Astrocyte Biomarkers in Alzheimer’s Disease

Carter, Stephen F.; Herholz, Karl; Rosa‐Neto, Pedro; Pellerin, Luc; Nordberg, Agneta; Zimmer, Eduardo R.

doi:10.1016/j.molmed.2018.11.006

Cited by 224 publications

(207 citation statements)

References 169 publications

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“…Inflammation biomarkers are of interest in clinical trials, for patient stratification and to track biological effects of drugs. 4 In this respect, our results using 11 C-DED PET and recent studies emphasizing the role of astrocyte biomarkers in AD 46,47 motivate further research on the use of astrocyte PET biomarkers in clinical trials. Our results also showed that both MD and CTh are topographic biomarkers secondary to neuroinflammatory processes as measured by 11 C-DED PET, supporting the potential added value of MD and CTh as AD biomarkers.…”

Section: Discussionmentioning

confidence: 53%

Cortical microstructural correlates of astrocytosis in autosomal-dominant Alzheimer disease

et al. 2020

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ObjectiveTo study the macrostructural and microstructural MRI correlates of brain astrocytosis, measured with 11C-deuterium-L-deprenyl (11C-DED)–PET, in familial autosomal-dominant Alzheimer disease (ADAD).MethodsThe total sample (n = 31) comprised ADAD mutation carriers (n = 10 presymptomatic, 39.2 ± 10.6 years old; n = 3 symptomatic, 55.5 ± 2.0 years old) and noncarriers (n = 18, 44.0 ± 13.7 years old) belonging to families with mutations in either the presenilin-1 or amyloid precursor protein genes. All participants underwent structural and diffusion MRI and neuropsychological assessment, and 20 participants (6 presymptomatic and 3 symptomatic mutation carriers and 11 noncarriers) also underwent 11C-DED-PET.ResultsVertex-wise interaction analyses revealed a differential relationship between carriers and noncarriers in the association between 11C-DED binding and estimated years to onset (EYO) and between cortical mean diffusivity (MD) and EYO. These differences were due to higher 11C-DED binding in presymptomatic carriers, with lower binding in symptomatic carriers compared to noncarriers, and to lower cortical MD in presymptomatic carriers, with higher MD in symptomatic carriers compared to noncarriers. Using a vertex-wise local correlation approach, 11C-DED binding was negatively correlated with cortical MD and positively correlated with cortical thickness.ConclusionsOur proof-of-concept study is the first to show that microstructural and macrostructural changes can reflect underlying neuroinflammatory mechanisms in early stages of Alzheimer disease (AD). The findings support a role for neuroinflammation in AD pathogenesis, with potential implications for the correct interpretation of neuroimaging biomarkers as surrogate endpoints in clinical trials.

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Section: Discussionmentioning

confidence: 53%

Cortical microstructural correlates of astrocytosis in autosomal-dominant Alzheimer disease

et al. 2020

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“…In the context of M4 glycolytic metabolism, it is interesting to speculate on the origin of the reduced fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) signal observed in AD brain. Recent animal model work has suggested that loss of a proper microglial response through mutations in either TREM2 or PGRN leads to reduced cerebral glucose metabolism 95 , and that normal astrocyte function is also important for brain glucose uptake 96,97 . Therefore, it is possible that the failure of a proper astroglial compensatory or protective response in AD may lead to general neuronal metabolic failure in susceptible brain regions, as assessed by the FDG-PET signal, and cognitive deterioration.…”

Section: Discussionmentioning

confidence: 99%

A Consensus Proteomic Analysis of Alzheimer’s Disease Brain and Cerebrospinal Fluid Reveals Early Changes in Energy Metabolism Associated with Microglia and Astrocyte Activation

