Electrical stimulation of the nucleus basalis of meynert:a systematic review of preclinical and clinical data

Deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM) has been clinically investigated in Alzheimer's disease (AD) and Lewy body dementia (LBD). However, the clinical effects are highly variable, which questions the suggested basic principles underlying these clinical trials. Therefore, preclinical and clinical data on the design of NBM stimulation experiments and its effects on behavioral and neurophysiological aspects are systematically reviewed here. Animal studies have shown that electrical stimulation of the NBM enhanced cognition, increased the release of acetylcholine, enhanced cerebral blood flow, released several neuroprotective factors, and facilitates plasticity of cortical and subcortical receptive fields. However, the translation of these outcomes to current clinical practice is hampered by the fact that mainly animals with an intact NBM were used, whereas most animals were stimulated unilaterally, with different stimulation paradigms for only restricted timeframes. Future animal research has to refine the NBM stimulation methods, using partially lesioned NBM nuclei, to better resemble the clinical situation in AD, and LBD. More preclinical data on the effect of stimulation of lesioned NBM should be present, before DBS of the NBM in human is explored further

Longitudinal positron emission tomography and postmortem analysis reveals widespread neuroinflammation in SARS-CoV-2 infected rhesus macaques

BACKGROUND: Coronavirus disease 2019 (COVID-19) patients initially develop respiratory symptoms, but they may also suffer from neurological symptoms. People with long-lasting effects after acute infections with severe respiratory syndrome coronavirus 2 (SARS-CoV-2), i.e., post-COVID syndrome or long COVID, may experience a variety of neurological manifestations. Although we do not fully understand how SARS-CoV-2 affects the brain, neuroinflammation likely plays a role. METHODS: To investigate neuroinflammatory processes longitudinally after SARS-CoV-2 infection, four experimentally SARS-CoV-2 infected rhesus macaques were monitored for 7 weeks with 18-kDa translocator protein (TSPO) positron emission tomography (PET) using [18F]DPA714, together with computed tomography (CT). The baseline scan was compared to weekly PET-CTs obtained post-infection (pi). Brain tissue was collected following euthanasia (50 days pi) to correlate the PET signal with TSPO expression, and glial and endothelial cell markers. Expression of these markers was compared to brain tissue from uninfected animals of comparable age, allowing the examination of the contribution of these cells to the neuroinflammatory response following SARS-CoV-2 infection. RESULTS: TSPO PET revealed an increased tracer uptake throughout the brain of all infected animals already from the first scan obtained post-infection (day 2), which increased to approximately twofold until day 30 pi. Postmortem immunohistochemical analysis of the hippocampus and pons showed TSPO expression in cells expressing ionized calcium-binding adaptor molecule 1 (IBA1), glial fibrillary acidic protein (GFAP), and collagen IV. In the hippocampus of SARS-CoV-2 infected animals the TSPO+ area and number of TSPO+ cells were significantly increased compared to control animals. This increase was not cell type specific, since both the number of IBA1+TSPO+ and GFAP+TSPO+ cells was increased, as well as the TSPO+ area within collagen IV+ blood vessels. CONCLUSIONS: This study manifests [18F]DPA714 as a powerful radiotracer to visualize SARS-CoV-2 induced neuroinflammation. The increased uptake of [18F]DPA714 over time implies an active neuroinflammatory response following SARS-CoV-2 infection. This inflammatory signal coincides with an increased number of TSPO expressing cells, including glial and endothelial cells, suggesting neuroinflammation and vascular dysregulation. These results demonstrate the long-term neuroinflammatory response following a mild SARS-CoV-2 infection, which potentially precedes long-lasting neurological symptoms

Correction:How the COVID-19 pandemic highlights the necessity of animal research (vol 30, pg R1014, 2020)

