Evidence map›Paper›PMID 40958169›Full record

ArticleAnnals of clinical and translational neurology2025

Functional Connectivity Associations With Markers of Disease Progression in GRN Pathogenic Variant Carriers.

Taru M Flagan, Stephanie A Chu, Suvi Häkkinen, Liwen Zhang, David McFall, Jonathan D Rohrer, Jesse A Brown, Alex J Lee, Kristen Fernhoff, Lorenzo Pasquini and 37 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Annals of clinical and translational neurology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Article
  2. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

47 authors.

Taru M FlaganDepartment of Neurology, Weill Institute for Neurosciences, Memory and Aging Center, University of California, San Francisco, San Francisco, California, USA.ORCID https://orcid.org/0009-0003-6566-9696
Stephanie A ChuDepartment of Neurology, Weill Institute for Neurosciences, Memory and Aging Center, University of California, San Francisco, San Francisco, California, USA.
Suvi HäkkinenDepartment of Neurology, Weill Institute for Neurosciences, Memory and Aging Center, University of California, San Francisco, San Francisco, California, USA.
Liwen ZhangDepartment of Neurology, Weill Institute for Neurosciences, Memory and Aging Center, University of California, San Francisco, San Francisco, California, USA.
David McFallDepartment of Pathology, University of California, San Francisco, San Francisco, California, USA.
Jonathan D RohrerDementia Research Centre, UCL Queen Square Institute of Neurology, University College London, London, UK.ORCID https://orcid.org/0000-0002-6155-8417
Jesse A BrownDepartment of Neurology, Weill Institute for Neurosciences, Memory and Aging Center, University of California, San Francisco, San Francisco, California, USA.
Alex J LeeDepartment of Neurology, Weill Institute for Neurosciences, Memory and Aging Center, University of California, San Francisco, San Francisco, California, USA.
Kristen FernhoffDepartment of Neurology, Weill Institute for Neurosciences, Memory and Aging Center, University of California, San Francisco, San Francisco, California, USA.
Lorenzo PasquiniDepartment of Neurology, Weill Institute for Neurosciences, Memory and Aging Center, University of California, San Francisco, San Francisco, California, USA.
Katherine P RankinDepartment of Neurology, Weill Institute for Neurosciences, Memory and Aging Center, University of California, San Francisco, San Francisco, California, USA.
Maria Luisa MandelliDepartment of Neurology, Weill Institute for Neurosciences, Memory and Aging Center, University of California, San Francisco, San Francisco, California, USA.
Maria Luisa Gorno-TempiniDepartment of Neurology, Weill Institute for Neurosciences, Memory and Aging Center, University of California, San Francisco, San Francisco, California, USA.
Jennifer S YokoyamaDepartment of Neurology, Weill Institute for Neurosciences, Memory and Aging Center, University of California, San Francisco, San Francisco, California, USA.
Virginia E SturmDepartment of Neurology, Weill Institute for Neurosciences, Memory and Aging Center, University of California, San Francisco, San Francisco, California, USA.
Brian ApplebyDepartment of Neurology, Case Western Reserve University, Cleveland, Ohio, USA.
Bradford C DickersonDepartment of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Kimiko Domoto-ReillyDepartment of Neurology, University of Washington, Seattle, Washington, USA.
Tatiana ForoudDepartment of Medical and Molecular Genetics, Indiana University, Indianapolis, Indiana, USA.
Daniel H GeschwindDepartment of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
Nupur GhoshalDepartment of Neurology, Washington University School of Medicine, St Louis, Missouri, USA.
Neill R Graff-RadfordDepartment of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
Ging-Yuek Robin HsiungDivision of Neurology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Eric J HuangDepartment of Pathology, University of California, San Francisco, San Francisco, California, USA.
Edward HueyDepartment of Psychiatry and Human Behavior, Brown University, Providence, Rhode Island, USA.
Kejal KantarciDepartment of Neurology, Mayo Clinic, Rochester, Minnesota, USA.ORCID https://orcid.org/0000-0002-8001-2081
Irene LitvanDepartment of Neurosciences, University of California, San Diego, La Jolla, California, USA.
Ian R MackenzieDepartment of Pathology, University of British Columbia, Vancouver, British Columbia, Canada.
Mario F MendezDepartment of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
Chiadi U OnyikeDepartment of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Leonard PetrucelliDepartment of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
Eliana Marisa RamosDepartment of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
Erik D RobersonDepartment of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Julio C RojasDepartment of Neurology, Weill Institute for Neurosciences, Memory and Aging Center, University of California, San Francisco, San Francisco, California, USA.
Maria Carmela TartagliaTanz Centre for Research in Neurodegenerative Diseases, Division of Neurology, University of Toronto, Toronto, Ontario, Canada.ORCID https://orcid.org/0000-0002-5944-8497
Arthur W TogaLaboratory of Neuroimaging (LONI), USC Stevens Neuroimaging and Informatics Institute, University of Southern California, Los Angeles, California, USA.
Sandra WeintraubDepartment of Psychiatry and Behavioral Sciences, Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Northwestern Feinberg School of Medicine, Chicago, Illinois, USA.
Leah K ForsbergDepartment of Psychiatry and Human Behavior, Brown University, Providence, Rhode Island, USA.
Hilary W HeuerDepartment of Neurology, Weill Institute for Neurosciences, Memory and Aging Center, University of California, San Francisco, San Francisco, California, USA.
Brad F BoeveDepartment of Psychiatry and Human Behavior, Brown University, Providence, Rhode Island, USA.
Adam L BoxerDepartment of Neurology, Weill Institute for Neurosciences, Memory and Aging Center, University of California, San Francisco, San Francisco, California, USA.
Howard J RosenDepartment of Neurology, Weill Institute for Neurosciences, Memory and Aging Center, University of California, San Francisco, San Francisco, California, USA.
Bruce L MillerDepartment of Neurology, Weill Institute for Neurosciences, Memory and Aging Center, University of California, San Francisco, San Francisco, California, USA.
Fermin MorenoCognitive Disorders Unit, Department of Neurology, Donostia University Hospital, San Sebastian, Spain.
William W SeeleyDepartment of Neurology, Weill Institute for Neurosciences, Memory and Aging Center, University of California, San Francisco, San Francisco, California, USA.
Suzee E LeeDepartment of Neurology, Weill Institute for Neurosciences, Memory and Aging Center, University of California, San Francisco, San Francisco, California, USA.
ALLFTD Consortium

