Aß-induced vulnerability propagates via the brain's default mode network.

The link between brain amyloid-ß (Aß), metabolism, and dementia symptoms remains a pressing question in Alzheimer's disease. Here, using positron emission tomography ([18F]florbetapir tracer for Aß and [18F]FDG tracer for glucose metabolism) with a novel analytical framework, we found that Aß aggregation within the brain's default mode network leads to regional hypometabolism in distant but functionally connected brain regions. Moreover, we found that an interaction between this hypometabolism with overlapping Aß aggregation is associated with subsequent cognitive decline. These results were also observed in transgenic Aß rats that do not form neurofibrillary tangles, which support these findings as an independent mechanism of cognitive deterioration. These results suggest a model in which distant Aß induces regional metabolic vulnerability, whereas the interaction between local Aß with a vulnerable environment drives the clinical progression of dementia.

Impact of Global Mean Normalization on Regional Glucose Metabolism in the Human Brain.

Because the human brain consumes a disproportionate fraction of the resting body's energy, positron emission tomography (PET) measurements of absolute glucose metabolism (CMRglc) can serve as disease biomarkers. Global mean normalization (GMN) of PET data reveals disease-based differences from healthy individuals as fractional changes across regions relative to a global mean. To assess the impact of GMN applied to metabolic data, we compared CMRglc with and without GMN in healthy awake volunteers with eyes closed (i.e., control) against specific physiological/clinical states, including healthy/awake with eyes open, healthy/awake but congenitally blind, healthy/sedated with anesthetics, and patients with disorders of consciousness. Without GMN, global CMRglc alterations compared to control were detected in all conditions except in congenitally blind where regional CMRglc variations were detected in the visual cortex. However, GMN introduced regional and bidirectional CMRglc changes at smaller fractions of the quantitative delocalized changes. While global information was lost with GMN, the quantitative approach (i.e., a validated method for quantitative baseline metabolic activity without GMN) not only preserved global CMRglc alterations induced by opening eyes, sedation, and varying consciousness but also detected regional CMRglc variations in the congenitally blind. These results caution the use of GMN upon PET-measured CMRglc data in health and disease.

Multimodal Imaging in Rat Model Recapitulates Alzheimer's Disease Biomarkers Abnormalities.

Imaging biomarkers are frequently proposed as endpoints for clinical trials targeting brain amyloidosis in Alzheimer's disease (AD); however, the specific impact of amyloid-ß (Aß) aggregation on biomarker abnormalities remains elusive in AD. Using the McGill-R-Thy1-APP transgenic rat as a model of selective Aß pathology, we characterized the longitudinal progression of abnormalities in biomarkers commonly used in AD research. Middle-aged (9-11 months) transgenic animals (both male and female) displayed mild spatial memory impairments and disrupted cingulate network connectivity measured by resting-state fMRI, even in the absence of hypometabolism (measured with PET [18F]FDG) or detectable fibrillary amyloidosis (measured with PET [18F]NAV4694). At more advanced ages (16-19 months), cognitive deficits progressed in conjunction with resting connectivity abnormalities; furthermore, hypometabolism, Aß plaque accumulation, reduction of CSF Aß1-42 concentrations, and hippocampal atrophy (structural MRI) were detectable at this stage. The present results emphasize the early impact of Aß on brain connectivity and support a framework in which persistent Aß aggregation itself is sufficient to impose memory circuits dysfunction, which propagates to adjacent brain networks at later stages.SIGNIFICANCE STATEMENT The present study proposes a "back translation" of the Alzheimer pathological cascade concept from human to animals. We used the same set of Alzheimer imaging biomarkers typically used in large human cohorts and assessed their progression over time in a transgenic rat model, which allows for a finer spatial resolution not attainable with mice. Using this translational platform, we demonstrated that amyloid-ß pathology recapitulates an Alzheimer-like profile of biomarker abnormalities even in the absence of other hallmarks of the disease such as neurofibrillary tangles and widespread neuronal losses.

[18F]FDG PET signal is driven by astroglial glutamate transport.

Contributions of glial cells to neuroenergetics have been the focus of extensive debate. Here we provide positron emission tomography evidence that activation of astrocytic glutamate transport via the excitatory amino acid transporter GLT-1 triggers widespread but graded glucose uptake in the rodent brain. Our results highlight the need for a reevaluation of the interpretation of [18F]FDG positron emission tomography data, whereby astrocytes would be recognized as contributing to the [18F]FDG signal.

Deletion of the mu opioid receptor gene in mice reshapes the reward-aversion connectome.

