Astrocyte Biomarkers in Alzheimer’s Disease Carter, Stephen F.; Herholz, Karl; Rosa-Neto, Pedro ...
Trends in molecular medicine,
02/2019, Letnik:
25, Številka:
2
Journal Article
Recenzirano
Astrocytic contributions to Alzheimer’s disease (AD) progression were, until recently, largely overlooked. Astrocytes are integral to normal brain function and astrocyte reactivity is an early ...feature of AD, potentially providing a promising target for preclinical diagnosis and treatment. Several in vivo AD biomarkers already exist, but presently there is a paucity of specific and sensitive in vivo astrocyte biomarkers that can accurately measure preclinical AD. Measuring monoamine oxidase-B with neuroimaging and glial fibrillary acidic protein from bodily fluids are biomarkers that are currently available. Developing novel, more specific, and sensitive astrocyte biomarkers will make it possible to pharmaceutically target chemical pathways that preserve beneficial astrocytic functions in response to AD pathology. This review discusses astrocyte biomarkers in the context of AD.
The neurocentric view of AD is evolving and the contributions astrocytes make to the disease’s pathological processes are finally considered.
AD pathology triggers astrocyte reactivity, which imaging and fluid biomarkers can measure in vivo.
Astrocyte dysfunction in AD could contribute to 18FFDG-PET hypometabolism.
Astrocytes are promising targets for developing novel, specific fluid or imaging biomarkers for detecting preclinical AD.
Pharmacologically targeting astrocytes may lead to developing an effective treatment for AD.
Alzheimer's disease is a multifactorial dementia disorder characterized by early amyloid-β, tau deposition, glial activation and neurodegeneration, where the interrelationships between the different ...pathophysiological events are not yet well characterized. In this study, longitudinal multitracer positron emission tomography imaging of individuals with autosomal dominant or sporadic Alzheimer's disease was used to quantify the changes in regional distribution of brain astrocytosis (tracer (11)C-deuterium-L-deprenyl), fibrillar amyloid-β plaque deposition ((11)C-Pittsburgh compound B), and glucose metabolism ((18)F-fluorodeoxyglucose) from early presymptomatic stages over an extended period to clinical symptoms. The 52 baseline participants comprised autosomal dominant Alzheimer's disease mutation carriers (n = 11; 49.6 ± 10.3 years old) and non-carriers (n = 16; 51.1 ± 14.2 years old; 10 male), and patients with sporadic mild cognitive impairment (n = 17; 61.9 ± 6.4 years old; nine male) and sporadic Alzheimer's disease (n = 8; 63.0 ± 6.5 years old; five male); for confidentiality reasons, the gender of mutation carriers is not revealed. The autosomal dominant Alzheimer's disease participants belonged to families with known mutations in either presenilin 1 (PSEN1) or amyloid precursor protein (APPswe or APParc) genes. Sporadic mild cognitive impairment patients were further divided into (11)C-Pittsburgh compound B-positive (n = 13; 62.0 ± 6.4; seven male) and (11)C-Pittsburgh compound B-negative (n = 4; 61.8 ± 7.5 years old; two male) groups using a neocortical standardized uptake value ratio cut-off value of 1.41, which was calculated with respect to the cerebellar grey matter. All baseline participants underwent multitracer positron emission tomography scans, cerebrospinal fluid biomarker analysis and neuropsychological assessment. Twenty-six of the participants underwent clinical and imaging follow-up examinations after 2.8 ± 0.6 years. By using linear mixed-effects models, fibrillar amyloid-β plaque deposition was first observed in the striatum of presymptomatic autosomal dominant Alzheimer's disease carriers from 17 years before expected symptom onset; at about the same time, astrocytosis was significantly elevated and then steadily declined. Diverging from the astrocytosis pattern, amyloid-β plaque deposition increased with disease progression. Glucose metabolism steadily declined from 10 years after initial amyloid-β plaque deposition. Patients with sporadic mild cognitive impairment who were (11)C-Pittsburgh compound B-positive at baseline showed increasing amyloid-β plaque deposition and decreasing glucose metabolism but, in contrast to autosomal dominant Alzheimer's disease carriers, there was no significant longitudinal decline in astrocytosis over time. The prominent initially high and then declining astrocytosis in autosomal dominant Alzheimer's disease carriers, contrasting with the increasing amyloid-β plaque load during disease progression, suggests astrocyte activation is implicated in the early stages of Alzheimer's disease pathology.
