#neuroinflammation

[liminalbeauty]

The original poster turned off reposting, so I’m copying the relevant information to here. I’ve seen this before, and I’m so glad it’s getting more attention.

Dorsomedial striatal neuroinflammation causes excessive goal-directed action control by disrupting astrocyte fu

[fivehundredwords]

Alzheimer's Disease: biomarkers and neuroimaging markers cheatsheet for research articles

As Alzheimer's Disease (AD) research skews toward understanding the brain than the pathogenic proteins, studies exploring biomarkers and neuroimaging are hopeful toward developing a method for successful prevention of AD. A biomarker is a molecule, whose presence indicates abnormality or disease, and thus, is crucial in diagnostic procedures. Levels of certain molecules is notably altered in cerebrospinal fluid and in blood plasma, which helps in diagnosing the occurrence of AD. Neuroimaging involves the use of techniques such as magnetic resonance imaging and computed tomography to observe neuronal activity in the brain. This is good news, especially for AD, as the asymptomatic stage of the disease can be identified early enough.

Although the exact function and involvement in clinical practice is not profuse, altered concentrations of these biomarkers in plasma or cerebrospinal fluid encourage further research:

Amyloid and tau serve as the unsurprising biomarkers of AD pathology.

Neurofilament-light chain (NF-L) and visinin-like protein-1 (VILIP-1) are the most promising biomarkers of neuronal injury.

Post-synaptic protein neurogranin (Ng) and pre-synaptic proteins synaptosome-associated protein-25 (SNAP-25) and synaptotagmin-1 (Syt-1) are considered major biomarkers of synaptic injury.

Brain and CSF levels of tumor necrosis factor alpha (TNF-α) and increased levels of interleukin group of proteins (ILs) indicate intensified microglial response to neuroinflammation.

TREM2 receptor and YKL-40 glycoprotein are also reliable indicators of inflammation and impaired clearance of amyloid beta.

Heart-type fatty acid-binding protein (hFABP) could be a marker for pathology in blood vessels supplying the brain. Some vascular markers also show potential as markers of vascular injury in AD: von Willebrand factor (vWF) and monokine induced by γ-interferon (MIG, also known as CXCL-9).

Concentrations of TAR-DNA binding protein (TDP-43) in the brain and plasma and serum indicate, even contribute to, inflammation, mitochondrial dysfunction, and neuronal/synaptic injury in AD.

Neuroimaging techniques reveal structural, functional, and diffusion-related activities of the neurons. To identify them, markers are tracked in images obtained. Each marker is determined with the activity and biochemistry of the group of/individual neurons being studied.

Structural MRI will show location and severity of atrophy which can be identified in grey scale images by applying programs that create analogous color grading.

Functional MRI relies on blood oxygenation level dependent (BOLD) signal which reflects changes in blood oxygenation levels in response to neural activity.

Diffusion weighted imaging (DWI) focuses on diffusion of water molecules. A tensor model is applied to images obtained from DWI. The diffusion tensor imaging (DTI) metrics thus obtained help in studying connectivity through structural integrity of white matter tracts.

Tractography involves 3-D reconstruction of white matter as observed in DWI, which provides a more detailed look into a patient’s neural networks.

In positron emission tomography (PET), markers are identified and labelled so their features or functions can be traced during this procedure to obtain a resulting PET scan. The imaging procedure is named according to its marker: amyloid-PET, tau-PET, FDG-PET, inflammation-PET, receptor-PET.

FDA approved drugs Galantamine, Rivastigmine, and Donepezil alleviate symptoms such as memory loss and confusion in mild to moderate AD, although their effects seem to be negligible. They also cause nausea and vomiting as side effects and are not suitable for every patient. Recently approved drugs, Aducanumab and Lecanemab focus on removing accumulated amyloid. Their effectiveness is still doubted on the basis of studies finding that targeting amyloid has little to do with curbing the actual progression of the disease.

bibliography -

Tarawneh R. Biomarkers: our path towards a cure for Alzheimer disease. Biomarker insights. 2020 Nov;15:1177271920976367.

Cavedo E, Lista S, Khachaturian Z, Aisen P, Amouyel P, Herholz K, Jack Jr CR, Sperling R, Cummings J, Blennow K, O’Bryant S. The road ahead to cure Alzheimer’s disease: development of biological markers and neuroimaging methods for prevention trials across all stages and target populations. The journal of prevention of Alzheimer's disease. 2014 Dec;1(3):181.

Medications for Alzheimer's Disease Stanford Healthcare. Accessed 21-04-2023.

