Biomarkers of Inflammation Increase with Tau and Neurodegeneration but not with Amyloid-β in a Heterogenous Clinical Cohort

Michopoulou, Sofia; Prosser, Angus; Kipps, Christopher; Dickson, J.; Guy, Matthew; Teeling, Jessica L.

doi:10.3233/jad-220523

Cited by 3 publications

(8 citation statements)

References 41 publications

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“…Notably, inflammatory stimuli activate 4E-BP1 transcription in microglia in vivo (24,28). Consistent with this, microglial activation markers and disease progression in AD strongly correlate with increased 4E-BP1 levels in cerebrospinal fluid in AD patients (29,30). Although this association suggests a role of 4E-BP1 in the loss of the protective function of microglia, the mechanisms underlying this association remain to be elucidated.…”

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confidence: 75%

“…4E-BP1 has been proposed as a disease-specific biomarker in AD (27). 4E-BP1 levels in CSF of AD patients are positively correlated with microglia activation markers and worsened AD pathology (29, 30). Our in vitro results highlight the role of 4E-BPs inhibition in limiting the microglial pro-inflammatory responses.…”

Section: E-bp1 Levels In Csf Moderate the Relationship Between Microg...mentioning

confidence: 99%

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Translational control of microglial inflammatory and neurodegenerative responses

Bermudez,

Choi,

Vogel

et al. 2024

Preprint

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In Alzheimer’s Disease (AD), activation of the mechanistic target of rapamycin (mTOR) pathway is essential for microglia neuroprotective roles, but it is unclear which mTOR effectors promote these neuroprotective functions. The mTOR complex 1 (mTORC1) inactivates the translation suppressors eukaryotic translation Initiation Factor 4E (eIF4E)-Binding Proteins (4E-BP) to promote mRNA translation. We show that 4E-BP1 inactivation is impaired in microglia under AD-relevant conditions. Depleting 4E-BPs in microglia increases mitochondrial metabolism, suppresses the pro-inflammatory profile, and mitigates amyloid-induced apoptosis. Furthermore, in the cerebrospinal fluid of patients with amyloid pathology, there was a positive association between microglia activation and neurodegeneration, which increases along 4E-BP1 levels. Thus, we propose the engagement mTORC1-4E-BP1 axis as a neuroprotective mechanism and a therapeutic target or biomarker for microglia modulation in AD.

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confidence: 75%

Section: E-bp1 Levels In Csf Moderate the Relationship Between Microg...mentioning

confidence: 99%

Translational control of microglial inflammatory and neurodegenerative responses

Bermudez,

Choi,

Vogel

et al. 2024

Preprint

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“…It was demonstrated in a recent cohort study that inflammation levels increased in presence of tau pathology but not of Aβ in AD pateints, 26 and Braak 6 area has the lowest tau pathology theoretically in the mild to moderate stage of AD. 11 C‐DPA713‐BP ND image of a representative AD patient is illustrated in Fig.…”

Section: Methodsmentioning

confidence: 92%

“…We used the Braak 6 area as a reference tissue region for TSPO quantification with 11 C-DPA-713-PET imaging, as the Braak 6 area was shown to be a non-target of 11 C-DPA-713 in mild to moderate AD in a previous study. 20 It was demonstrated in a recent cohort study that inflammation levels increased in presence of tau pathology but not of Aβ in AD pateints, 26 and Braak 6 area has the lowest tau pathology theoretically in the mild to moderate stage of AD. 11 C-DPA713-BP ND image of a representative AD patient is illustrated in Fig.…”

Section: Mri Image Acquisitionmentioning

confidence: 97%

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Involvement of inflammation in the medial temporal region in the development of agitation in Alzheimer's disease: an in vivo positron emission tomography study

et al. 2022

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Background The evaluation of 11C‐DPA‐713 binding using positron emission tomography for quantifying the translocator protein can be a sensitive approach in determining the level of glial activation induced by neuroinflammation. Herein, we aimed to investigate the relationship between regional 11C‐DPA713‐binding potential (BPND) and neuropsychiatric symptoms (NPS) in amyloid‐positive Alzheimer's disease (AD) patients. Methods Fifteen AD patients were enrolled in this study. Correlations were evaluated between the 11C‐DPA713‐BPND and Neuropsychiatric Inventory Questionnaire (NPI‐Q) scores, including scores in its four domains: agitation, psychosis, affective, and apathy. 11C‐DPA713‐BPND values were compared between groups with and without the neuropsychiatric symptoms for which a relationship was observed in the abovementioned correlation analysis. Results A positive correlation was found between the severity of agitation and 11C‐DPA713‐BPND in the Braak 1–3 area, including the amygdala, hippocampal and parahippocampal regions, and lingual and fusiform areas. An increase in the 11C‐DPA713‐BPND was observed in AD patients with agitation. We did not find any significant effects of possible confounding factors, such as age, duration of illness, education, gender, Mini‐Mental State Examination score, cerebrospinal fluid amyloid β 42/40 ratio, and apolipoprotein E4 positivity, on either the 11C‐DPA713‐BPND or agitation score. Conclusions Neuroinflammation in the medial temporal region and its neighbouring area was shown to be associated with the development of agitation symptoms in AD patients. Our findings extend those of previous studies showing an association between some NPS and inflammation, suggesting that immunologically based interventions for agitation can serve as an alternative treatment for dementia.

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Perfusion Imaging and Inflammation Biomarkers Provide Complementary Information in Alzheimer’s Disease

Michopoulou,

Prosser,

Dickson

et al. 2023

JAD

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Background: Single photon emission tomography (SPECT) can detect early changes in brain perfusion to support the diagnosis of dementia. Inflammation is a driver for dementia progression and measures of inflammation may further support dementia diagnosis. Objective: In this study, we assessed whether combining imaging with markers of inflammation improves prediction of the likelihood of Alzheimer’s disease (AD). Methods: We analyzed 91 participants datasets (Institutional Ethics Approval 20/NW/0222). AD biomarkers and markers of inflammation were measured in cerebrospinal fluid. Statistical parametric mapping was used to quantify brain perfusion differences in perfusion SPECT images. Logistic regression models were trained to evaluate the ability of imaging and inflammation markers, both individually and combined, to predict AD. Results: Regional perfusion reduction in the precuneus and medial temporal regions predicted Aβ42 status. Increase in inflammation markers predicted tau and neurodegeneration. Matrix metalloproteneinase-10, a marker of blood-brain barrier regulation, was associated with perfusion reduction in the right temporal lobe. Adenosine deaminase, an enzyme involved in sleep homeostasis and inflammation, was the strongest predictor of neurodegeneration with an odds ratio of 10.3. The area under the receiver operator characteristic curve for the logistic regression model was 0.76 for imaging and 0.76 for inflammation. Combining inflammation and imaging markers yielded an area under the curve of 0.85. Conclusions: Study results showed that markers of brain perfusion imaging and markers of inflammation provide complementary information in AD evaluation. Inflammation markers better predict tau status while perfusion imaging measures represent amyloid status. Combining imaging and inflammation improves AD prediction.

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Biomarkers of Inflammation Increase with Tau and Neurodegeneration but not with Amyloid-β in a Heterogenous Clinical Cohort

Cited by 3 publications

References 41 publications

Translational control of microglial inflammatory and neurodegenerative responses

Translational control of microglial inflammatory and neurodegenerative responses

Involvement of inflammation in the medial temporal region in the development of agitation in Alzheimer's disease: an in vivo positron emission tomography study

Perfusion Imaging and Inflammation Biomarkers Provide Complementary Information in Alzheimer’s Disease

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