Plasma glial fibrillary acidic protein in autosomal dominant Alzheimer's disease: Associations with Aβ‐PET, neurodegeneration, and cognition

Alzheimer s & Dementia, Год журнала: 2022, Номер 19(7), С. 2790 - 2804

Опубликована: Дек. 28, 2022

Abstract Background Glial fibrillary acidic protein (GFAP) is a promising candidate blood‐based biomarker for Alzheimer's disease (AD) diagnosis and prognostication. The timing of its disease‐associated changes, clinical correlates, biofluid‐type dependency will influence utility. Methods We evaluated plasma, serum, cerebrospinal fluid (CSF) GFAP in families with autosomal dominant AD (ADAD), leveraging the predictable age at symptom onset to determine changes by stage disease. Results Plasma elevations appear decade before expected onset, after amyloid beta (Aβ) accumulation prior neurodegeneration cognitive decline. distinguished Aβ‐positive from Aβ‐negative ADAD participants showed stronger relationship Aβ load asymptomatic than symptomatic ADAD. Higher plasma was associated degree rate impairment. Serum similar relationships, but these were less pronounced CSF GFAP. Conclusion Our findings support role as Aβ‐related astrocyte reactivity that decline neurodegeneration. Highlights glial (ADAD). positivity increased severity predicted progression. serum carried information ADAD, while did not.

Язык: Английский

---

Imaging of Reactive Astrogliosis by Positron Emission Tomography

Frontiers in Neuroscience, Год журнала: 2022, Номер 16

Опубликована: Фев. 8, 2022

Many neurodegenerative diseases are neuropathologically characterized by neuronal loss, gliosis, and the deposition of misfolded proteins such as β-amyloid (Aβ) plaques tau tangles in Alzheimer’s disease (AD). In postmortem AD brains, reactive astrocytes activated microglia observed surrounding Aβ tangles. These glial cells secrete pro-inflammatory cytokines oxygen species, which may contribute to neurodegeneration. Therefore, vivo imaging response positron emission tomography (PET) combined with PET would provide new insights better understand process, well aid differential diagnosis, monitoring disease-specific therapeutics. There two promising targets proposed for astrogliosis: monoamine oxidase-B (MAO-B) imidazoline 2 binding site (I BS), predominantly expressed mitochondrial membranes upregulated various conditions. tracers targeting these MAO-B I BS have been evaluated humans. [ 18 F]THK-5351, was originally designed target aggregates AD, showed high affinity clearly visualized progressive supranuclear palsy (PSP). However, lack selectivity F]THK-5351 both tau, severely limits its clinical utility a biomarker. Recently, F]SMBT-1 developed selective reversible tracer via compound optimization F]THK-5351. this review, we summarize strategy underlying molecular astrogliosis studies using tracers.

Язык: Английский

---

Visualizing reactive astrocyte-neuron interaction in Alzheimer’s disease using 11C-acetate and 18F-FDG

Brain, Год журнала: 2023, Номер 146(7), С. 2957 - 2974

Опубликована: Апрель 17, 2023

Abstract Reactive astrogliosis is a hallmark of Alzheimer’s disease (AD). However, clinically validated neuroimaging probe to visualize the reactive yet be discovered. Here, we show that PET imaging with 11C-acetate and 18F-fluorodeoxyglucose (18F-FDG) functionally visualizes astrocyte-mediated neuronal hypometabolism in brains neuroinflammation AD. To investigate alterations acetate glucose metabolism diseased their impact on AD pathology, adopted multifaceted approaches including microPET imaging, autoradiography, immunohistochemistry, metabolomics, electrophysiology. Two rodent models, APP/PS1 5xFAD transgenic mice, one adenovirus-induced rat model astrogliosis, post-mortem human brain tissues were used this study. We further curated proof-of-concept study included 18F-FDG analyses along neuropsychological assessments from 11 patients 10 healthy control subjects. demonstrate astrocytes excessively absorb through elevated monocarboxylate transporter-1 (MCT1) models both The uptake associated boosts aberrant astrocytic GABA synthesis when amyloid-β present. excessive subsequently suppresses activity, which could lead decreased transporter-3 brains. was significantly increased entorhinal cortex, hippocampus temporo-parietal neocortex compared controls, while reduced same regions. Additionally, discover strong correlation between patients’ cognitive function signals 18F-FDG. potential value by visualizing hypometablosim for patients. Our findings suggest acetate-boosted astrocyte-neuron interaction contribute decline

