Biology subjects

Madsen, C. A.

Publications and source records attributed to Madsen, C. A..

4 recordsLinked to original sources

bioRxiv2026

Scaling of anesthesia-dependent cerebrospinal fluid dynamics across rat and pig brains

This study presents a novel in vivo neuroimaging approach using dynamic single photon emission computed tomography (SPECT/CT) to investigate cerebrospinal fluid (CSF) dynamics in pigs, a translationally relevant model due to their human-like brain structure. The distribution, brain penetration of [99mTc]-DTPA and subsequent clearance were followed by brain SPECT for three hours after injection into the cisterna magna of anesthetized pigs and rats. To investigate the effects of anesthesia and across-species effects, we examine CSF dynamics under two types of anesthesia, propofol and ketamine/dexmedetomidine (K/D), and compare the outcome in pigs to that of rats, in which we also compared isoflurane. Propofol and K/D produced largely similar tracer distribution patterns across both pigs and rats: In both species, K/D was associated with higher tracer penetration into the dorsal striatum compared to propofol while neither species showed a tracer accumulation difference in the thalamus. K/D also increased intracranial radiotracer retention and reduced urinary tracer clearance in rats, but not in pigs. In rats, propofol and isoflurane showed similar tracer distribution, reflecting their shared GABAergic mechanism of action. The differences observed between pigs and rats may reflect species-specific physiology, differences in anesthesia dosing, or methodological factors. The work demonstrates the feasibility of using SPECT/CT to study CSF transport in the large gyrencephalic pig brain to advance understanding of human brain fluid dynamics.

neuroscience↗

bioRxiv2022

Kinetic models for PET displacement studies

The traditional design of PET target engagement studies is based on a baseline scan and one or more scans after drug administration. We here evaluate an alternative design in which the drug is administered during an on-going scan (i.e., a displacement study). This approach results both in lower radiation exposure and lower costs. Existing kinetic models assume steady state. This condition is not present during a drug displacement and consequently, our aim here was to develop kinetic models for analysing PET displacement data. We modified existing compartment models to accommodate a time-variant increase in occupancy following the pharmacological in-scan intervention. Since this implies the use of differential equations that cannot be solved analytically, we developed instead one approximate and one numerical solution. Through simulations, we show that if the occupancy is relatively high, it can be estimated without bias and with good accuracy. The models were applied to PET data from six pigs where [11C]UCB-J was displaced by intravenous brivaracetam. The dose-occupancy relationship estimated from these scans showed good agreement with occupancies calculated with Lassen plot applied to baseline-block scans of two pigs. In summary, the proposed models provide a framework to determine target occupancy from a single displacement scan.

neuroscience↗

bioRxiv2022

Evaluation of the α-synuclein PET radiotracer (d3)-MODAG-001 in pigs

BackgroundA positron emission tomography (PET) radiotracer to neuroimage -synuclein aggregates would be a crucial addition for early diagnosis and treatment development in disorders such as Parkinsons disease, where elevated aggregate levels is a histopathological hallmark. The radiotracer (d3)-[11C]MODAG-001 has recently shown promise for visualization of -synuclein pre-formed fibrils (-PFF) in rodents. We here test the radiotracer in a pig model where proteins are intracerebrally injected immediately before scanning. Four pigs were injected in one hemisphere with 150 {micro}g -PFF, and in the other hemisphere, either 75 {micro}g -PFF or human brain homogenate from either dementia with Lewy bodies (DLB) or Alzheimers disease (AD) was injected. All pigs underwent one or two (d3)-[11C]MODAG-001 PET scans, quantified with the non-invasive Logan graphical analysis using the occipital cortex as a reference region. ResultsThe -PFF and AD homogenate injected brain regions had high uptake of (d3)-[11C]MODAG-001 compared to the occipital cortex or cerebellum. BPND values in 150 {micro}g -PFF injected regions was 0.78, and in the AD homogenate injected regions was 0.73. By contrast, the DLB homogenate injected region did not differ in uptake and clearance compared to the reference regions. The time-activity curves and BPND values in the 150 {micro}g and 75 {micro}g injected region of -PFFs show a dose-dependent effect, and the PET signal could be blocked by pretreatment with unlabeled MODAG-001. ConclusionWe find that both -PFF and AD brain homogenates give rise to increased binding of (d3)-[11C]MODAG-001 when injected into the pig brain. Despite its limited specificity for cerebral -synuclein pathology, (d3)-[11C]MODAG-001 shows promise as a lead tracer for future radiotracer development.

neuroscience↗

bioRxiv2022

An in vivo pig model for testing novel PET radioligands targeting cerebral protein aggregates

Positron emission tomography (PET) has become an essential clinical tool for diagnosing neurodegenerative diseases with abnormal accumulation of proteins like amyloid-{beta} or tau. Despite many attempts, it has not been possible to develop an appropriate radioligand for imaging aggregated -synuclein in the brain for diagnosing, e.g., Parkinsons Disease. Access to a large animal model with -synuclein pathology would critically enable a more translationally appropriate evaluation of novel radioligands. We here establish a pig model with cerebral injections of -synuclein preformed fibrils or brain homogenate from postmortem human brain tissue from individuals with Alzheimers disease (AD) or dementia with Lewy body (DLB) into the pigs brain, using minimally invasive surgery and validated against saline injections. In the absence of a suitable -synuclein radioligand, we validated the model with the unselective amyloid-{beta} tracer [11C]PIB, which has a high affinity for {beta}-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 -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 brains 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.

neuroscience↗