An in vivo Pig Model for Testing Novel Positron Emission Tomography Radioligands Targeting Cerebral Protein Aggregates
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
An in vivo Pig Model for Testing Novel Positron Emission Tomography Radioligands Targeting Cerebral Protein Aggregates. / Raval, Nakul Ravi; Nasser, Arafat; Madsen, Clara Aabye; Beschorner, Natalie; Beaman, Emily Eufaula; Juhl, Morten; Lehel, Szabolcs; Palner, Mikael; Svarer, Claus; Plavén-Sigray, Pontus; Jørgensen, Louise Møller; Knudsen, Gitte Moos.
In: Frontiers in Neuroscience, Vol. 16, 847074, 2022.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - An in vivo Pig Model for Testing Novel Positron Emission Tomography Radioligands Targeting Cerebral Protein Aggregates
AU - Raval, Nakul Ravi
AU - Nasser, Arafat
AU - Madsen, Clara Aabye
AU - Beschorner, Natalie
AU - Beaman, Emily Eufaula
AU - Juhl, Morten
AU - Lehel, Szabolcs
AU - Palner, Mikael
AU - Svarer, Claus
AU - Plavén-Sigray, Pontus
AU - Jørgensen, Louise Møller
AU - Knudsen, Gitte Moos
N1 - Publisher Copyright: Copyright © 2022 Raval, Nasser, Madsen, Beschorner, Beaman, Juhl, Lehel, Palner, Svarer, Plavén-Sigray, Jørgensen and Knudsen.
PY - 2022
Y1 - 2022
N2 - Positron emission tomography (PET) has become an essential clinical tool for diagnosing neurodegenerative diseases with abnormal accumulation of proteins like amyloid-β or tau. Despite many attempts, it has not been possible to develop an appropriate radioligand for imaging aggregated α-synuclein in the brain for diagnosing, e.g., Parkinson’s Disease. Access to a large animal model with α-synuclein pathology would critically enable a more translationally appropriate evaluation of novel radioligands. We here establish a pig model with cerebral injections of α-synuclein preformed fibrils or brain homogenate from postmortem human brain tissue from individuals with Alzheimer’s disease (AD) or dementia with Lewy body (DLB) into the pig’s brain, using minimally invasive surgery and validated against saline injections. In the absence of a suitable α-synuclein radioligand, we validated the model with the unselective amyloid-β tracer [11C]PIB, which has a high affinity for β-sheet structures in aggregates. Gadolinium-enhanced MRI confirmed that the blood-brain barrier was intact. A few hours post-injection, pigs were PET scanned with [11C]PIB. Quantification was done with Logan invasive graphical analysis and simplified reference tissue model 2 using the occipital cortex as a reference region. After the scan, we retrieved the brains to confirm successful injection using autoradiography and immunohistochemistry. We found four times higher [11C]PIB uptake in AD-homogenate-injected regions and two times higher uptake in regions injected with α-synuclein-preformed-fibrils compared to saline. The [11C]PIB uptake was the same in non-injected (occipital cortex, cerebellum) and injected (DLB-homogenate, saline) regions. With its large brain and ability to undergo repeated PET scans as well as neurosurgical procedures, the pig provides a robust, cost-effective, and good translational model for assessment of novel radioligands including, but not limited to, proteinopathies.
AB - Positron emission tomography (PET) has become an essential clinical tool for diagnosing neurodegenerative diseases with abnormal accumulation of proteins like amyloid-β or tau. Despite many attempts, it has not been possible to develop an appropriate radioligand for imaging aggregated α-synuclein in the brain for diagnosing, e.g., Parkinson’s Disease. Access to a large animal model with α-synuclein pathology would critically enable a more translationally appropriate evaluation of novel radioligands. We here establish a pig model with cerebral injections of α-synuclein preformed fibrils or brain homogenate from postmortem human brain tissue from individuals with Alzheimer’s disease (AD) or dementia with Lewy body (DLB) into the pig’s brain, using minimally invasive surgery and validated against saline injections. In the absence of a suitable α-synuclein radioligand, we validated the model with the unselective amyloid-β tracer [11C]PIB, which has a high affinity for β-sheet structures in aggregates. Gadolinium-enhanced MRI confirmed that the blood-brain barrier was intact. A few hours post-injection, pigs were PET scanned with [11C]PIB. Quantification was done with Logan invasive graphical analysis and simplified reference tissue model 2 using the occipital cortex as a reference region. After the scan, we retrieved the brains to confirm successful injection using autoradiography and immunohistochemistry. We found four times higher [11C]PIB uptake in AD-homogenate-injected regions and two times higher uptake in regions injected with α-synuclein-preformed-fibrils compared to saline. The [11C]PIB uptake was the same in non-injected (occipital cortex, cerebellum) and injected (DLB-homogenate, saline) regions. With its large brain and ability to undergo repeated PET scans as well as neurosurgical procedures, the pig provides a robust, cost-effective, and good translational model for assessment of novel radioligands including, but not limited to, proteinopathies.
KW - alpha-synucein
KW - amyloid-β
KW - large animal PET
KW - PET
KW - PiB - Pittsburgh compound B
KW - pig brain imaging
KW - pig model
KW - protein injection model
UR - http://www.scopus.com/inward/record.url?scp=85127790940&partnerID=8YFLogxK
U2 - 10.3389/fnins.2022.847074
DO - 10.3389/fnins.2022.847074
M3 - Journal article
C2 - 35368260
AN - SCOPUS:85127790940
VL - 16
JO - Frontiers in Neuroscience
JF - Frontiers in Neuroscience
SN - 1662-4548
M1 - 847074
ER -
ID: 317508663