Johnson

Dammer

Duong

et al. 2019

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Our understanding of the biological changes in the brain associated with Alzheimer's disease (AD) pathology and cognitive impairment remains incomplete. To increase our understanding of these changes, we analyzed dorsolateral prefrontal cortex of control, asymptomatic AD, and AD brains from four different centers by label-free quantitative mass spectrometry and weighted protein co-expression analysis to obtain a consensus protein co-expression network of AD brain.This network consisted of 13 protein co-expression modules. Six of these modules correlated with amyloid-β plaque burden, tau neurofibrillary tangle burden, cognitive function, and clinical functional status, and were altered in asymptomatic AD, AD, or in both disease states. These modules reflected synaptic, mitochondrial, sugar metabolism, extracellular matrix, cytoskeletal, and RNA binding/splicing biological functions. The identified protein network modules were preserved in a community-based cohort analyzed by a different quantitative mass spectrometry approach. They were also preserved in temporal lobe and precuneus brain regions. Some of the modules were influenced by aging, and showed changes in other neurodegenerative diseases such as frontotemporal dementia and corticobasal degeneration. The module most strongly associated with AD pathology and cognitive impairment was the sugar metabolism module, which was enriched in AD genetic risk factors and correlated with APOE genetic risk. This module was also highly enriched in microglia and astrocyte protein markers associated with an antiinflammatory state, suggesting that the biological functions it represents serve a protective role in AD. Proteins from this module were increased in cerebrospinal fluid from asymptomatic AD and AD cases, highlighting their potential as biomarkers of the altered brain network. In this study of >2000 brains and nearly 400 cerebrospinal fluid samples by quantitative proteomics, we identify proteins and biological processes in AD brain that may serve as therapeutic targets and fluid biomarkers for the disease. IntroductionAlzheimer's disease (AD) is a leading cause of death worldwide, with increasing prevalence as global life expectancy increases 1 . Although AD is currently defined on the basis of amyloid-β plaque and tau neurofibrillary tangle deposition within the neocortex 2 , the biochemical and cellular changes in the brain that characterize the disease beyond amyloid-β and tau deposition remain incompletely understood. The genetic architecture of late-onset AD has been extensively studied, and the results of these studies implicate multiple biological pathways that contribute to development of the disease, including immune function, endocytic vesicle trafficking, and lipid homeostasis, among others 3-5 . In addition to genetic studies, transcriptomic studies on postmortem AD brain tissue have identified changes in mRNA co-expression that correlate with disease traits and cognitive decline 6,7 . However, given that mRNA levels correlate only modestly to protein le...

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“…Last, some astrocyte proteins like GFAP or their break‐down products may also end up in the cerebrospinal fluid of patients subject to traumatic brain injury [TBI, (Halford et al, )], but also in more progressive diseases like Creutzfeldt‐Jakob disease or AD [for review, see (Carter et al, ; Perez‐Nievas & Serrano‐Pozo, )].…”

Section: Why Bother With Reactive Astrocytes?mentioning

confidence: 99%

“…Such improvements will be facilitated by basic studies that establish the molecular and functional profile of reactive astrocytes (see Section 6) but also of their microglia or neuronal neighbors, allowing the identification of new and specific astrocyte targets. Last, some astrocyte proteins like GFAP or their break-down products may also end up in the cerebrospinal fluid of patients subject to traumatic brain injury [TBI, (Halford et al, 2017)], but also in more progressive diseases like Creutzfeldt-Jakob disease or AD [for review, see (Carter et al, 2019;Perez-Nievas & Serrano-Pozo, 2018)].…”

Section: Why Bother With Reactive Astrocytes?mentioning

confidence: 99%

Questions and (some) answers on reactive astrocytes

Escartin

Guillemaud

Sauvage

2019

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Astrocytes are key cellular partners for neurons in the central nervous system. Astrocytes react to virtually all types of pathological alterations in brain homeostasis by significant morphological and molecular changes. This response was classically viewed as stereotypical and is called astrogliosis or astrocyte reactivity. It was long considered as a nonspecific, secondary reaction to pathological conditions, offering no clues on disease‐causing mechanisms and with little therapeutic value. However, many studies over the last 30 years have underlined the crucial and active roles played by astrocytes in physiology, ranging from metabolic support, synapse maturation, and pruning to fine regulation of synaptic transmission. This prompted researchers to explore how these new astrocyte functions were changed in disease, and they reported alterations in many of them (sometimes beneficial, mostly deleterious). More recently, cell‐specific transcriptomics revealed that astrocytes undergo massive changes in gene expression when they become reactive. This observation further stressed that reactive astrocytes may be very different from normal, nonreactive astrocytes and could influence disease outcomes. To make the picture even more complex, both normal and reactive astrocytes were shown to be molecularly and functionally heterogeneous. Very little is known about the specific roles that each subtype of reactive astrocytes may play in different disease contexts. In this review, we have interrogated researchers in the field to identify and discuss points of consensus and controversies about reactive astrocytes, starting with their very name. We then present the emerging knowledge on these cells and future challenges in this field.

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Astrocyte Biomarkers in Alzheimer’s Disease

Cited by 224 publications

References 169 publications

Cortical microstructural correlates of astrocytosis in autosomal-dominant Alzheimer disease

Cortical microstructural correlates of astrocytosis in autosomal-dominant Alzheimer disease

A Consensus Proteomic Analysis of Alzheimer’s Disease Brain and Cerebrospinal Fluid Reveals Early Changes in Energy Metabolism Associated with Microglia and Astrocyte Activation

Questions and (some) answers on reactive astrocytes

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