[longhaulerbear]

There is accumulating evidence of endothelial dysfunction, muscle and cerebral hypoperfusion in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). In this paper we deduce the pathomechanisms resulting in central nervous pathology and the myriad of neurocognitive symptoms. We outline tentative mechanisms of impaired cerebral blood flow, increase in intracranial pressure and central adrenergic hyperactivity and how they can well explain the key symptoms of cognitive impairment, brain fog, headache, hypersensitivity, sleep disturbances and dysautonomia.

In the first two hypothesis papers we identified ß2 adrenergic receptor (ß2AdR) dysfunction, high sympathetic tone (stress), hypovolemia (preload failure), endothelial or vascular dysfunction, and an energetic disturbance in skeletal muscle as the main critical factors in the ME/CFS pathophysiology [43]. Meanwhile more evidence for endothelial dysfunction has accumulated. Altered endothelial dysfunction-related microRNAs were found in plasma from ME/CFS patients recently [5]. In Covid-19 infection the endothelium is severely affected and the disturbance seems to persist in post-Covid Syndrome (PCS) [12, 16, 24, 27, 38]. Particularly the finding of severe endothelial affection in Covid-19 and the persisting endothelial dysfunction corroborates our hypothesis of a role of endothelial and vascular dysfunction in the pathogenesis of PCS. Endothelial dysfunction may result in decreased CBF.

As a possible explanation for the orthostatic intolerance and the decrease in CBF we assume the presence of both a strong vasoconstrictor effect mediated by an elevated sympathetic tone and weakened vasodilator influences, that occurred in particular by dysfunction of ß2AdR and other causes of endothelial and vascular dysfunction. Covid-19 seriously affects the endothelium and there is evidence of chronic endothelial dysfunction in the post-Covid-syndrome similar to that in ME/CFS [12]. ß2AdRs have vasodilator effects in the brain, skeletal muscle and the heart, a mechanism to increase blood flow during muscular activity (a functional unit with the brain steering and coordinating muscle activity and the heart providing the blood flow for both organs). Since orthostatic stress is permanent during human activities (standing and even sitting) it is the basic stressor to which all other forms of stress are additive. It can desensitize ß2AdR and cause vasoconstrictor predominance by the α1-adrenergic effects that do not desensitize upon chronic stimulation in contrast to ß2AdR [43]. Chronic psychosocial stress itself can cause endothelial dysfunction and an increase in vasconstrictor mechanisms by functional and structural changes fixing the state of vasoconstriction (similar to the mechanisms that lead to fixed hypertension) [23, 47]. Endothelial dysfunction, which is clearly present in ME/CFS and PCS, has been found associated with cognitive impairment in different conditions, in the elderly as well as in children [17, 41]. Since the decrease in CBF already occurs after changing position from horizonal to sitting, orthostatic stress can be considered as the basic and permanent stressor during human activities in the awake state. We think that a decrease in CBF by 25% already in a sitting position, a concomitantly disturbed neurovascular coupling and endothelial dysfunction will not allow enduring cognitive efforts or mental work, with mental fatigue being the consequence.

Psychomotor slowing, ataxia and loss of coordination of movements in ME/CFS [11, 39] can also be explained by reduced perfusion, hypoperfusion of the motorcortex and other structures involved in motor function not being able to maintain coordinated neuronal activity in the motor cortex, a disturbance similar to impaired cognition. Since cognitive as well as motor function are disturbed by reduced (global) CBF there is good reason to believe that other brain functions can also be disturbed as will be explained in the following.

A reduction of global CBF is not the only cerebrovascular finding in ME/CFS. Consistent observation of sluggish fMRI signals suggests abnormal neurovascular coupling meaning that local blood flow regulation is also disturbed [32, 33, 37]. Endothelial dysfunction may play a role in the disturbance of neurovascular coupling. The question is whether the inflammatory mediators released from skeletal muscle can also affect neurovascular coupling, the local regulation of blood flow adjusting local perfusion to local neurophysiological activitiy. We think that influx of vasodilators, which otherwise also regulate local perfusion in other organs, into the cerebrovascular bed being under excessive vasoconstrictor influences via heightened sympathetic tone (stress), dysfunction of ß2AdR and endothelial dysfunction can only disturb a highly regulated fine tuning of vascular regulation and local blood distribution (neurovascular coupling).

Hypoperfusion of skeletal muscle together with mitochondrial dysfunction leads to the excessive production of various endogenous vasodilators in skeletal muscles and to their spillover into the systemic circulation, from where they can reach every organ including the brain [43]. One of these mediators, bradykinin, is the most potent opener of the blood brain barrier (BBB) [1, 31] which may be of relevance for the neurological findings and symptoms. Opening of the BBB may explain moderate IH for which we have provided the evidence above. We could not find in the literature what the symptoms of isolated opening of the BBB would be but we assume it to be rather pathological. The algesic and hyperalgesic properties of the tissue mediators released from skeletal muscles may cause headache by directly acting on cerebrovascular nociceptors, by the release of CGRP and substance P and by edematous distension. Headache could also originate from myalgia of head and neck muscles and from IH [18].

