Astrocyte Biomarkers in Alzheimer Disease

Bellaver, Bruna; Ferrari‐Souza, João Pedro; Ros, Lucas Uglione da; Carter, Stephen F.; Rodriguez‐Vieitez, Elena; Nordberg, Agneta; Pellerin, Luc; Rosa‐Neto, Pedro; Leffa, Douglas Teixeira; Zimmer, Eduardo R.

doi:10.1212/wnl.0000000000012109

Cited by 89 publications

(56 citation statements)

References 70 publications

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“…12,13 Cerebrospinal fluid (CSF) levels have been shown to differentiate individuals with dementia from cognitively unimpaired adults. 14,15 With the use of ultrasensitive assays, GFAP levels can be detected in blood, and some recent studies have reported that circulating levels associate with poorer cognition and ADRD status. [16][17][18][19][20] Relevant to secondary prevention efforts, plasma GFAP levels have also been found to predict amyloid positivity among cognitively unimpaired adults.…”

Section: Introductionmentioning

confidence: 99%

A population‐based meta‐analysis of circulating GFAP for cognition and dementia risk

Gonzales

Wiedner

Wang

et al. 2022

Ann Clin Transl Neurol

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Objective Expression of glial fibrillary acidic protein (GFAP), a marker of reactive astrocytosis, colocalizes with neuropathology in the brain. Blood levels of GFAP have been associated with cognitive decline and dementia status. However, further examinations at a population‐based level are necessary to broaden generalizability to community settings. Methods Circulating GFAP levels were assayed using a Simoa HD‐1 analyzer in 4338 adults without prevalent dementia from four longitudinal community‐based cohort studies. The associations between GFAP levels with general cognition, total brain volume, and hippocampal volume were evaluated with separate linear regression models in each cohort with adjustment for age, sex, education, race, diabetes, systolic blood pressure, antihypertensive medication, body mass index, apolipoprotein E ε4 status, site, and time between GFAP blood draw and the outcome. Associations with incident all‐cause and Alzheimer's disease dementia were evaluated with adjusted Cox proportional hazard models. Meta‐analysis was performed on the estimates derived from each cohort using random‐effects models. Results Meta‐analyses indicated that higher circulating GFAP associated with lower general cognition (ß = −0.09, [95% confidence interval [CI]: −0.15 to −0.03], p = 0.005), but not with total brain or hippocampal volume (p > 0.05). However, each standard deviation unit increase in log‐transformed GFAP levels was significantly associated with a 2.5‐fold higher risk of incident all‐cause dementia (Hazard Ratio [HR]: 2.47 (95% CI: 1.52–4.01)) and Alzheimer's disease dementia (HR: 2.54 [95% CI: 1.42–4.53]) over up to 15‐years of follow‐up. Interpretation Results support the potential role of circulating GFAP levels for aiding dementia risk prediction and improving clinical trial stratification in community settings.

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Section: Introductionmentioning

confidence: 99%

A population‐based meta‐analysis of circulating GFAP for cognition and dementia risk

Gonzales

Wiedner

Wang

et al. 2022

Ann Clin Transl Neurol

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“…Chitinase 3-like-1 (CHI3L1), also known as YKL-40, has been extensively studied as a cerebrospinal fluid biomarker for diseases such as Alzheimer's disease and dementia (10). As a carbohydrate-binding lectin that mediates inflammation, YKL-40 is regulated by the circadian rhythm of astrocytes and increases the deposition of beta-amyloid during the inflammatory response, thereby accelerating the pathological process of Alzheimer's disease (11).…”

Section: Introductionmentioning

confidence: 99%

Adenosine A2A Receptor Suppressed Astrocyte-Mediated Inflammation Through the Inhibition of STAT3/YKL-40 Axis in Mice With Chronic Cerebral Hypoperfusion-induced White Matter Lesions

et al. 2022

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White matter lesions are an important pathological manifestation of cerebral small vessel disease, with inflammation playing a pivotal role in their development. The adenosine A2a receptor (ADORA2A) is known to inhibit the inflammation mediated by microglia, but its effect on astrocytes is unknown. Additionally, although the level of YKL-40 (expressed mainly in astrocytes) has been shown to be elevated in the model of white matter lesions induced by chronic cerebral hypoperfusion, the specific regulatory mechanism involved is not clear. In this study, we established in vivo and in vitro chronic cerebral hypoperfusion models to explore whether the ADORA2A regulated astrocyte-mediated inflammation through STAT3/YKL-40 axis and using immunohistochemical, western blotting, ELISA, PCR, and other techniques to verify the effect of astrocytes ADORA2A on the white matter injury. The in vivo experiments showed that activation of the ADORA2A decreased the expression of both STAT3 and YKL-40 in the astrocytes and alleviated the white matter injury, whereas its inhibition had the opposite effects. Similarly, ADORA2A inhibition significantly increased the expression of STAT3 and YKL-40 in astrocytes in vitro, with more proinflammatory cytokines being released by astrocytes. STAT3 inhibition enhanced the inhibitory effect of ADORA2A on YKL-40 synthesis, whereas its activation reversed the phenomenon. These results suggest that the activation of ADORA2A in astrocytes can inhibit the inflammation mediated by the STAT3/YKL-40 axis and thereby reduce white matter injury in cerebral small vessel disease.

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“…A large range of other targets, including noradrenergic [ 159 ], mitochondrial [ 160 ] and synaptic vesicular markers [ 161 ] have been explored in AD. In recent years, imaging of activated microglia and astrocytes has attracted most interest as a research area with therapeutic potential [ 162 , 163 ]. It will likely be relevant for predicting disease progression at the MCI stage but so far has not been associated with specific AD subtypes.…”

Section: Imaging Techniquesmentioning

confidence: 99%

Imaging Clinical Subtypes and Associated Brain Networks in Alzheimer’s Disease

Herholz

2022

Brain Sciences

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Alzheimer’s disease (AD) does not present uniform symptoms or a uniform rate of progression in all cases. The classification of subtypes can be based on clinical symptoms or patterns of pathological brain alterations. Imaging techniques may allow for the identification of AD subtypes and their differentiation from other neurodegenerative diseases already at an early stage. In this review, the strengths and weaknesses of current clinical imaging methods are described. These include positron emission tomography (PET) to image cerebral glucose metabolism and pathological amyloid or tau deposits. Magnetic resonance imaging (MRI) is more widely available than PET. It provides information on structural or functional changes in brain networks and their relation to AD subtypes. Amyloid PET provides a very early marker of AD but does not distinguish between AD subtypes. Regional patterns of pathology related to AD subtypes are observed with tau and glucose PET, and eventually as atrophy patterns on MRI. Structural and functional network changes occur early in AD but have not yet provided diagnostic specificity.

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Astrocyte Biomarkers in Alzheimer Disease

Cited by 89 publications

References 70 publications

A population‐based meta‐analysis of circulating GFAP for cognition and dementia risk

A population‐based meta‐analysis of circulating GFAP for cognition and dementia risk

Adenosine A2A Receptor Suppressed Astrocyte-Mediated Inflammation Through the Inhibition of STAT3/YKL-40 Axis in Mice With Chronic Cerebral Hypoperfusion-induced White Matter Lesions

Imaging Clinical Subtypes and Associated Brain Networks in Alzheimer’s Disease

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