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Cited by 61Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsDementia and Cognitive Impairment Research

Microglial Activation and Connectivity in Alzheimer Disease and Aging

Open access
Rauchmann, Boris‐Stephan, Brendel, Matthias, Franzmeier, Nicolai, Trappmann, Lena, Zaganjori, Mirlind, Ersoezlue, Ersin, Morenas‐Rodriguez, Estrella, Guersel, Selim +27 more·2022·Annals of Neurology
DOI 10.1002/ana.26465

Published version of a preprint

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Abstract

Objective: Alzheimer disease (AD) is characterized by amyloid β (Aβ) plaques and neurofibrillary tau tangles, but increasing evidence suggests that neuroinflammation also plays a key role, driven by the activation of microglia. Aβ and tau pathology appear to spread along pathways of highly connected brain regions, but it remains elusive whether microglial activation follows a similar distribution pattern. Here, we assess whether connectivity is associated with microglia activation patterns. Methods: We included 32 Aβ‐positive early AD subjects (18 women, 14 men) and 18 Aβ‐negative age‐matched healthy controls (10 women, 8 men) from the prospective ActiGliA (Activity of Cerebral Networks, Amyloid and Microglia in Aging and Alzheimer's Disease) study. All participants underwent microglial activation positron emission tomography (PET) with the third‐generation mitochondrial 18 kDa translocator protein (TSPO) ligand [ 18 F]GE‐180 and magnetic resonance imaging (MRI) to measure resting‐state functional and structural connectivity. Results: We found that inter‐regional covariance in TSPO‐PET and standardized uptake value ratio was preferentially distributed along functionally highly connected brain regions, with MRI structural connectivity showing a weaker association with microglial activation. AD patients showed increased TSPO‐PET tracer uptake bilaterally in the anterior medial temporal lobe compared to controls, and higher TSPO‐PET uptake was associated with cognitive impairment and dementia severity in a disease stage‐dependent manner. Interpretation: Microglial activation distributes preferentially along highly connected brain regions, similar to tau pathology. These findings support the important role of microglia in neurodegeneration, and we speculate that pathology spreads throughout the brain along vulnerable connectivity pathways. ANN NEUROL 2022;92:768–781

AI snapshot

Written from the paper’s full text.

TL;DR

In early Aβ-positive Alzheimer disease (AD) and age-matched controls, microglial activation measured with [18F]GE-180 TSPO-PET covaried preferentially along functionally highly connected brain regions, with weaker structural-connectivity associations. AD patients showed increased TSPO-PET uptake in bilateral anterior medial temporal lobe, and higher uptake was quadratically associated with cognitive impairment and dementia severity.

Key findings

  • TSPO-PET covariance was associated with functional connectivity in AD (β = 0.35, p < 0.001) and controls (β = 0.47, p < 0.001); structural connectivity showed weaker associations in both groups (β = 0.06, p < 0.001).
  • AD patients had increased TSPO-PET tracer uptake compared with Aβ-negative controls in the bilateral anterior medial temporal lobe (p < 0.001).
  • Anterior medial temporal lobe TSPO-PET SUVR showed quadratic associations with CDR SOB (R² = 0.39, p < 0.001), CERAD-NB total score (R² = 0.20, p < 0.017), and MMSE (R² = 0.15, p = 0.049), suggesting disease-stage-dependent microglial activation.
  • In AD, TSPO-PET uptake in anterior medial temporal regions was quadratically associated with CSF sTREM2 (R² = 0.39, p < 0.02); no association was found for the whole cohort (R² = 0.05, p < 0.49) or controls separately (R² = 0.12, p < 0.48).

Methods

  • Baseline data from the prospective, longitudinal, observational ActiGliA study; included 32 Aβ-positive early AD subjects (18 women, 14 men) and 18 Aβ-negative age-matched healthy controls (10 women, 8 men).
  • Participants underwent TSPO-PET with [18F]GE-180, MRI resting-state functional connectivity, and DTI structural connectivity; CSF biomarkers and APOE/TSPO genotyping were also assessed. Only high-affinity binders and mixed-affinity binders were included in PET analyses, with 6 low-affinity binders excluded, and analyses adjusted for binding status.
  • Imaging analyses used the Brainnetome 246-region atlas; TSPO-PET SUVR covariance matrices were calculated per diagnostic group and related to functional and structural connectivity using linear regression. Voxelwise group comparisons used SPM12, and clinical associations used quadratic regression in SPSS.