(Current Biology 30, R1014–R1018; September 21, 2020) As a result of an author oversight in the originally published version of this article, a number of errors were introduced in the author list and affiliations. First, the middle initials were omitted from the names of several authors. Second, the surname of Dr. van Dam was mistakenly written as “Dam.” Third, the first name of author Bernhard Englitz was misspelled as “Bernard” and the surname of author B.J.A. Pollux was misspelled as “Pullox.” Finally, Dr. Keijer's first name was abbreviated rather than written in full. These errors, as well as various errors in the author affiliations, have now been corrected online

Preclinical Marmoset Model for Targeting Chronic Inflammation as a Strategy to Prevent Alzheimer’s Disease

Due to the aging population, modern society is facing an increasing prevalence of neurological diseases such as Alzheimer′s disease (AD). AD is an age‐related chronic neurodegenerative disorder for which no satisfying therapy exists. Understanding the mechanisms underlying the onset of AD is necessary to find targets for protective treatment. There is growing awareness of the essential role of the immune system in the early AD pathology. Amyloidopathy, the main feature of early‐stage AD, has a deregulating effect on the immune function. This is reciprocal as the immune system also affects amyloidopathy. It seems that the inflammatory reaction shows a heterogeneous pattern depending on the stage of the disease and the variation between individuals, making not only the target but also the timing of treatment important. The lack of relevant translational animal models that faithfully reproduce clinical and pathogenic features of AD is a major cause of the delay in developing new disease‐modifying therapies and their optimal timing of administration. This review describes the communication between amyloidopathy and inflammation and the possibility of using nonhuman primates as a relevant animal model for preclinical AD research

A less stressful animal model: A conditioned avoidance behaviour task for guineapigs

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Preclinical Marmoset Model for Targeting Chronic Inflammation as a Strategy to Prevent Alzheimer’s Disease

Due to the aging population, modern society is facing an increasing prevalence of neurological diseases such as Alzheimer′s disease (AD). AD is an age‐related chronic neurodegenerative disorder for which no satisfying therapy exists. Understanding the mechanisms underlying the onset of AD is necessary to find targets for protective treatment. There is growing awareness of the essential role of the immune system in the early AD pathology. Amyloidopathy, the main feature of early‐stage AD, has a deregulating effect on the immune function. This is reciprocal as the immune system also affects amyloidopathy. It seems that the inflammatory reaction shows a heterogeneous pattern depending on the stage of the disease and the variation between individuals, making not only the target but also the timing of treatment important. The lack of relevant translational animal models that faithfully reproduce clinical and pathogenic features of AD is a major cause of the delay in developing new disease‐modifying therapies and their optimal timing of administration. This review describes the communication between amyloidopathy and inflammation and the possibility of using nonhuman primates as a relevant animal model for preclinical AD research

Individual and Familial Susceptibility to MPTP in a Common Marmoset Model for Parkinson's Disease

INTRODUCTION: Insight into susceptibility mechanisms underlying Parkinson's disease (PD) would aid the understanding of disease etiology, enable target finding and benefit the development of more refined disease-modifying strategies. METHODS: We used intermittent low-dose MPTP (0.5 mg/kg/week) injections in marmosets and measured multiple behavioral and neurochemical parameters. Genetically diverse monkeys from different breeding families were selected to investigate inter- and intrafamily differences in susceptibility to MPTP treatment. RESULTS: We show that such differences exist in clinical signs, in particular nonmotor PD-related behaviors, and that they are accompanied by differences in neurotransmitter levels. In line with the contribution of a genetic component, different susceptibility phenotypes could be traced back through genealogy to individuals of the different families. CONCLUSION: Our findings show that low-dose MPTP treatment in marmosets represents a clinically relevant PD model, with a window of opportunity to examine the onset of the disease, allowing the detection of individual variability in disease susceptibility, which may be of relevance for the diagnosis and treatment of PD in humans

Improvement of preclinical animal models for autoimmune-mediated disorders via reverse translation of failed therapies