Disturbances of reflexes and autonomic function, hypervigilance and hypersensitivity to sensory stimuli such as light, noises and smells and brain fog

Disturbances of the pupillary reflex [4] upon prolonged illumination of the pupils were also reported in patients with ME/CFS: “Two unusual responses were observed that are evident on prolonged illumination of the pupils. The more frequent finding seen in three quarters of patients is a rhythmic contraction and dilatation of the pupils. The second pattern is a paradoxical dilation of the pupils after an initial contraction.“ Thus, one should consider the possibility that also other regulatory mechanisms of body and autonomic functions and reflexes, like orthostatic regulation, vascular regulation, thermoregulation and sleep are also impaired as a consequence of a reduced CBF. This could result in either sluggish responses to sudden changes or the opposite, namely large overshooting swings unable to find a new stable level of regulation after a disturbance, similar as observed with the pupillary reflex. In such a way impaired regulation of orthostatic function may contribute to orthostatic dysregulation and intolerance without necessarily being the main cause of it. Hence, dysautonomia may be enhanced by a disturbed CBF. Primary disturbances of the autonomic nervous system and dysautonomia or autonomic dysfunction arising from the brain stem may play a role in triggering ME/CFS for instance by orthostatic dysfunction causing orthostatic stress that would desensitize ß2AdR and raise α-adrenergic mediated vasoconstriction. Based on these considerations, it should be considered that ME/CFS itself could cause or at least worsen autonomic dysfunction by cerebral hypoperfusion from which another vicious circle would arise. By these mechanisms autonomic dysfunction could also be expanded to other primarily undisturbed autonomic functions.

Hypervigilance and sympathetic hyperactivity are present in ME/CFS [14]. Stress may cause hypervigilance by centrally stimulatory effects of catecholamines and PGE2 (one of the mediators released into the circulation by the skeletal muscles). The latter has awakening effects [19]. The α2-adrenergic autoreceptor, a presynaptic receptor on noradrenergic neurons modulating and inhibiting norepinephrine release [30] shows desensitization [3] similar to the ß2AdR, but unlike α1-adrenergic receptors. Thus, chronic stress could also desensitize this inhibiting autoreceptor to enhance catecholamine release in activating noradrenergic nuclei of the brain stem like the locus coeruleus thereby causing arousal and increased vigilance, and in the sympathetic nervous system leading to enhanced vasoconstrictor output while the vasodilator ß2AdR is dysfunctional and endothelial dysfunction of other causes may be present. It would finally mean that chronic stress enhances stress responses (adrenergic hyperactivity). Orthostatic stress may play a particular role since it is already present in the sitting position in ME/CFS to decrease CBF and therefore almost unavoidable. Since orthostatic stress is operative over a considerable part of the day there is not sufficient time for recovery of desensitized adrenergic receptors. Episodes of stress in human life are usually followed by episodes of rest and recovery in which re-sensitization of adrenergic receptors can take place and therefore such enhancement of stress responses can fade if sufficient time of recovery is allowed (presumeably only few days of rest needed for receptor re-sensitization). In line with these considerations, long and intense periods of psychosocial stress, in which such desensitization could take place, precede the development of ME/CFS in a subset of patients which is a potential explanation for the initiation of the disease in this subset. By the mechanisms outlined in our previous paper, ME/CFS, once fully established, is a state in which a high level of stress is maintained and fixed by a number of dysregulations and vicious circles, which the patient can hardly escape [44]. Since there is no recovery from stress in ME/CFS, α2-adrenergic autoreceptors and ß2AdR remain desensitized.

Hypervigilance caused in the way just described may lead to increased stimulus uptake in all sensory organs while stimulus processing in the corresponding brain regions may be impaired by the reduced CBF as outlined above. Increased stimulus uptake and concomitantly reduced stimulus processing may lead to stimulus overload. Stimulus overload could be the cause of hypersensitivities against sensory stimuli such as light, noises and smells.