Funding

The Alzheimer's Clinical Trial Consortium - Down Syndrome Network (ACTC- DSN)U24AG057437 · NIA · UNIVERSITY OF SOUTHERN CALIFORNIA · PI Paul S. Aisen, RONALD C PETERSEN · 2018 to 2026
$198.4M
Technology and Remote Assessment CoreU19AG063911 · NIA · MAYO CLINIC ROCHESTER · PI Bradley F Boeve · 2019 to 2026
$120.9M
National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD)U24AG021886 · NIA · INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS · PI TATIANA M. FOROUD · 2002 to 2026
$119.8M
TDP-43 Loss-of-Function: Biology to BiomarkersP01AG019724 · NIA · UNIVERSITY OF PENNSYLVANIA · PI Jennifer Merrilees · 2002 to 2026
$67.2M
The Alzheimer's Disease Tau Platform Clinical TrialR01AG078457 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI BOXER, ADAM L., JOHNSON, KEITH A. · 2023 to 2024
$60.7M
Project 2: Biomarker Analysis, Non-Genetic Risk Factors, and Their Genetic InteractionsU19AG079774 · NIA · UNIVERSITY OF PENNSYLVANIA · PI HELENA Chang CHUI, Gyungah Jun · 2023 to 2026
$39.4M
Research Education ComponentP30AG062422 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Gil Dan Rabinovici · 2019 to 2026
$36.9M
Research Education ComponentP30AG062677 · NIA · MAYO CLINIC ROCHESTER · PI NILUFER ERTEKIN-TANER · 2019 to 2026
$33.5M
University of Washington Alzheimer's Disease Research CenterP30AG066509 · NIA · UNIVERSITY OF WASHINGTON · PI Thomas J. Grabowski · 2020 to 2026
$29.0M
USCADRC Diversity Supplement PachicanoP30AG066530 · NIA · UNIVERSITY OF SOUTHERN CALIFORNIA · PI HELENA Chang CHUI, ARTHUR W TOGA · 2020 to 2026
$27.8M
The Four Repeat Tauopathy Neuroimaging InitiativeR01AG038791 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI BOXER, ADAM L. · 2010 to 2020
$18.1M
Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS)U01AG045390 · NIA · MAYO CLINIC ROCHESTER · PI BOEVE, BRADLEY F, ROSEN, HOWARD J · 2014 to 2018
$16.9M
Alzheimer's AssociationAssociation for Frontotemporal DegenerationBluefield Project to Cure FTDGlobal Brain Health InstituteMary Oakley FoundationNIA NIH HHS 5P30AG0062677NIA NIH HHS K99 AG065457NIA NIH HHS K99AG065457NIA NIH HHS P01 AG019724NIA NIH HHS P01AG019724NIA NIH HHS P30 AG062422NIA NIH HHS P30AG062422NIA NIH HHS P30 AG062677NIA NIH HHS P30 AG066509NIA NIH HHS P30 AG066530NIA NIH HHS R00 AG065457NIA NIH HHS R00AG065457NIA NIH HHS R01 AG038791NIA NIH HHS R01AG038791NIA NIH HHS R01 AG052496NIA NIH HHS R01AG052496NIA NIH HHS R01 AG057234NIA NIH HHS R01AG057234NIA NIH HHS R01 AG057462NIA NIH HHS R01AG057462NIA NIH HHS R01 AG058233NIA NIH HHS R01AG058233NIA NIH HHS R01 AG062588NIA NIH HHS R01AG062588NIA NIH HHS R01 AG071756NIA NIH HHS R01AG071756NIA NIH HHS R01 AG073482NIA NIH HHS R01AG073482NIA NIH HHS R01 AG075775NIA NIH HHS R01AG075775NIA NIH HHS R01 AG078457NIA NIH HHS R01AG078457NIA NIH HHS R01 AG080396NIA NIH HHS R01AG080396NIA NIH HHS R01 AG080469NIA NIH HHS R01AG080469NIA NIH HHS R21 AG068757NIA NIH HHS R21AG068757NIA NIH HHS R56 AG075744NIA NIH HHS R56AG075744NIA NIH HHS RF1 AG077557NIA NIH HHS RF1AG077557NIA NIH HHS RF1NS050915NIA NIH HHS U01 AG045390NIA NIH HHS U01AG045390NIA NIH HHS U19 AG063911NIA NIH HHS U19AG063911NIA NIH HHS U19 AG079774NIA NIH HHS U19AG079774NIA NIH HHS U24 AG021886NIA NIH HHS U24AG021886NIA NIH HHS U24 AG057437NIA NIH HHS U24AG057437NIDA NIH HHS 75N95022C00031NIDCD NIH HHS K24 DC015544NIDCD NIH HHS K24DC015544NINDS NIH HHS 1R21NS114764-01A1NINDS NIH HHS 1RF1NS128908NINDS NIH HHS P01NS08497NINDS NIH HHS R01 NS131604NINDS NIH HHS R01NS131604NINDS NIH HHS R21 NS114764NINDS NIH HHS R25 NS098999NINDS NIH HHS R25NS098999NINDS NIH HHS R35 NS097273NINDS NIH HHS R35NS097273NINDS NIH HHS RF1 NS050915NINDS NIH HHS RF1 NS100440NINDS NIH HHS RF1NS100440NINDS NIH HHS RF1 NS128908NINDS NIH HHS U01 NS100610NINDS NIH HHS U01NS100610NINDS NIH HHS U54 NS092089NINDS NIH HHS U54NS092089NINDS NIH HHS U54 NS123743NINDS NIH HHS U54NS123743NINDS NIH HHS U54 NS123985NINDS NIH HHS U54NS123985Robert and Nancy Hall Brain Research FundTau Consortium
6 · The paper itself