The poor translational validity of autoimmune-mediated inflammatory disease (AIMID) models in inbred and specific pathogen-free (SPF) rodents underlies the high attrition of new treatments for the corresponding human disease. Experimental autoimmune encephalomyelitis (EAE) is a frequently used preclinical AIMID model. We discuss here how crucial information needed for the innovation of current preclinical models can be obtained from postclinical analysis of the nonhuman primate EAE model, highlighting the mechanistic reasons why some therapies fail and others succeed. These new insights can also help identify new targets for treatment

Longitudinal positron emission tomography and postmortem analysis reveals widespread neuroinflammation in SARS-CoV-2 infected rhesus macaques

Abstract Background Coronavirus disease 2019 (COVID-19) patients initially develop respiratory symptoms, but they may also suffer from neurological symptoms. People with long-lasting effects after acute infections with severe respiratory syndrome coronavirus 2 (SARS-CoV-2), i.e., post-COVID syndrome or long COVID, may experience a variety of neurological manifestations. Although we do not fully understand how SARS-CoV-2 affects the brain, neuroinflammation likely plays a role. Methods To investigate neuroinflammatory processes longitudinally after SARS-CoV-2 infection, four experimentally SARS-CoV-2 infected rhesus macaques were monitored for 7 weeks with 18-kDa translocator protein (TSPO) positron emission tomography (PET) using [18F]DPA714, together with computed tomography (CT). The baseline scan was compared to weekly PET–CTs obtained post-infection (pi). Brain tissue was collected following euthanasia (50 days pi) to correlate the PET signal with TSPO expression, and glial and endothelial cell markers. Expression of these markers was compared to brain tissue from uninfected animals of comparable age, allowing the examination of the contribution of these cells to the neuroinflammatory response following SARS-CoV-2 infection. Results TSPO PET revealed an increased tracer uptake throughout the brain of all infected animals already from the first scan obtained post-infection (day 2), which increased to approximately twofold until day 30 pi. Postmortem immunohistochemical analysis of the hippocampus and pons showed TSPO expression in cells expressing ionized calcium-binding adaptor molecule 1 (IBA1), glial fibrillary acidic protein (GFAP), and collagen IV. In the hippocampus of SARS-CoV-2 infected animals the TSPO+ area and number of TSPO+ cells were significantly increased compared to control animals. This increase was not cell type specific, since both the number of IBA1+TSPO+ and GFAP+TSPO+ cells was increased, as well as the TSPO+ area within collagen IV+ blood vessels. Conclusions This study manifests [18F]DPA714 as a powerful radiotracer to visualize SARS-CoV-2 induced neuroinflammation. The increased uptake of [18F]DPA714 over time implies an active neuroinflammatory response following SARS-CoV-2 infection. This inflammatory signal coincides with an increased number of TSPO expressing cells, including glial and endothelial cells, suggesting neuroinflammation and vascular dysregulation. These results demonstrate the long-term neuroinflammatory response following a mild SARS-CoV-2 infection, which potentially precedes long-lasting neurological symptoms

Brain Inflammation and Intracellular α-Synuclein Aggregates in Macaques after SARS-CoV-2 Infection

SARS-CoV-2 causes acute respiratory disease, but many patients also experience neurological complications. Neuropathological changes with pronounced neuroinflammation have been described in individuals after lethal COVID-19, as well as in the CSF of hospitalized patients with neurological complications. To assess whether neuropathological changes can occur after a SARS-CoV-2 infection, leading to mild-to-moderate disease, we investigated the brains of four rhesus and four cynomolgus macaques after pulmonary disease and without overt clinical symptoms. Post-mortem analysis demonstrated the infiltration of T-cells and activated microglia in the parenchyma of all infected animals, even in the absence of viral antigen or RNA. Moreover, intracellular α-synu-clein aggregates were found in the brains of both macaque species. The heterogeneity of these manifestations in the brains indicates the virus’ neuropathological potential and should be considered a warning for long-term health risks, following SARS-CoV-2 infection