Astrogliosis and episodic memory in late life: higher GFAP is related to worse memory and white matter microstructure in healthy aging and Alzheimer's disease

Bettcher, Brianne M.; Olson, Kaitlin E.; Carlson, Nichole E.; McConnell, Brice V.; Boyd, Tim D.; Adame, Vanesa; Solano, Daniel; Anton, Paige; Markham, Neil E.; Thaker, Ashesh A.; Jensen, Alexandria; Dallmann, Erika N.; Potter, Huntington; Coughlan, Christina

doi:10.1016/j.neurobiolaging.2021.02.012

Cited by 35 publications

(45 citation statements)

References 51 publications

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“…Epidemiological studies suggest that elevated immune biomarkers in the blood may be evident years prior to the manifestation of clinical symptoms of AD or AD-related dementias (ADRDs) in the typical population (Schmidt et al, 2002 ; Ridolfi et al, 2013 ; Leszek et al, 2016 ; Busse et al, 2017 ; Wendeln et al, 2018 ). Higher plasma levels of GFAP are correlated with lower measures of episodic memory and microstructural integrity in AD, MCI, and also in healthy aged donors (Bettcher et al, 2021 ). As discussed, people with DS also have increasing levels of plasma GFAP starting in their mid-40s (Hendrix et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Innate Immune System Activation and Neuroinflammation in Down Syndrome and Neurodegeneration: Therapeutic Targets or Partners?

Ahmed

Johnson

Boyd

et al. 2021

Front. Aging Neurosci.

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Innate immune system activation and inflammation are associated with and may contribute to clinical outcomes in people with Down syndrome (DS), neurodegenerative diseases such as Alzheimer’s disease (AD), and normal aging. In addition to serving as potential diagnostic biomarkers, innate immune system activation and inflammation may play a contributing or causal role in these conditions, leading to the hypothesis that effective therapies should seek to dampen their effects. However, recent intervention studies with the innate immune system activator granulocyte-macrophage colony-stimulating factor (GM-CSF) in animal models of DS, AD, and normal aging, and in an AD clinical trial suggest that activating the innate immune system and inflammation may instead be therapeutic. We consider evidence that DS, AD, and normal aging are accompanied by innate immune system activation and inflammation and discuss whether and when during the disease process it may be therapeutically beneficial to suppress or promote such activation.

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Section: Introductionmentioning

confidence: 99%

Innate Immune System Activation and Neuroinflammation in Down Syndrome and Neurodegeneration: Therapeutic Targets or Partners?

Ahmed

Johnson

Boyd

et al. 2021

Front. Aging Neurosci.

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“…Mutations in GFAP lead to Alexander disease, a genetic disorder characterized by fibrinoid degeneration of astrocytes, demyelination and white matter anomalies 64 . GFAP variations have also been associated with white matter microstructure phenotypes and Alzheimer’s disease 57, 65, 66 . While astrocytes are present in both grey and white matter, GFAP expression is higher in white matter astrocytes than in grey matter astrocytes 67 .…”

Section: Resultsmentioning

confidence: 99%

Phenotypic and genetic associations of quantitative magnetic susceptibility in UK Biobank brain imaging

Wang

Martins-Bach

Alfaro-Almagro

et al. 2021

Preprint

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A key aim of epidemiological neuroscience studies is the identification of novel markers to assess brain health and evaluate the efficacy of therapeutic interventions. A broad range of tissue constituents associated with healthy brain functions and diseases (e.g., iron, myelin and calcium) are characterised by unique magnetic properties, motivating the development of measurements sensitive to these effects. Quantitative susceptibility mapping (QSM) is an emerging MRI technique which enables in vivo quantification of tissue magnetic susceptibility, providing the opportunity to identify such markers. In this study, we developed a robust QSM modelling pipeline and evaluated the potential of QSM in a cohort of 35,885 subjects (ages 45-82), alongside extensive genetic and phenotypic associations as part of UK Biobank. Our analysis identified a rich set of distinctive phenotypic and genetic associations with QSM. This included phenotypic associations with body iron, diet, alcohol and diseases, and genetic associations related to a broad range of biological functions including iron, calcium homeostasis, myelination, extracellular matrix. Importantly, we found that QSM and T2* have unique patterns of associations, demonstrating the added value in including QSM IDPs in the UK Biobank brain imaging resource, with considerable promise to identify novel in vivo brain health markers.