Язык: Английский

---

[18F]F-DED PET imaging of reactive astrogliosis in neurodegenerative diseases: preclinical proof of concept and first-in-human data

Journal of Neuroinflammation, Год журнала: 2023, Номер 20(1)

Опубликована: Март 11, 2023

Reactive gliosis is a common pathological hallmark of CNS pathology resulting from neurodegeneration and neuroinflammation. In this study we investigate the capability novel monoamine oxidase B (MAO-B) PET ligand to monitor reactive astrogliosis in transgenic mouse model Alzheimer`s disease (AD). Furthermore, performed pilot patients with range neurodegenerative neuroinflammatory conditions.A cross-sectional cohort 24 (PS2APP) 25 wild-type mice (age range: 4.3-21.0 months) underwent 60 min dynamic [18F]fluorodeprenyl-D2 ([18F]F-DED), static 18 kDa translocator protein (TSPO, [18F]GE-180) β-amyloid ([18F]florbetaben) imaging. Quantification was via image derived input function (IDIF, cardiac input), simplified non-invasive reference tissue modelling (SRTM2, DVR) late-phase standardized uptake value ratios (SUVr). Immunohistochemical (IHC) analyses glial fibrillary acidic (GFAP) MAO-B were validate imaging by gold standard assessments. Patients belonging Alzheimer's continuum (AD, n = 2), Parkinson's (PD, multiple system atrophy (MSA, autoimmune encephalitis (n 1), oligodendroglioma 1) one healthy control [18F]F-DED data analyzed using equivalent quantification strategies.We selected cerebellum as pseudo-reference region based on immunohistochemical comparison age-matched PS2APP WT mice. Subsequent revealed that showed elevated hippocampal thalamic DVR when compared at 5 months (thalamus: + 4.3%; p 0.048), 13 (hippocampus: 7.6%, 0.022) 19 12.3%, < 0.0001; thalamus: 15.2%, 0.0001). Specific increases occurred earlier signal alterations TSPO correlated quantitative immunohistochemistry R 0.720, 0.001; 0.727, 0.002). Preliminary experience VT SUVr patterns, matching expected topology (MSA) conditions, whereas patient indicated binding following known physiological expression brain.[18F]F-DED promising approach assess AD models neurological diseases.

Язык: Английский

---

Aquaporin 4 is differentially increased and dislocated in association with tau and amyloid-beta

Life Sciences, Год журнала: 2023, Номер 321, С. 121593 - 121593

Опубликована: Март 17, 2023

Neurovascular-glymphatic dysfunction plays an important role in Alzheimer's disease and has been analysed mainly relation to amyloid-beta (Aβ) pathology. Here, we aim investigate the neurovascular alterations mapping of aquaporin 4 (AQP4) distribution dislocation associated with tau Aβ.Perfusion, susceptibility weighted imaging structural magnetic resonance (MRI) were performed pR5 mouse model 4-repeat arcAβ amyloidosis. Immunofluorescence staining was using antibodies against AQP4, vessel, astroglia, microglia, phospho-tau Aβ brain tissue slices from pR5, non-transgenic mice.pR5 mice showed regional atrophy, preserved cerebral blood flow, reduced vessel density compared mice, while microbleeds density. AQP4 peri-tau enrichment hippocampus increased levels cortex detected mice. In comparison, cortical cortical/hippocampal peri-plaque increases observed Increased expression reactive astrocytes around inclusions plaques mice.We demonstrated alterations, microgliosis, astrogliosis We a divergent region-specific association pathologies.

