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Encephalopathy induced by Alzheimer brain inoculation in a non-human primate.

ABSTRACT: Alzheimer's disease is characterized by cognitive alterations, cerebral atrophy and neuropathological lesions including neuronal loss, accumulation of misfolded and aggregated ?-amyloid peptides (A?) and tau proteins. Iatrogenic induction of A? is suspected in patients exposed to pituitary-derived hormones, dural grafts, or surgical instruments, presumably contaminated with A?. Induction of A? and tau lesions has been demonstrated in transgenic mice after contamination with Alzheimer's disease brain homogenates, with very limited functional consequences. Unlike rodents, primates naturally express A? or tau under normal conditions and attempts to transmit Alzheimer pathology to primates have been made for decades. However, none of earlier studies performed any detailed functional assessments. For the first time we demonstrate long term memory and learning impairments in a non-human primate (Microcebus murinus) following intracerebral injections with Alzheimer human brain extracts. Animals inoculated with Alzheimer brain homogenates displayed progressive cognitive impairments (clinical tests assessing cognitive and motor functions), modifications of neuronal activity (detected by electroencephalography), widespread and progressive cerebral atrophy (in vivo MRI assessing cerebral volume loss using automated voxel-based analysis), neuronal loss in the hippocampus and entorhinal cortex (post mortem stereology). They displayed parenchymal and vascular A? depositions and tau lesions for some of them, in regions close to the inoculation sites. Although these lesions were sparse, they were never detected in control animals. Tau-positive animals had the lowest performances in a memory task and displayed the greatest neuronal loss. Our study is timely and important as it is the first one to highlight neuronal and clinical dysfunction following inoculation of Alzheimer's disease brain homogenates in a primate. Clinical signs in a chronic disease such as Alzheimer take a long time to be detectable. Documentation of clinical deterioration and/or dysfunction following intracerebral inoculations with Alzheimer human brain extracts could lead to important new insights about Alzheimer initiation processes.

SUBMITTER: Gary C

PROVIDER: S-EPMC6724379 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Encephalopathy induced by Alzheimer brain inoculation in a non-human primate.

Gary Charlotte C Lam Suzanne S Hérard Anne-Sophie AS Koch James E JE Petit Fanny F Gipchtein Pauline P Sawiak Stephen J SJ Caillierez Raphaëlle R Eddarkaoui Sabiha S Colin Morvane M Aujard Fabienne F Deslys Jean-Philippe JP Brouillet Emmanuel E Buée Luc L Comoy Emmanuel E EE Pifferi Fabien F Picq Jean-Luc JL Dhenain Marc M

Acta neuropathologica communications 20190904 1

Alzheimer's disease is characterized by cognitive alterations, cerebral atrophy and neuropathological lesions including neuronal loss, accumulation of misfolded and aggregated β-amyloid peptides (Aβ) and tau proteins. Iatrogenic induction of Aβ is suspected in patients exposed to pituitary-derived hormones, dural grafts, or surgical instruments, presumably contaminated with Aβ. Induction of Aβ and tau lesions has been demonstrated in transgenic mice after contamination with Alzheimer's disease b ...[more]

PMID: 31481130

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Project description:Numerous studies have used functional magnetic resonance imaging (fMRI) to characterize functional connectivity between cortical regions by analyzing correlations in blood oxygenation level dependent (BOLD) signals in a resting state. However, to date, there have been only a handful of studies reporting resting state BOLD signals in white matter. Nonetheless, a growing number of reports has emerged in recent years suggesting white matter BOLD signals can be reliably detected, though their biophysical origins remain unclear. Moreover, recent studies have identified robust correlations in a resting state between signals from cortex and specific white matter tracts. In order to further validate and interpret these findings, we studied a non-human primate model to investigate resting-state connectivity patterns between parcellated cortical volumes and specific white matter bundles. Our results show that resting-state connectivity patterns between white and gray matter structures are not randomly distributed but share notable similarities with diffusion- and histology-derived anatomic connectivities. This suggests that resting-state BOLD correlations between white matter fiber tracts and the gray matter regions to which they connect are directly related to the anatomic arrangement and density of WM fibers. We also measured how different levels of baseline neural activity, induced by varying levels of anesthesia, modulate these patterns. As anesthesia levels were raised, we observed weakened correlation coefficients between specific white matter tracts and gray matter regions while key features of the connectivity pattern remained similar. Overall, results from this study provide further evidence that neural activity is detectable by BOLD fMRI in both gray and white matter throughout the resting brain. The combined use of gray and white matter functional connectivity could also offer refined full-scale functional parcellation of the entire brain to characterize its functional architecture.

Dataset Information

Encephalopathy induced by Alzheimer brain inoculation in a non-human primate.

Publications

Encephalopathy induced by Alzheimer brain inoculation in a non-human primate.

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