Abstract

objectiveAutosomal dominant progranulin (GRN) pathogenic variants are a genetic cause of frontotemporal lobar degeneration. Though clinical trials for GRN-related therapies are underway, there is an unmet need for biomarkers that can predict symptom onset and track disease progression. We previously showed that asymptomatic GRN variant carriers exhibit thalamocortical hyperconnectivity that increases with age, presumably as they are approaching symptom onset. Whether hyperconnectivity arises concomitantly with markers of neurodegeneration remains unclear.

methodsUtilizing T1 and task-free functional magnetic resonance imaging from 49 asymptomatic and 26 symptomatic GRN variant carriers, we determined the relationships between functional connectivity, as measured by voxelwise whole-brain degree, and GRN-relevant markers of disease progression, including plasma neurofilament light chain concentrations, cerebrospinal fluid complement C1q and C3b protein levels, obsessive-compulsive disorder symptom severity, and gray matter volume.

resultsNeurofilament light chain concentrations were associated with frontotemporoparietal and thalamic hyperconnectivity in asymptomatic GRN variant carriers and extensive regions of atrophy in symptomatic carriers. Complement levels were associated with regions of hyperconnectivity, but not gray matter volume, in symptomatic carriers. Obsessive-compulsive disorder symptom severity was associated with hypoconnectivity across all GRN carriers. Asymptomatic carriers with thalamic hyperconnectivity tended to have lower gray matter volume in the bilateral insula and left lateral parietal cortex, early regions of atrophy in GRN-frontotemporal dementia.

interpretationIn asymptomatic carriers, the co-occurrence of hyperconnectivity, high neurofilament light chain, and low gray matter volume suggests that functional hyperconnectivity may portend the onset of clinical decline. These findings point toward hyperconnectivity as an indicator of approaching symptomatic onset.

Indexed as

ConnectomeFrontotemporal Lobar DegenerationNerve NetProgranulinsAdultAgedBiomarkersDisease ProgressionFemaleGray MatterHeterozygoteHumansMagnetic Resonance ImagingMaleMiddle AgedNeurofilament ProteinsBiomarkersGRN protein, humanNeurofilament ProteinsProgranulinsfrontotemporal dementia with GRN pathogenic variantsfunctional connectivitymarkers of disease progression

Identifiers

PMID40958169
PMCPMC12698941

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.