1,721,015 research outputs found
In vivo imaging of neuroinflammation in neurodegenerative diseases.
No full textIn this thoroughly updated and revised edition of his much praised book, Paul L. Wood and a panel of leading researchers capture these new developments in a masterful synthesis of what is known today about the inflammatory mediators and cells involved in neurodegenerative diseases. This second edition contains extensive updates on the mediators produced by microglia and their role in neuroinflammatory-induced neuronal lysis. There is also increased coverage of the animal models used in the study of neuroinflammatory mechanisms, of the new imaging methods that allow the noninvasive evaluation of microglial activation in human neurodegernerative disorders, and of the role of neuroinflammation in amyloid-dependent neuronal lysis
In vivo detection of microglial activation in frontotemporal dementia
Full text linkUsing positron emission tomography and [(11)C](R)-PK11195, a marker of "peripheral benzodiazepine sites" that is upregulated on activated microglia during progressive tissue pathology, we show increased binding of [(11)C](R)-PK11195 in frontotemporal lobar degeneration in the typically affected frontotemporal brain regions. This implies the presence of an active glial response reflecting progressive neuronal degeneration. It also suggests that increased [(11)C](R)-PK11195 binding, previously demonstrated for Alzheimer's disease, may occur independently from increased amyloid plaque formation, given that it is not a characteristic feature of frontotemporal lobar degeneration
The concept of in-vivo imaging of neuroinflammation with [11C]PK11195 PET.
No full textThis book deals with the subject of neuroinflammation and attempts to take the reader on a journey from the bench to the bedside. The microglia and their response to brain injury as well as the importance of the chemokine family are discussed. The relevance of neuroinflammation in experimental models of BSE, scrapie and vCJD as well as Alzheimer's disease, stroke and multiple sclerosis is investigated before proceeding to clinical aspects of neuroinflammation and its involvement in human disease pathophysiology. The book provides an excellent introduction to the field of neuroinflammation and its involvement in human neurodegenerative disease
Positron emission tomography imaging of neuroinflammation
No full textIn the diseased brain, upon activation microglia express binding sites for synthetic ligands designed to recognize the 18-kDa translocator protein TP-18, which is part of the so-called peripheral benzodiazepine receptor complex. PK11195 [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide], the prototype synthetic ligand, has been widely used for the functional characterization of TP-18. Its cellular source in activated microglia has been established using high-resolution, single-cell autoradiography with the R-enantiomer [3H](R)-PK11195. Radiolabeled [11C](R)-PK11195 has been used to image active brain disease with positron emission tomography. Consistent with experimental and postmortem observations of a characteristically distributed pattern of microglia activation in areas of focal pathology, as well as in anterograde and retrograde projection areas, the in vivo regional [11C](R)-PK11195 signal is found in active focal lesions and over time also along the affected neural tracts and their respective cortical and subcortical projection areas. Thus, a profile of active disease emerges that matches some of the typical distribution patterns known from structural neuroimaging techniques, but additionally shows involvement of brain regions linked through neural pathways. In the context of cell-based in vivo neuropathology, the image data are thus best interpreted in the context of the emerging cellular understanding of brain disease or damage, rather than the definitions of clinical diagnosis. One important observation, borne out by experiment, is the long latency with which activated microglia or increased PK11195 retention appear to gradually emerge and remain in distal areas secondarily affected by disease, supporting speculations that the presence of activated microglia is an important corollary of brain plasticity
The activation of microglia as an early sign of disease progression in Alzheimerâ€TMs disease
No full textThis chapter focuses on the contribution of activated microglia to the progression of Alzheimer's disease (AD) at various stages of the pathological cascade. Clusters of activated microglia occur only in complement-positive amyloidβ (Aβ) plaques, and effector functions of complement include the modulation of microglial activity in vitro. It addresses the question of whether microglia are detrimental or beneficial in AD pathogenesis, especially in relation to the presence and modulating activities of activation products of the complement system.
This chapter focuses on the contribution of activated microglia to the progression of Alzheimer's disease (AD) at various stages of the pathological cascade. Clusters of activated microglia occur only in complement-positive amyloidβ (Aβ) plaques, and effector functions of complement include the modulation of microglial activity in vitro. It addresses the question of whether microglia are detrimental or beneficial in AD pathogenesis, especially in relation to the presence and modulating activities of activation products of the complement system
In-vivo measurement of activated microglia in dementia
No full textBACKGROUND: Activated microglia have a key role in the brain's immune response to neuronal degeneration. The transition of microglia from the normal resting state to the activated state is associated with an increased expression of receptors known as peripheral benzodiazepine binding sites, which are abundant on cells of mononuclear phagocyte lineage. We used brain imaging to study expression of these sites in healthy individuals and patients with Alzheimer's disease.
