Evidence map›Paper›PMID 37961381›Full record

ArticlemedRxiv : the preprint server for health sciences2023

FTLD targets brain regions expressing recently evolved genes.

Lorenzo Pasquini, Felipe L Pereira, Sahba Seddighi, Yi Zeng, Yongbin Wei, Ignacio Illán-Gala, Sarat C Vatsavayai, Adit Friedberg, Alex J Lee, Jesse A Brown and 14 more

Open access · greenAbstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in medRxiv : the preprint server for health sciences, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed, 1 pooled it
–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

1 citing paper in PubMed, 1 synthesis or guideline pooled it, 1 citations in OpenAlex.

  1. Pooled it
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

24 authors at 7 institutions in 4 countries.

Lorenzo PasquiniDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
Felipe L PereiraDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
Sahba SeddighiNational Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
Yi ZengDepartment of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
Yongbin WeiSchool of Artificial Intelligence, Beijing University of Posts and Telecommunications, Beijing, China.
Ignacio Illán-GalaDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
Sarat C VatsavayaiDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
Adit FriedbergDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
Alex J LeeDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
Jesse A BrownDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
Salvatore SpinaDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
Lea T GrinbergDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
Daniel W SirkisDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
Luke W BonhamDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
Jennifer S YokoyamaDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
Adam L BoxerDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
Joel H KramerDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
Howard J RosenDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
Jack HumphreyNash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Aaron D GitlerDepartment of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
Bruce L MillerDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
Katherine S PollardGladstone Institute of Data Science and Biotechnology, San Francisco, CA, USA.
Michael E WardNational Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
William W SeeleyDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
University of California, San Francisco · USNational Institute of Neurological Disorders and Stroke · USStanford University · USAllen Institute for Brain Science · USBeijing University of Posts and Telecommunications · CNGladstone Institutes · USUniversitat Autònoma de Barcelona · ES

Funding

Technology and Remote Assessment CoreU19AG063911 · NIA · MAYO CLINIC ROCHESTER · PI ADAM L. BOXER, Bradley F Boeve · 2019 to 2026
$120.9M
Early Onset AD Consortium - the LEAD Study (LEADS)U01AG057195 · NIA · INDIANA UNIVERSITY INDIANAPOLIS · PI APOSTOLOVA, LIANA G, CARRILLO, MARIA C · 2018 to 2023
$70.3M
TDP-43 Loss-of-Function: Biology to BiomarkersP01AG019724 · NIA · UNIVERSITY OF PENNSYLVANIA · PI BRUCE L MILLER · 2002 to 2026
$67.2M
Research Education ComponentP30AG062422 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI HOWARD J ROSEN · 2019 to 2026
$36.9M
Clinical Features and Neuropathological Basis of Sleep Wake Behavior in Alzheimer's and PSPR01AG060477 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Lea Tenenholz Grinberg, Thomas C Neylan · 2019 to 2026
$8.2M
Resolving single-cell brain regulatory elements with bulk data supervised modelsR01MH123178 · NIMH · J. DAVID GLADSTONE INSTITUTES · PI POLLARD, KATHERINE S. · 2020 to 2023
$2.4M
Neuropathological changes underlying clinical heterogeneity in Alzheimer diseaseK24AG053435 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI GRINBERG, LEA TENENHOLZ · 2016 to 2025
$1.8M
Dynamic neural systems underlying socioemotional functionR00AG065457 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI PASQUINI, LORENZO · 2022 to 2024
$898k
Dynamic neural systems underlying socioemotional functionK99AG065457 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI PASQUINI, LORENZO · 2020 to 2021
$250k
NIA NIH HHS K24 AG053435NIA NIH HHS K99 AG065457NIA NIH HHS P01 AG019724NIA NIH HHS P30 AG062422NIA NIH HHS R00 AG065457NIA NIH HHS R01 AG060477NIA NIH HHS U01 AG057195NIA NIH HHS U19 AG063911NIMH NIH HHS R01 MH123178
6 · The paper itself

Abstract

In frontotemporal lobar degeneration (FTLD), pathological protein aggregation is associated with a decline in human-specialized social-emotional and language functions. Most disease protein aggregates contain either TDP-43 (FTLD-TDP) or tau (FTLD-tau). Here, we explored whether FTLD targets brain regions that express genes containing human accelerated regions (HARs), conserved sequences that have undergone positive selection during recent human evolution. To this end, we used structural neuroimaging from patients with FTLD and normative human regional transcriptomic data to identify genes expressed in FTLD-targeted brain regions. We then integrated primate comparative genomic data to test our hypothesis that FTLD targets brain regions expressing recently evolved genes. In addition, we asked whether genes expressed in FTLD-targeted brain regions are enriched for genes that undergo cryptic splicing when TDP-43 function is impaired. We found that FTLD-TDP and FTLD-tau subtypes target brain regions that express overlapping and distinct genes, including many linked to neuromodulatory functions. Genes whose normative brain regional expression pattern correlated with FTLD cortical atrophy were strongly associated with HARs. Atrophy-correlated genes in FTLD-TDP showed greater overlap with TDP-43 cryptic splicing genes compared with atrophy-correlated genes in FTLD-tau. Cryptic splicing genes were enriched for HAR genes, and vice versa, but this effect was due to the confounding influence of gene length. Analyses performed at the individual-patient level revealed that the expression of HAR genes and cryptically spliced genes within putative regions of disease onset differed across FTLD-TDP subtypes. Overall, our findings suggest that FTLD targets brain regions that have undergone recent evolutionary specialization and provide intriguing potential leads regarding the transcriptomic basis for selective vulnerability in distinct FTLD molecular-anatomical subtypes.

Indexed as

cryptic exonFrontotemporal lobar degenerationgene expressionhuman accelerated regionstauTDP-43

Identifiers

PMID37961381
PMCPMC10635220
OpenAlexW4388011128

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

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.