Limitations

  • The paper states a relatively small sample size restricts statistical power for some analyses, the data are exploratory and should be confirmed in independent datasets, and the small sample may explain nonsignificant group differences in CSF sTREM2.
  • The paper states no pathological verification was available to confirm clinical diagnoses; limited blood-brain barrier passage of [18F]GE-180 must be acknowledged; late static SUVR with an intracerebral reference tissue may be biased by cerebral blood flow alterations and attenuation of a polymorphism effect; and AD patients were predominantly early stage, so cross-sectional group differences may be diluted if multiple activity peaks occur as AD progresses.
  • Evident from the text: the cross-sectional design cannot establish that microglial activation spreads along connectivity pathways or determine causal direction between tau, microglial activation, and connectivity; the current analysis did not directly assess spatial colocalization of microglial and tau PET, although follow-up tau-PET is planned.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1002/ana.26465

Cites

73 of 73 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 16 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In AD patients, more strongly interconnected brain regions showed a greater covariance in TSPO-PET (β = 0.35, p < 0.001).

    “Supporting our hypothesis, we found that more strongly interconnected brain regions showed a greater covariance in TSPO-PET in AD (β = 0.35, p < 0.001) and in the control group (β = 0.47, p < 0.001).”
    Quote in the paperSubstantial claim
  • Findingown data

    In healthy controls, functional connectivity from seed regions with higher TSPO-PET uptake was associated with higher TSPO-PET uptake in target regions (β = 0.57, p < 0.001).

    “For seed regions with higher levels of TSPO-PET uptake, functional connectivity was associated with higher levels of TSPO-PET uptake in the target regions and vice versa in the AD group (β = 0.83, p < 0.001) and healthy controls (β = 0.57, p < 0.001; Fig 6A).”
    Quote in the paperSubstantial claim
  • Findingown data

    Structural connectivity analysis did not reveal any significant positive or negative associations between hot spot or cold spot seed regions and TSPO-PET uptake in target regions.

    “The same analysis based on structural connectivity did not reveal any significant positive or negative associations (see Fig 7B).”
    Quote in the paperSubstantial claim
  • Findingown data

    AD patients showed more pathological CSF biomarker concentrations compared to controls (lower Aβ42 and Aβ42/40 ratio, higher ptau181 and ttau).

    “As expected, AD patients showed more pathological CSF biomarker concentrations compared to the control group (lower Aβ42 and Aβ42/40 ratio, higher ptau181 and ttau).”
    Quote in the paperSubstantial claim
  • Findingown data

    In cognitively normal controls, more strongly interconnected brain regions showed a greater covariance in TSPO-PET (β = 0.47, p < 0.001).

    “Supporting our hypothesis, we found that more strongly interconnected brain regions showed a greater covariance in TSPO-PET in AD (β = 0.35, p < 0.001) and in the control group (β = 0.47, p < 0.001).”
    Quote in the paperSubstantial claim
  • May combine two claims. 19
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 13

  • May combine two claims.

    Findingown data

    Structural and functional connectivity were decreased on the whole brain level and within the default mode network in AD patients compared with healthy controls.

    “structural and functional connectivity were decreased on the whole brain level and within the default mode network comparing AD patients with healthy controls (results not shown).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    AD subjects had significantly worse cognitive performance (CERAD-NB and MMSE) and higher CDR SOB ratings than cognitively normal controls (p < 0.001).

    “Compared to cognitively normal controls, AD subjects had significantly (p < 0.001) worse cognitive performance (CERAD-NB and MMSE) and higher CDR Sum of the Boxes (SOB) ratings.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    For regions with high microglial activation (seed), a higher functional connectivity was associated with higher microglial activation (target) and vice versa.

    “For regions with high microglial activation (seed) a higher functional connectivity was associated with higher microglial activation (target) and vice versa.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    AD patients showed increased TSPO-PET tracer uptake bilaterally in the anterior medial temporal lobe compared to Aβ-negative healthy controls (p < 0.001).

    “AD patients showed increased TSPO-PET tracer uptake bilaterally in the anterior medial temporal lobe compared to controls”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the analysis of the association between functional connectivity and microglial activation in hot spots and cold spots, there was a significant positive beta in the hot spot and a significant negative beta in the cold spot area.

    “In the analysis of the association between functional connectivity and microglial activation in the hot spots and cold spots, we observed a significant positive beta in the hot spot and a significant negative beta in the cold spot area”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Despite lack of a significant difference in sTREM2 between the two diagnostic groups, a quadratic association between sTREM2 concentration and TSPO-PET uptake was revealed.

    “Despite lack of a significant difference in sTREM2 between the two diagnostic groups, a quadratic association between sTREM2 concentration and TSPO-PET uptake was revealed.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In this study, [18F]GE-180-PET binding was higher in HABs compared to MABs, although not significantly.