Язык: Английский

---

Characterization of monoamine oxidase-B (MAO-B) as a biomarker of reactive astrogliosis in Alzheimer’s disease and related dementias

Acta Neuropathologica, Год журнала: 2024, Номер 147(1)

Опубликована: Апрель 3, 2024

Язык: Английский

---

Gut microbiota–astrocyte axis: new insights into age-related cognitive decline

Neural Regeneration Research, Год журнала: 2024, Номер 20(4), С. 990 - 1008

Опубликована: Апрель 16, 2024

With the rapidly aging human population, age-related cognitive decline and dementia are becoming increasingly prevalent worldwide. Aging is considered main risk factor for acts through alterations in composition of gut microbiota, microbial metabolites, functions astrocytes. The microbiota–gut–brain axis has been focus multiple studies closely associated with function. This article provides a comprehensive review specific changes that occur microbiota metabolites older individuals discusses how astrocytes reactive astrocytosis related to neurodegenerative diseases. also summarizes components affect astrocyte function, mainly vagus nerve, immune responses, circadian rhythms, metabolites. Finally, this mechanism by which microbiota–astrocyte plays role Alzheimer’s Parkinson’s Our findings have revealed critical decline, aiding deeper understanding potential microbiome-based adjuvant therapy strategies condition.

Язык: Английский

---

PET brain imaging in neurological disorders

Physics of Life Reviews, Год журнала: 2024, Номер 49, С. 100 - 111

Опубликована: Март 24, 2024

Язык: Английский

---

Plasma Glial Fibrillary Acidic Protein Is Associated with 18F-SMBT-1 PET: Two Putative Astrocyte Reactivity Biomarkers for Alzheimer’s Disease

Journal of Alzheimer s Disease, Год журнала: 2023, Номер 92(2), С. 615 - 628

Опубликована: Фев. 10, 2023

Background: Astrocyte reactivity is an early event along the Alzheimer’s disease (AD) continuum. Plasma glial fibrillary acidic protein (GFAP), posited to reflect astrocyte reactivity, elevated across AD continuum from preclinical dementia stages. Monoamine oxidase-B (MAO-B) also in reactive astrocytes observed using 18F-SMBT-1 PET AD. Objective: The objective of this study was evaluate association between abovementioned biomarkers. Methods: GFAP and Aβ were measured Simoa® platform participants who underwent brain Aβ–PET imaging, comprising 54 healthy control (13 Aβ–PET+ 41 Aβ–PET–), 11 mild cognitively impaired (3 8 Aβ–PET–) 6 probable (5 1 individuals. Linear regressions used assess associations interest. Results: associated with signal regions prone deposition AD, such as supramarginal gyrus (SG), posterior cingulate (PC), lateral temporal (LT) occipital cortex (LO). After adjusting for age, sex, APOE ɛ4 genotype, soluble (plasma Aβ42/40 ratio), plasma SG, PC, LT, LO, superior parietal (SP). On genotype insoluble (Aβ–PET), SG. Conclusion: There regional PET, appears be dependent on load.

Язык: Английский

---

Relationship Between Reactive Astrocytes, by [18F]SMBT-1 Imaging, with Amyloid-Beta, Tau, Glucose Metabolism, and TSPO in Mouse Models of Alzheimer’s Disease

Molecular Neurobiology, Год журнала: 2024, Номер 61(10), С. 8387 - 8401

Опубликована: Март 19, 2024

Reactive astrocytes play an important role in the development of Alzheimer's disease (AD). Here, we aimed to investigate temporospatial relationships among monoamine oxidase-B, tau and amyloid-β (Aβ), translocator protein, glucose metabolism by using multitracer imaging AD transgenic mouse models. Positron emission tomography (PET) with [

Язык: Английский

---