Astrocytes colocalize with fibrillar amyloid-β (Aβ) plaques in postmortem Alzheimer disease (AD) brain tissue. It is therefore of great interest to develop a PET tracer for visualizing astrocytes in ...vivo, enabling the study of the regional distribution of both astrocytes and fibrillar Aβ. A multitracer PET investigation was conducted for patients with mild cognitive impairment (MCI), patients with mild AD, and healthy controls using (11)C-deuterium-L-deprenyl ((11)C-DED) to measure monoamine oxidase B located in astrocytes. Along with (11)C-DED PET, (11)C-Pittsburgh compound B ((11)C-PIB; fibrillar Aβ deposition), (18)F-FDG (glucose metabolism), T1 MRI, cerebrospinal fluid, and neuropsychologic data were acquired from the patients.
(11)C-DED PET was performed in MCI patients (n = 8; mean age ± SD, 62.6 ± 7.5 y; mean Mini Mental State Examination, 27.5 ± 2.1), AD patients (n = 7; mean age, 65.1 ± 6.3 y; mean Mini Mental State Examination, 24.4 ± 5.7), and healthy age-matched controls (n = 14; mean age, 64.7 ± 3.6 y). A modified reference Patlak model, with cerebellar gray matter as a reference, was chosen for kinetic analysis of the (11)C-DED data. (11)C-DED data from 20 to 60 min were analyzed using a digital brain atlas. Mean regional (18)F-FDG uptake and (11)C-PIB retention were calculated for each patient, with cerebellar gray matter as a reference.
ANOVA analysis of the regional (11)C-DED binding data revealed a significant group effect in the bilateral frontal and bilateral parietal cortices related to increased binding in the MCI patients. All patients, except 3 with MCI, showed high (11)C-PIB retention. Increased (11)C-DED binding in most cortical and subcortical regions was observed in MCI (11)C-PIB+ patients relative to controls, MCI (11)C-PIB (negative) patients, and AD patients. No regional correlations were found between the 3 PET tracers.
Increased (11)C-DED binding throughout the brain of the MCI (11)C-PIB+ patients potentially suggests that astrocytosis is an early phenomenon in AD development.
Purpose
The spatial resolution of
18
F-fluorodeoxyglucose PET does not allow the specific cellular origin of its signal to be determined, but it is commonly accepted that transport and trapping of
18
...F-fluorodeoxyglucose reflects neuronal glucose metabolism. The main frameworks for the diagnosis of Alzheimer’s disease suggest that hypometabolism measured with
18
F-fluorodeoxyglucose PET is a biomarker of neuronal injury and neurodegeneration. There is preclinical evidence to suggest that astrocytes contribute, at least partially, to the in vivo
18
F-fluorodeoxyglucose PET signal. However, due to a paucity of PET tracers for imaging astrocytic processes, the relationship between astrocyte function and glucose metabolism in human brain is not fully understood. The aim of this study was to investigate the longitudinal association between astrocyte function and glucose metabolism in Alzheimer’s disease.
Methods
The current investigation combined longitudinal PET data from patients with autosomal dominant Alzheimer’s disease, including data on astrocyte function (
11
C-deuterium-
l
-deprenyl binding) and glucose metabolism (
18
F-fluorodeoxyglucose uptake). Research participants included 7 presymptomatic and 4 symptomatic mutation carriers (age 44.9 ± 9.8 years and 58.0 ± 3.7 years, respectively) and 16 noncarriers (age 51.1 ± 14.2 years). Eight carriers and eight noncarriers underwent longitudinal follow-up PET imaging at an average of 2.8 ± 0.2 and 3.0 ± 0.5 years from baseline, respectively.
Results
Longitudinal decline in astrocyte function as measured using
11
C-deuterium-
l
-deprenyl PET was significantly associated with progressive hypometabolism (
18
F-fluorodeoxyglucose uptake) in mutation carriers; no significant association was observed in noncarriers.
Conclusion
The emerging data shift the accepted wisdom that decreases in cerebral metabolism measured with
18
F-fluorodeoxyglucose solely reflect neuronal injury, and places astrocytes more centrally in the development of Alzheimer’s disease.