    “Furthermore, data in this study showed higher [18F]GE-180-PET binding in HABs compared to MABs, although not significantly.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    sTREM2 levels were higher in AD compared to controls, but the difference did not reach statistical significance in an analysis of variance adjusted for age, sex, and education.

    “sTREM2 levels were higher in AD compared to controls, but this numerical difference did not reach statistical significance in an analysis of variance adjusted for age, sex, and education”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Microglial activation distributes preferentially along highly connected brain regions, similar to tau pathology.

    “Microglial activation distributes preferentially along highly connected brain regions, similar to tau pathology.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    All TSPO-PET analyses were adjusted for TSPO binding status.

    “All TSPO-PET analyses were adjusted for binding status.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    An inflammatory profile of the aged human brain has been demonstrated by molecular analysis, CSF, neuroimaging, and histological studies, suggesting enhanced microglial activation in healthy aging independently from Aβ pathology.

    “An inflammatory profile of the aged human brain has been demonstrated by molecular analysis, CSF, neuroimaging, and histological studies, suggesting enhanced microglial activation in healthy aging independently from Aβ pathology.47”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Late static SUVRs were calculated with an intracerebral reference tissue, which is a limitation of the quantification approach of TSPO-PET.

    “As a limitation of the quantification approach of TSPO-PET, we note that late static SUVRs were calculated with an intracerebral reference tissue.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationown data

    These observations indicate a functional burnout of microglia with increasing activity.

    “where we interpreted these observations as an indication of a functional burnout of microglia with increasing activity.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    Only HABs and MABs were included in the PET analyses, with 6 LABs excluded.

    “Only HABs and MABs were included in the PET analyses, with 6 LABs excluded.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Microglia phagocytose tau and therefore might play an important role in spreading of tau pathology throughout the brain.

    “Microglia phagocytose tau and therefore might play an important role in spreading of tau pathology throughout the brain.51,52”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [51]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [52]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Study design and conductreasoning

    No pathological verification was available to confirm the clinical diagnoses; however, a careful biomarker-based stratification and in-depth phenotyping minimizes the likelihood of diagnostic misclassification.

    “No pathological verification was available to confirm the clinical diagnoses; however, a careful biomarkerbased stratification and in-depth phenotyping minimizes the likelihood of diagnostic misclassification.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Study design and conductnone given

    The assessed cohort is the largest and best characterized dataset of its kind with both TSPO and amyloid PET, CSF biomarkers, and resting-state fMRI available for all participants.

    “However, to the best of our knowledge, the assessed cohort is the largest and best characterized dataset of its kind with both TSPO and amyloid PET, CSF biomarkers, and resting-state fMRI available for all participants.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Microglia is directly involved in the regulation of neural activity, providing a negative feedback mechanism operating similarly to inhibitory neurons.

    “Recently, it has been shown that microglia is directly involved in the regulation of neural activity, providing a negative feedback mechanism operating similarly to inhibitory neurons.56”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    The small sample size may also be the reason for the nonsignificant group differences for CSF sTREM2.

    “The small sample size may also be the reason for the nonsignificant group differences for CSF sTREM2.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Regions with low microglia activation are sparsely connected with other brain regions exhibiting lower microglial activation, whereas regions with high microglia activation seem to be highly connected with other regions exhibiting high microglia activation.

    “suggesting that regions with low microglia activation are sparsely connected with other brain regions exhibiting lower microglial activation, whereas regions with high microglia activation seem to be highly connected with other regions exhibiting high microglia activation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductcitation

    Limited blood-brain barrier passing of [18F]GE-180 is a limitation, but previous data indicated strong agreement with immunohistochemistry in AD models and patterns matching known topology of microglial activation in neurodegenerative diseases.

    “Limited blood-brain barrier passing of [ 18 F]GE-180 needs to be acknowledged, but our previous data indicated strong agreement with immunohistochemistry in AD models 58 and patterns matching known topology of microglial activation in neurodegenerative diseases.10,59”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [58]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [10]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [59]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    TSPO-PET uptake is associated with age, with increased uptake in healthy older participants.

    “Furthermore, TSPO-PET uptake was shown to be associated with age, with increased uptake in healthy older participants.[48][49][50]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [48]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [49]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [50]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    The analysis was controlled for HAB and MAB binding status to avoid possible confounding.

    “To avoid possible confounding, we controlled our analysis for HAB and MAB binding status.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    Group differences of microglial activation may have been diluted in the cross-sectional analysis if several activity peaks exist as AD progresses.