These considerations also help to understand the simultaneous presence of signs of hypervigilance and mental fatigue in ME/CFS patients. This paradox can be explained by the discrepancy between the higher energy demand caused by neuronal overstimulation and the reduced energy supply by cerebral hypoperfusion resulting in an early energetic deficit to explain the high level of mental fatigability. The ability to perform mental work may be additionally diminished by hypervigilance (nonspecific overstimulation) reducing the ability to concentrate on a single mental task which may be part of the mechanisms causing the feeling of brain fog. Finally, brain fog may be the result of central overstimulation, cerebral hypoperfusion, IH and opening of the BBB allowing the endogenous mediators released from skeletal muscle like bradykinin and PGE2 to exert effects in the brain.

Cerebral blood flow velocity of the middle cerebral artery was reduced during head‐up tilt associated with hyperventilation. Thus the decrease in CBF can be explained only by a rise in cerebrovascular resistance by vasoconstriction.

We consider hyperventilation, an overshooting response to a respiratory stimulus, resulting from autonomic dysfunction with sympathetic overactivity. In PCS hyperventilation has recently been identified as cause of dyspnea. Hyperventilation occurred early during exercise resulting in an impaired ventilatory efficiency [2, 26]. The cause may be excessive stimulation of the respiratory center in the brain stem causing the feeling of air hunger (dyspnea). A physiological early mechanism of respiratory stimulation is via skeletal muscle afferents involving movement sensors and metabolic afferents [34]. It is obvious to incriminate a disturbed metabolic situation in skeletal muscle in this early, excessive stimulation of respiration during exercise. The latter could then be further enhanced by dysautonomia (as an overshooting response). The resulting dyspnea is not only limiting the ability to exercise but aggravates the key pathophysiological mechanisms in skeletal muscle in ME/CFS.

Difficulties to fall asleep and altered day-night rhythm may result directly from enhanced catecholamine release in activating noradrenergic nuclei of the brain stem like the locus coeruleus as a consequence of desensitized α2-autoreceptors and stress causing arousal and increased vigilance. Stimulus overload just explained above could be an indirect cause of sleep disturbances. In sleep medicine it is considered an important cause of insomnia.

Decreased CBF, disturbed local blood flow regulation and neurovascular coupling, central adrenergic hyperactivity, hypocapnia and increase in intracranial pressure seem to play a strong role in the pathophysiology of the neurological symptoms in ME/CFS (Fig. 1). They can well explain cognitive impairment, brain fog, headache, psychomotor slowing, ataxia and loss of coordination of movements, hypersensitivity, sleep disturbances and dysautonomia.

[medicomunicare]

USP15: from brain inflammation to cancer, the master-zyme tags the repair and shows itself as a target

USP15: from brain inflammation to cancer, the master-zyme tags the repair and shows itself as a target

Ubiquitin is a highly conserved peptide molecule, composed of 76 amino acids that mark proteins for degradation. Protein ubiquitination changes proteins half-life and tightly regulates the levels of proteins that should be erased before they start to put in danger cellular homeostasis. Ubiquitination often affects protein stability, localization, activity, and interactions, and is widely involved…

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[hatofpositivity]

Add some black pepper to the juice and it will make the turmeric root more bio-available!

[neurosciencenews]

Reducing brain inflammation could treat tinnitus and other hearing loss-related disorders

Rodent study reveals noise-induced hearing loss is associated with elevated expression of proinflammatory cytokines and microglia activation in the primary auditory cortex. Pharmacologically depleting microglia helps prevent tinnitus in mice with noise-induced hearing loss.

[currentsinbiology]

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction, verbal and non-verbal communication, …

Highlights

•There is a significant relationship between ASD and various environmental factors.

•A possible association exists between ASD and exposure to toxic metals.

•Lead, mercury, aluminum, and arsenic may be involved in the etiology of ASD.

•Toxic metals may induce neuroinflammation and oxidative stress.

•Modulation of toxic metal body burden may improve ASD.

[bpod-bpod]

Offending Defenders

A stage of battle 30,000 times smaller than a roman amphitheatre, this microfluidic device recreates the microscopic events of Alzheimer’s disease. Ageing brains often build up waste proteins – gunky amyloid plaques and tangled tau proteins. Although these can interfere with signals between brain cells like those seen here (highlighted in green), they may also build up harmlessly for decades. The real problem is how the brain responds – microglial cells (red), part of the brain’s own immune defences, flood towards affected areas of the brain (or down the spindly channels here) and attack the struggling neurons. While the overzealous defenders attempt to get rid of the plaques, levels of neuroinflammation rise, causing irreparable damage. This lab-grown model can now be put to use in finding new ways to stop plaques from forming in the first place, but also testing drugs designed to calm the microglial cells of those at risk.

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Written by John Ankers

Image from work by Joseph Park and colleagues

University of North Carolina at Charlotte, NC, USA

Image copyright held by the original authors

Research published in Nature Neuroscience, June 2018

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