Connectome genetics seeks to uncover how genetic factors shape brain functional connectivity; however, the causal impact of a single gene's activity on whole-brain networks remains unknown. We tested whether the sole targeted deletion of the mu opioid receptor gene (Oprm1) alters the brain connectome in living mice. Hypothesis-free analysis of combined resting-state fMRI diffusion tractography showed pronounced modifications of functional connectivity with only minor changes in structural pathways. Fine-grained resting-state fMRI mapping, graph theory, and intergroup comparison revealed Oprm1-specific hubs and captured a unique Oprm1 gene-to-network signature. Strongest perturbations occurred in connectional patterns of pain/aversion-related nodes, including the mu receptor-enriched habenula node. Our data demonstrate that the main receptor for morphine predominantly shapes the so-called reward/aversion circuitry, with major influence on negative affect centers.

Imaging in vivo glutamate fluctuations with [(11)C]ABP688: a GLT-1 challenge with ceftriaxone.

Molecular imaging offers unprecedented opportunities for investigating dynamic changes underlying neuropsychiatric conditions. Here, we evaluated whether [(11)C]ABP688, a positron emission tomography (PET) ligand that binds to the allosteric site of the metabotropic glutamate receptor type 5 (mGluR5), is sensitive to glutamate fluctuations after a pharmacological challenge. For this, we used ceftriaxone (CEF) administration in rats, an activator of the GLT-1 transporter (EAAT2), which is known to decrease extracellular levels of glutamate. MicroPET [(11)C]ABP688 dynamic acquisitions were conducted in rats after a venous injection of either saline (baseline) or CEF 200 mg/kg (challenge). Binding potentials (BP(ND)) were obtained using the simplified reference tissue method. Between-condition statistical parametric maps indicating brain regions showing the highest CEF effects guided placement of microdialysis probes for subsequent assessment of extracellular levels of glutamate. The CEF administration increased [(11)C]ABP688 BP(ND) in the thalamic ventral anterior (VA) nucleus bilaterally. Subsequent microdialysis assessment revealed declines in extracellular glutamate concentrations in the VA. The present results support the concept that availability of mGluR5 allosteric binding sites is sensitive to extracellular concentrations of glutamate. This interesting property of mGluR5 allosteric binding sites has potential applications for assessing the role of glutamate in the pathogenesis of neuropsychiatric conditions.

Deficit in sustained attention following selective cholinergic lesion of the pedunculopontine tegmental nucleus in rat, as measured with both post-mortem immunocytochemistry and in vivo PET imaging with [¹8F]fluoroethoxybenzovesamicol.

Cholinergic neurons of the pedunculopontine tegmental nucleus (PPTg) are thought to be involved in cognitive functions such as sustained attention, and lesions of these cells have been documented in patients showing fluctuations of attention such as in Parkinson's disease or dementia with Lewy Body. Animal studies have been conducted to support the role of these cells in attention, but the lesions induced in these animals were not specific to the cholinergic PPTg system, and were assessed by post-mortem methods remotely performed from the in vivo behavioral assessments. Moreover, sustained attention have not been directly assessed in these studies, but rather deduced from indirect measurements. In the present study, rats were assessed on the 5-Choice Serial Reaction Time Task (5-CSRTT), and a specific measure of variability in response latency was created. Animals were observed both before and after selective lesion of the PPTg cholinergic neurons. Brain cholinergic denervation was assessed both in vivo and ex vivo, using PET imaging with [(18)F]fluoroethoxybenzovesamicol ([(18)F]FEOBV) and immunocytochemistry respectively. Results showed that the number of correct responses and variability in response latency in the 5-CSRTT were the only behavioral measures affected following the lesions. These measures were found to correlate significantly with the number of PPTg cholinergic cells, as measured with both [(18)F]FEOBV and immunocytochemistry. This suggests the primary role of the PPTg cholinergic cells in sustained attention. It also allows to reliably use the PET imaging with [(18)F]FEOBV for the purpose of assessing the relationship between behavior and cholinergic innervation in living animals.

MicroPET imaging and transgenic models: a blueprint for Alzheimer's disease clinical research.

Over the past decades, developments in neuroimaging have significantly contributed to the understanding of Alzheimer's disease (AD) pathophysiology. Specifically, positron emission tomography (PET) imaging agents targeting amyloid deposition have provided unprecedented opportunities for refining in vivo diagnosis, monitoring disease propagation, and advancing AD clinical trials. Furthermore, the use of a miniaturized version of PET (microPET) in transgenic (Tg) animals has been a successful strategy for accelerating the development of novel radiopharmaceuticals. However, advanced applications of microPET focusing on the longitudinal propagation of AD pathophysiology or therapeutic strategies remain in their infancy. This review highlights what we have learned from microPET imaging in Tg models displaying amyloid and tau pathology, and anticipates cutting-edge applications with high translational value to clinical research.