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“…The early phases of AD are characterized by a gradual decline in neurocognitive functions including impairments in episodic and semantic memory and word fluency [5,6] . In the later stages of AD, patients suffer from deficits in memory, language and naming, orientation, executive functions, perceptual-motor functions, attention, and social skills including communication and judgement [6,7] . At that stage, difficulties to perform activities of daily living (ADL) and neuropsychiatric symptoms, such as behavioral dysregulation, irritability and aggression, inertia, and depressive, vegetative, and psychotic symptoms may be evident [7] .…”

Section: Introductionmentioning

confidence: 99%

“…In the later stages of AD, patients suffer from deficits in memory, language and naming, orientation, executive functions, perceptual-motor functions, attention, and social skills including communication and judgement [6,7] . At that stage, difficulties to perform activities of daily living (ADL) and neuropsychiatric symptoms, such as behavioral dysregulation, irritability and aggression, inertia, and depressive, vegetative, and psychotic symptoms may be evident [7] . The pathophysiology of AD comprises neuroinflammation with astrogliosis, neurofibrillary tangles, accumulation of amyloid plaques, dystrophic neurites with tau protein, and synaptic, neuronal, and neuropil loss [2,3,8,9] .…”

Section: Introductionmentioning

confidence: 99%

Interplay among norepinephrine, NOX2, and neuroinflammation: key players in Parkinson’s disease and prime targets for therapies

Wang¹,

Song²,

Jiang³

et al. 2021

AND

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Aim: No studies have examined whether interactions between the apolipoprotein E4 (ApoE4) allele and peripheral biomarkers, hypertension, and type 2 diabetes mellitus (T2DM) may impact the neurocognitive, behavioral, and social dysfunctions in amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD). We aimed to clinically define and biologically validate a subgroup of aMCI subjects who take up an intermediate position between controls and AD patients. Methods:In 61 healthy controls, 60 subjects with aMCI, and 60 AD patients, we measured the features of aMCI/AD using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD). A composite BIORISK score was computed using the ApoE4 allele, serum folate, albumin, white blood cells, fasting blood glucose, atherogenic index of plasma, T2DM, and hypertension.Results: Clustering and nearest neighbor analyses were unable to validate the aMCI subgroup. We constructed two z unit-based composite scores, the first indicating overall burden of cognitive, social, and behavioral deterioration (OBD) and the second reflecting the interactions among ApoE4, all other biomarkers, hypertension, and T2DM (BIORISK). We found that 40.2% of the variance in the OBD score was explained by BIORISK, ApoE4, age, and education. The OBD index was used to construct three subgroups (normal, medium, and high OBD) with the medium group (n = 45) showing mild cognitive dysfunctions (MCD) in memory, language, orientation, and ADL. People with MCD show OBD and BIORISK scores that are significantly different from controls and AD. Conclusion:Petersen's aMCI criteria cannot be validated and should be replaced by the more restrictive, biologically validated MCD class.

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Astrogliosis and episodic memory in late life: higher GFAP is related to worse memory and white matter microstructure in healthy aging and Alzheimer's disease

Cited by 35 publications

References 51 publications

Innate Immune System Activation and Neuroinflammation in Down Syndrome and Neurodegeneration: Therapeutic Targets or Partners?

Innate Immune System Activation and Neuroinflammation in Down Syndrome and Neurodegeneration: Therapeutic Targets or Partners?

Phenotypic and genetic associations of quantitative magnetic susceptibility in UK Biobank brain imaging

Interplay among norepinephrine, NOX2, and neuroinflammation: key players in Parkinson’s disease and prime targets for therapies

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