Neurosciences Group of Antioquia, Universidad de Antioquia, Medellín, Colombia.
Guzmán-Vélez E
Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Pardilla-Delgado E
Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Vila-Castelar C
Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Fox-Fuller JT
Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Boston University, Boston, MA, USA.
Hu N
Genentech Inc., South San Francisco, CA, USA.
Clayton D
Genentech Inc., South San Francisco, CA, USA.
Thomas RG
University of California San Diego School of Medicine, La Jolla, CA, USA.
Alvarez S
Hospital Pablo Tobón Uribe, Medellín, Colombia.
Espinosa A
Neurosciences Group of Antioquia, Universidad de Antioquia, Medellín, Colombia.
Acosta-Baena N
Neurosciences Group of Antioquia, Universidad de Antioquia, Medellín, Colombia.
Giraldo MM
Neurosciences Group of Antioquia, Universidad de Antioquia, Medellín, Colombia.
Rios-Romenets S
Neurosciences Group of Antioquia, Universidad de Antioquia, Medellín, Colombia.
Langbaum JB
Banner Alzheimer's Institute, Phoenix, AZ, USA; Arizona Alzheimer's Consortium, Phoenix, AZ, USA.
Chen K
Banner Alzheimer's Institute, Phoenix, AZ, USA; Arizona Alzheimer's Consortium, Phoenix, AZ, USA; Arizona State University, Tempe, AZ, USA; University of Arizona, Tucson, AZ, USA.
Su Y
Banner Alzheimer's Institute, Phoenix, AZ, USA; Arizona Alzheimer's Consortium, Phoenix, AZ, USA.
Tariot PN
Banner Alzheimer's Institute, Phoenix, AZ, USA; Arizona Alzheimer's Consortium, Phoenix, AZ, USA.
Quiroz YT
Neurosciences Group of Antioquia, Universidad de Antioquia, Medellín, Colombia; Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: yquiroz@mgh.harvard.edu.
Reiman EM
Banner Alzheimer's Institute, Phoenix, AZ, USA; Arizona Alzheimer's Consortium, Phoenix, AZ, USA; Arizona State University, Tempe, AZ, USA; University of Arizona, Tucson, AZ, USA; Translational Genomics Research Institute, Phoenix, AZ, USA. Electronic address: eric.reiman@bannerhealth.com.
API ADAD Colombia Trial Group
No affiliation info available

MeSH

AdultAlzheimer DiseaseAmyloid beta-PeptidesAniline CompoundsCross-Sectional StudiesHumansMiddle AgedMutationPlaque, AmyloidPositron-Emission TomographyPresenilin-1

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

34252876

Clinical Trial Links

Clinical trial which this article describes

Citation

Ghisays, Valentina, et al. "PET Evidence of Preclinical Cerebellar Amyloid Plaque Deposition in Autosomal Dominant Alzheimer's Disease-causing Presenilin-1 E280A Mutation Carriers." NeuroImage. Clinical, vol. 31, 2021, p. 102749.
Ghisays V, Lopera F, Goradia DD, et al. PET evidence of preclinical cerebellar amyloid plaque deposition in autosomal dominant Alzheimer's disease-causing Presenilin-1 E280A mutation carriers. Neuroimage Clin. 2021;31:102749.
Ghisays, V., Lopera, F., Goradia, D. D., Protas, H. D., Malek-Ahmadi, M. H., Chen, Y., Devadas, V., Luo, J., Lee, W., Baena, A., Bocanegra, Y., Guzmán-Vélez, E., Pardilla-Delgado, E., Vila-Castelar, C., Fox-Fuller, J. T., Hu, N., Clayton, D., Thomas, R. G., Alvarez, S., ... Reiman, E. M. (2021). PET evidence of preclinical cerebellar amyloid plaque deposition in autosomal dominant Alzheimer's disease-causing Presenilin-1 E280A mutation carriers. NeuroImage. Clinical, 31, 102749. https://doi.org/10.1016/j.nicl.2021.102749
Ghisays V, et al. PET Evidence of Preclinical Cerebellar Amyloid Plaque Deposition in Autosomal Dominant Alzheimer's Disease-causing Presenilin-1 E280A Mutation Carriers. Neuroimage Clin. 2021;31:102749. PubMed PMID: 34252876.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - PET evidence of preclinical cerebellar amyloid plaque deposition in autosomal dominant Alzheimer's disease-causing Presenilin-1 E280A mutation carriers. AU - Ghisays,Valentina, AU - Lopera,Francisco, AU - Goradia,Dhruman D, AU - Protas,Hillary D, AU - Malek-Ahmadi,Michael H, AU - Chen,Yinghua, AU - Devadas,Vivek, AU - Luo,Ji, AU - Lee,Wendy, AU - Baena,Ana, AU - Bocanegra,Yamile, AU - Guzmán-Vélez,Edmarie, AU - Pardilla-Delgado,Enmanuelle, AU - Vila-Castelar,Clara, AU - Fox-Fuller,Joshua T, AU - Hu,Nan, AU - Clayton,David, AU - Thomas,Ronald G, AU - Alvarez,Sergio, AU - Espinosa,Alejandro, AU - Acosta-Baena,Natalia, AU - Giraldo,Margarita M, AU - Rios-Romenets,Silvia, AU - Langbaum,Jessica B, AU - Chen,Kewei, AU - Su,Yi, AU - Tariot,Pierre N, AU - Quiroz,Yakeel T, AU - Reiman,Eric M, AU - ,, Y1 - 2021/07/04/ PY - 2021/02/02/received PY - 2021/06/21/revised PY - 2021/06/26/accepted PY - 2021/7/13/pubmed PY - 2021/9/14/medline PY - 2021/7/12/entrez KW - Amyloid KW - Autosomal dominant Alzheimer’s disease KW - Brain imaging KW - Cerebellum KW - PET KW - Pons SP - 102749 EP - 102749 JF - NeuroImage. Clinical JO - Neuroimage Clin VL - 31 N2 - 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. SN - 2213-1582 UR - https://www.unboundmedicine.com/medline/citation/34252876/PET_evidence_of_preclinical_cerebellar_amyloid_plaque_deposition_in_autosomal_dominant_Alzheimer's_disease_causing_Presenilin_1_E280A_mutation_carriers_ DB - PRIME DP - Unbound Medicine ER -