Studying autosomal dominant Alzheimer's disease (ADAD), caused by gene mutations yielding nearly complete penetrance and a distinct age of symptom onset, allows investigation of presymptomatic ...pathological processes that can identify a therapeutic window for disease-modifying therapies. Astrocyte activation may occur in presymptomatic Alzheimer's disease (AD) because reactive astrocytes surround β-amyloid (Aβ) plaques in autopsy brain tissue. Positron emission tomography was performed to investigate fibrillar Aβ, astrocytosis and cerebral glucose metabolism with the radiotracers (11)C-Pittsburgh compound-B (PIB), (11)C-deuterium-L-deprenyl (DED) and (18)F-fluorodeoxyglucose (FDG) respectively in presymptomatic and symptomatic ADAD participants (n = 21), patients with mild cognitive impairment (n = 11) and sporadic AD (n = 7). Multivariate analysis using the combined data from all radiotracers clearly separated the different groups along the first and second principal components according to increased PIB retention/decreased FDG uptake (component 1) and increased DED binding (component 2). Presymptomatic ADAD mutation carriers showed significantly higher PIB retention than non-carriers in all brain regions except the hippocampus. DED binding was highest in presymptomatic ADAD mutation carriers. This suggests that non-fibrillar Aβ or early stage plaque depostion might interact with inflammatory responses indicating astrocytosis as an early contributory driving force in AD pathology. The novelty of this finding will be investigated in longitudinal follow-up studies.
To perform a systematic review and meta-analysis to determine whether fluid and imaging astrocyte biomarkers are altered in Alzheimer disease (AD).
PubMed and Web of Science databases were searched ...for articles reporting fluid or imaging astrocyte biomarkers in AD. Pooled effect sizes were determined with standardized mean differences (SMDs) using the Hedge G method with random effects to determine biomarker performance. Adapted questions from the Quality Assessment of Diagnostic Accuracy Studies were applied for quality assessment. A protocol for this study has been previously registered in PROSPERO (registration number: CRD42020192304).
The initial search identified 1,425 articles. After exclusion criteria were applied, 33 articles (a total of 3,204 individuals) measuring levels of glial fibrillary acidic protein (GFAP), S100B, chitinase-3-like protein 1 (YKL-40), and aquaporin 4 in the blood and CSF, as well as monoamine oxidase-B indexed by PET
C-deuterium-l-deprenyl, were included. GFAP (SMD 0.94, 95% confidence interval CI 0.71-1.18) and YKL-40 (SMD 0.76, 95% CI 0.63-0.89) levels in the CSF and S100B levels in the blood (SMD 2.91, 95% CI 1.01-4.8) were found to be significantly increased in patients with AD.
Despite significant progress, applications of astrocyte biomarkers in AD remain in their early days. This meta-analysis demonstrated that astrocyte biomarkers are consistently altered in AD and supports further investigation for their inclusion in the AD clinical research framework for observational and interventional studies.
The current model of Alzheimer disease (AD) stipulates that brain amyloidosis biomarkers turn abnormal earliest, followed by cortical hypometabolism, and finally brain atrophy ones. The aim of this ...study is to provide clinical evidence of the model in patients with mild cognitive impairment (MCI).
A total of 73 patients with MCI from 3 European memory clinics were included. Brain amyloidosis was assessed by CSF Aβ42 concentration, cortical metabolism by an index of temporoparietal hypometabolism on FDG-PET, and brain atrophy by automated hippocampal volume. Patients were divided into groups based on biomarker positivity: 1) Aβ42- FDG-PET- Hippo-, 2) Aβ42+ FDG-PET- Hippo-, 3) Aβ42 + FDG-PET + Hippo-, 4) Aβ42 + FDG-PET+ Hippo+, and 5) any other combination not in line with the model. Measures of validity were prevalence of group 5, increasing incidence of progression to dementia with increasing biological severity, and decreasing conversion time.
When patients with MCI underwent clinical follow-up, 29 progressed to dementia, while 44 remained stable. A total of 26% of patients were in group 5. Incident dementia was increasing with greater biological severity in groups 1 to 5 from 4% to 27%, 64%, and 100% (p for trend < 0.0001), and occurred increasingly earlier (p for trend = 0.024).
The core biomarker pattern is in line with the current pathophysiologic model of AD. Fully normal and fully abnormal pattern is associated with exceptional and universal development of dementia. Cases not in line might be due to atypical neurobiology or inaccurate thresholds for biomarker (ab)normality.
There is an increasing role for biological markers (biomarkers) in the understanding and diagnosis of neurodegenerative disorders. The application of imaging biomarkers specifically for the in vivo ...investigation of neurodegenerative disorders has increased substantially over the past decades and continues to provide further benefits both to the diagnosis and understanding of these diseases. This review forms part of a series of articles which stem from the University College London/University of Gothenburg course "Biomarkers in neurodegenerative diseases". In this review, we focus on neuroimaging, specifically positron emission tomography (PET) and magnetic resonance imaging (MRI), giving an overview of the current established practices clinically and in research as well as new techniques being developed. We will also discuss the use of machine learning (ML) techniques within these fields to provide additional insights to early diagnosis and multimodal analysis.