    “group differences of microglial activation may have been diluted in the cross-sectional analysis if several activity peaks exist as AD progresses.63”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Study design and conductreasoning

    Our quantification approach may be subject to some bias by cerebral blood flow alterations and attenuation of a polymorphism effect.

    “Thus, we acknowledge that our quantification approach may be subject to some bias by cerebral blood flow alterations and attenuation of a polymorphism effect.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductcitation

    Although late static SUVRs showed suitability for TSPO-PET quantification, this method was inferior to scaling by a late-tissue-to-blood ratio.

    “Although late static SUVRs showed suitability for TSPO-PET quantification, 62 this method was inferior to scaling by a late-tissue-to-blood ratio.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [62]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Study design and conductown data

    There were no differences in age, sex, body weight, and years of education between AD patients and controls.

    “There were no differences in age, sex, body weight, and years of education.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A similar pattern was found in our previous study in 4-repeat tauopathies.

    “A similar pattern was found in our previous study in 4-repeat tauopathies, 10”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    All results were adjusted for age, sex, and education with false discovery rate correction for multiple comparisons, with a significance level of p < 0.05.

    “All results were adjusted for age, sex, and education with false discovery rate correction for multiple comparisons, with a significance level of p < 0.05.”
    Quote in the paperSubstantial claim
29 of 29

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Cold-spot connectivity interpretation reverses the reported association

    Minor

    The reported negative association means that greater connectivity to a low-uptake seed is associated with lower uptake in target regions. The discussion instead says regions with low activation are sparsely connected to other low-activation regions.

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Authors
Rauchmann, B., Brendel, M., Franzmeier, N., Trappmann, L., Zaganjori, M., Ersoezlue, E., Morenas‐Rodriguez, E., Guersel, S., Burow, L., Kurz, C., Haeckert, J., Tatò, M., Utecht, J., Papazov, B., Pogarell, O., Janowitz, D., Buerger, K., Ewers, M., Palleis, C., Weidinger, E., Biechele, G., Schuster, S., Finze, A., Eckenweber, F., Rupprecht, R., Rominger, A., Goldhardt, O., Grimmer, T., Keeser, D., Stoecklein, S., Dietrich, O., Bartenstein, P., Levin, J., Höglinger, G., & Perneczky, R.
Affiliations
  • German Center for Neurodegenerative Diseases (DE)
  • Munich Cluster for Systems Neurology (DE)
  • Institut für Schlaganfall- und Demenzforschung (DE)
  • Ludwig-Maximilians-Universität München (DE)
  • German Center for Neurodegenerative Diseases Munich Germany
  • University of Augsburg (DE)
  • University of Regensburg (DE)
  • University of Bern (CH)
  • TUM Klinikum (DE)
Corresponding author
Perneczky, Robert
ORCID
Venue
Annals of Neurology
Publisher
Wiley
Published
2022-08-25
Volume
92
Issue
5
Pages
768-781
ISSN
  • 0364-5134 (ISSN-L)
  • 1531-8249
DOI
10.1002/ana.26465
OpenAlex
W4289344793
Semantic Scholar
3dc05209e71555465f7b95a4c6a8430b78f3991b
Cited by
61
References
67
Citations by year
2026: 11 · 2025: 14 · 2024: 20 · 2023: 14 · 2022: 2
FWCI
3.55
Type
journal article
Language
en
Open access
Licence
Locations
  • Annals of Neurology (publishedVersion, cc-by-nc)
  • medRxiv (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • University of Regensburg Publication Server (University of Regensburg) (acceptedVersion)
  • BORIS (University Library Bern) (submittedVersion, cc-by-nc)
  • Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion, cc-by-nc)
  • mediaTUM (Technical University of Munich) (submittedVersion)
  • DZNE Pub (submittedVersion, other-oa)
  • OPUS (Augsburg University) (submittedVersion, cc-by-nc)
  • University of Regensburg Publication Server (University of Regensburg)
Funders
  • Deutsche Forschungsgemeinschaft (EXC 2145, EXC 2145SyNergy, 390857198)
  • Deutsches Zentrum für Neurodegenerative Erkrankungen
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, microglial activation, neuroinflammation, amyloid-beta, tau pathology, brain connectivity, resting-state functional connectivity, structural connectivity, translocator protein (TSPO), [18F]GE-180, amyloid PET, dementia severity, cognitive impairment
MeSH terms
Alzheimer Disease, Brain, Female, Humans, Ligands, Male, Prospective Studies, Amyloid beta-Peptides, tau Proteins, Microglia, Receptors, GABA, Positron-Emission Tomography, Plaque, Amyloid

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