METHODS: We studied 15 normal individuals (age 32-80 years), eight patients with Alzheimer's disease, and one patient with minimal cognitive impairment. Quantitative in-vivo measurements of glial activation were obtained with positron emission tomography (PET) and carbon-11-labelled (R)-PK11195, a specific ligand for the peripheral benzodiazepine binding site.
FINDINGS: In normal individuals, regional [11C](R)-PK11195 binding did not significantly change with age, except in the thalamus, where an age-dependent increase was found. By contrast, patients with Alzheimer's disease showed significantly increased regional [11C](R)-PK11195 binding in the entorhinal, temporoparietal, and cingulate cortex.
INTERPRETATION: In-vivo detection of increased [11C](R)-PK11195 binding in Alzheimer-type dementia, including mild and early forms, suggests that microglial activation is an early event in the pathogenesis of the disease
Long-term trans-synaptic glial responses in the human thalamus after peripheral nerve injury
No full textLimb denervation leads to reorganization of the representational zones of the somatosensory cortex. Using [11C](R)-PK11195, a sensitive in vivo marker of glial cell activation, and PET, we provide first evidence that limb denervation induces a trans-synaptic increase in [11C](R)-PK11195 binding in the human thalamus but not somatosensory cortex: these brain structures appeared morphologically normal on magnetic resonance imaging (MRI). The increased thalamic signal was detectable many years after nerve injury, indicating persistent reorganization of the thalamus. This glial activation, beyond the first-order projection area of the injured neurons, may reflect continually altered afferent activity. Our findings support the view that long-term rearrangement of cortical representational maps is significantly determined within the thalamus
In vivo-visualisation of activated glia by [11C]PK11195 PET following herpes encephalitis reveals projected neuronal damage beyond the primary focal lesion.
No full textA major challenge in the assessment of brain injury and its relationship to the ensuing functional deficits is the accurate delineation of the areas of damage. Here, we test the hypothesis that the anatomical distribution pattern of activated microglia, a normally dormant population of resident brain macrophages, can be used as a surrogate marker of neuronal injury not only at the primary lesion site but also in the antero- and retrograde projection areas of the lesioned neurones. Two patients with asymmetrical herpes simplex encephalitis were serially scanned 6 and 12 months after the acute illness using PET with [11C] (R)-PK11195, a marker of activated microglia/brain macrophages. The evolving structural changes in the brain were measured by volumetric MRI and compared with the pattern of [11C](R)-PK11195 binding. Corresponding to the clinically observed cognitive deficits, quantitative [11C](R)-PK11195-PET revealed highly significant signal increases within the affected limbic system and additionally in areas connected to the limbic system by neural pathways, including the lingual gyrus in the occipital lobe and the inferior parietal lobe, which had normal morphology on structural MRI. The increased [11C](R)-PK11195 binding, signifying the presence of activated microglia, persisted many months (>12) after antiviral treatment. Cortical areas that showed early high [11C](R)-PK11195 binding subsequently underwent atrophy. These observations demonstrate that in vivo imaging of activated microglia/brain macrophages provides a dynamic measure of active tissue changes following an acute focal lesion. Importantly, the glial tissue response in the wake of neuronal damage is protracted and widespread within the confines of the affected distributed neural system and can be related to the long-term functional deficits
Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study.
No full textMicroglial activation is implicated in the pathogenesis of ALS and can be detected in animal models of the disease that demonstrate increased survival when treated with anti-inflammatory drugs. PK11195 is a ligand for the "peripheral benzodiazepine binding site" expressed by activated microglia. Ten ALS patients and 14 healthy controls underwent [(11)C](R)-PK11195 PET of the brain. Volumes of interest were defined to obtain [(11)C](R)-PK11195 regional binding potential values for motor and "extra-motor" regions. Significantly increased binding was found in motor cortex (P = 0.003), pons (P = 0.004), dorsolateral prefrontal cortex (P = 0.010) and thalamus (P = 0.005) in the ALS patients, with significant correlation between binding in the motor cortex and the burden of upper motor neuron signs clinically (r = 0.73, P = 0.009). These findings indicate that cerebral microglial activation can be detected in vivo during the evolution of ALS, and support the previous observations that cerebral pathology is widespread. They also argue for the development of therapeutic strategies aimed at inflammatory pathways
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