The PET tracer (11)C-deuterium-L-deprenyl ((11)C-DED) has been used to visualize activated astrocytes in vivo in patients with Alzheimer disease (AD). In this multitracer PET study, early-phase ...(11)C-DED and (11)C-Pittsburgh compound B ((11)C-PiB) (eDED and ePiB, respectively) were compared as surrogate markers of brain perfusion, and the extent to which (11)C-DED binding is influenced by brain perfusion was investigated.
(11)C-DED, (11)C-PiB, and (18)F-FDG dynamic PET scans were obtained in age-matched groups comprising AD patients (n = 8), patients with mild cognitive impairment (n = 17), and healthy controls (n = 16). A modified reference Patlak model was used to quantify (11)C-DED binding. A simplified reference tissue model was applied to both (11)C-DED and (11)C-PiB to measure brain perfusion relative to the cerebellar gray matter (R1) and binding potentials. (11)C-PiB retention and (18)F-FDG uptake were also quantified as target-to-pons SUV ratios in 12 regions of interest (ROIs).
The strongest within-subject correlations with the corresponding R1 values (R1,DED and R1,PiB, respectively) and with (18)F-FDG uptake were obtained when the eDED and ePiB PET data were measured 1-4 min after injection. The optimum eDED/ePiB intervals also showed strong, significant ROI-based intersubject Pearson correlations with R1,DED/R1,PiB and with (18)F-FDG uptake, whereas (11)C-DED binding was largely independent of brain perfusion, as measured by eDED. Corresponding voxelwise correlations confirmed the ROI-based results. Temporoparietal eDED or ePiB brain perfusion measurements were highly discriminative between patient and control groups, with discriminative ability statistically comparable to that of temporoparietal (18)F-FDG glucose metabolism. Hypometabolism extended over wider regions than hypoperfusion in patient groups compared with controls.
The 1- to 4-min early-frame intervals of (11)C-DED or (11)C-PiB are suitable surrogate measures for brain perfusion. (11)C-DED binding is independent of brain perfusion, and thus (11)C-DED PET can provide information on both functional (brain perfusion) and pathologic (astrocytosis) aspects from a single PET scan. In comparison with glucose metabolism, early-phase (11)C-DED and (11)C-PiB perfusion appear to provide complementary rather than redundant information.
One of the challenges of developing influenza A vaccines is the diversity of antigenically distinct isolates. Previously, a novel hemagglutinin (HA) for H5N1 influenza was derived from a methodology ...termed computationally optimized broadly reactive antigen (COBRA). This COBRA HA elicited a broad antibody response against H5N1 isolates from different clades. We now report the development and characterization of a COBRA-based vaccine for both seasonal and pandemic H1N1 influenza virus isolates. Nine prototype H1N1 COBRA HA proteins were developed and tested in mice using a virus-like particle (VLP) format for the elicitation of broadly reactive, functional antibody responses and protection against viral challenge. These candidates were designed to recognize H1N1 viruses isolated within the last 30 years. In addition, several COBRA candidates were designed based on sequences of H1N1 viruses spanning the past 100 years, including modern pandemic H1N1 isolates. Four of the 9 H1N1 COBRA HA proteins (X1, X3, X6, and P1) had the broadest hemagglutination inhibition (HAI) activity against a panel of 17 H1N1 viruses. These vaccines were used in cocktails or prime-boost combinations. The most effective regimens that both elicited the broadest HAI response and protected mice against a pandemic H1N1 challenge were vaccines that contained the P1 COBRA VLP and either the X3 or X6 COBRA VLP vaccine. These mice had little or no detectable viral replication, comparable to that observed with a matched licensed vaccine. This is the first report describing a COBRA-based HA vaccine strategy that elicits a universal, broadly reactive, protective response against seasonal and pandemic H1N1 isolates.
Universal influenza vaccine approaches have the potential to be paradigm shifting for the influenza vaccine field, with the goal of replacing the current standard of care with broadly cross-protective vaccines. We have used COBRA technology to develop an HA head-based strategy that elicits antibodies against many H1 strains that have undergone genetic drift and has potential as a "subtype universal" vaccine. Nine HA COBRA candidates were developed, and these vaccines were used alone, in cocktails or in prime-boost combinations. The most effective regimens elicited the broadest hemagglutination inhibition (HAI) response against a panel of H1N1 viruses isolated over the past 100 years. This is the first report describing a COBRA-based HA vaccine strategy that elicits a broadly reactive response against seasonal and pandemic H1N1 isolates.
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