PET imaging with [¹8F]fluoroethoxybenzovesamicol ([¹8F]FEOBV) following selective lesion of cholinergic pedunculopontine tegmental neurons in rat.

INTRODUCTION: [(18)F]fluoroethoxybenzovesamicol ([(18)F]FEOBV) is a PET radiotracer with high selectivity and specificity to the vesicular acetylcholine transporter (VAChT). It has been shown to be a sensitive in vivo measurement of changes of cholinergic innervation densities following lesion of the nucleus basalis of Meynert (NBM) in rat. The current study used [(18)F]FEOBV with PET imaging to detect the effect of a highly selective lesion of the pedunculopontine (PPTg) nucleus in rat. METHODS: After bilateral and selective lesions of the PPTg cholinergic neurons, rats were scanned using [(18)F]FEOBV, then sacrificed, and their brain tissues collected for immunostaining and quantification of the VAChT. RESULTS: Comparisons with control rats revealed that cholinergic losses can be detected in the brainstem, lateral thalamus, and pallidum by using both in vivo imaging methods with [(18)F]FEOBV, and ex vivo measurements. In the brainstem PPTg area, significant correlations were observed between in vivo and ex vivo measurements, while this was not the case in the thalamic and pallidal projection sites. CONCLUSIONS: These findings support PET imaging with [(18)F]FEOBV as a reliable in vivo method for the detection of neuronal terminal losses resulting from lesion of the PPTg. Useful applications can be found in the study of neurodegenerative diseases in human, such as Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, or dementia with Lewy bodies.

Cholinergic Depletion in Alzheimer's Disease Shown by [ (18) F]FEOBV Autoradiography.

Rationale. Alzheimer's Disease (AD) is a neurodegenerative condition characterized in part by deficits in cholinergic basalocortical and septohippocampal pathways. [(18)F]Fluoroethoxybenzovesamicol ([(18)F]FEOBV), a Positron Emission Tomography ligand for the vesicular acetylcholine transporter (VAChT), is a potential molecular agent to investigate brain diseases associated with presynaptic cholinergic losses. Purpose. To demonstrate this potential, we carried out an [(18)F]FEOBV autoradiography study to compare postmortem brain tissues from AD patients to those of age-matched controls. Methods. [(18)F]FEOBV autoradiography binding, defined as the ratio between regional grey and white matter, was estimated in the hippocampus (13 controls, 8 AD) and prefrontal cortex (13 controls, 11 AD). Results. [(18)F]FEOBV binding was decreased by 33% in prefrontal cortex, 25% in CA3, and 20% in CA1. No changes were detected in the dentate gyrus of the hippocampus, possibly because of sprouting or upregulation toward the resilient glutamatergic neurons of the dentate gyrus. Conclusion. This is the first demonstration of [(18)F]FEOBV focal binding changes in cholinergic projections to the cortex and hippocampus in AD. Such cholinergic synaptic (and more specifically VAChT) alterations, in line with the selective basalocortical and septohippocampal cholinergic losses documented in AD, indicate that [(18)F]FEOBV is indeed a promising ligand to explore cholinergic abnormalities in vivo.

Concordance between in vivo and postmortem measurements of cholinergic denervation in rats using PET with [18F]FEOBV and choline acetyltransferase immunochemistry.

BACKGROUND: Fluorine-18 fluoroethoxybenzovesamicol ([18F]FEOBV) is a radioligand for the selective imaging of the vesicular acetylcholine transporter with positron emission tomography (PET). The current study demonstrates that pathological cortical cholinergic deafferentation can be quantified in vivo with [18F]FEOBV PET, yielding analogous results to postmortem histological techniques. METHODS: Fifteen male rats (3 months old) underwent a cerebral infusion of 192 IgG-saporin at the level of the nucleus basalis magnocellularis. They were scanned using [18F]FEOBV PET, then sacrificed, and their brain tissues collected for immunostaining and quantification of cholinergic denervation using optical density (OD). RESULTS: For both PET binding and postmortem OD, the highest losses were found in the cortical areas, with the highest reductions in the orbitofrontal, sensorimotor, and cingulate cortices. In addition, OD quantification in the affected areas accurately predicts [18F]FEOBV uptake in the same regions when regressed linearly. CONCLUSIONS: These findings support [18F]FEOBV as a reliable imaging agent for eventual use in human neurodegenerative conditions in which cholinergic losses are an important aspect.