Evidence map›Paper›PMID 34810247›Full record

ArticleNeurology2022

Association of Neurofibrillary Tangle Distribution With Age at Onset-Related Clinical Heterogeneity in Alzheimer Disease: An Autopsy Study.

Denis S Smirnov, David P Salmon, Douglas Galasko, Vanessa S Goodwill, Lawrence A Hansen, Yu Zhao, Steven D Edland, Gabriel C Léger, Guerry M Peavy, Diane M Jacobs and 3 more

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PubMed Full text at PMC Publisher
In one paragraph

Article in Neurology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
18citing papers in PubMed, 1 pooled it
2.5field-weighted citation impact, top 10% of its field
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

18 citing papers in PubMed, 1 synthesis or guideline pooled it, 27 citations in OpenAlex.

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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

13 authors at 1 institution in 1 country.

Denis S SmirnovFrom the Departments of Neurosciences (D.S.S., D.P.S., D.G., G.C.L., G.M.P., D.M.J., R.R., A.H.), Pathology (V.S.G., L.A.H., D.P.P., A.H.), and Family Medicine and Public Health (Y.Z., S.D.E.), University of California, San Diego; and VA San Diego Healthcare System (D.G., R.R., A.H.), CA.
David P SalmonFrom the Departments of Neurosciences (D.S.S., D.P.S., D.G., G.C.L., G.M.P., D.M.J., R.R., A.H.), Pathology (V.S.G., L.A.H., D.P.P., A.H.), and Family Medicine and Public Health (Y.Z., S.D.E.), University of California, San Diego; and VA San Diego Healthcare System (D.G., R.R., A.H.), CA.
Douglas GalaskoFrom the Departments of Neurosciences (D.S.S., D.P.S., D.G., G.C.L., G.M.P., D.M.J., R.R., A.H.), Pathology (V.S.G., L.A.H., D.P.P., A.H.), and Family Medicine and Public Health (Y.Z., S.D.E.), University of California, San Diego; and VA San Diego Healthcare System (D.G., R.R., A.H.), CA.
Vanessa S GoodwillFrom the Departments of Neurosciences (D.S.S., D.P.S., D.G., G.C.L., G.M.P., D.M.J., R.R., A.H.), Pathology (V.S.G., L.A.H., D.P.P., A.H.), and Family Medicine and Public Health (Y.Z., S.D.E.), University of California, San Diego; and VA San Diego Healthcare System (D.G., R.R., A.H.), CA.
Lawrence A HansenFrom the Departments of Neurosciences (D.S.S., D.P.S., D.G., G.C.L., G.M.P., D.M.J., R.R., A.H.), Pathology (V.S.G., L.A.H., D.P.P., A.H.), and Family Medicine and Public Health (Y.Z., S.D.E.), University of California, San Diego; and VA San Diego Healthcare System (D.G., R.R., A.H.), CA.
Yu ZhaoFrom the Departments of Neurosciences (D.S.S., D.P.S., D.G., G.C.L., G.M.P., D.M.J., R.R., A.H.), Pathology (V.S.G., L.A.H., D.P.P., A.H.), and Family Medicine and Public Health (Y.Z., S.D.E.), University of California, San Diego; and VA San Diego Healthcare System (D.G., R.R., A.H.), CA.
Steven D EdlandFrom the Departments of Neurosciences (D.S.S., D.P.S., D.G., G.C.L., G.M.P., D.M.J., R.R., A.H.), Pathology (V.S.G., L.A.H., D.P.P., A.H.), and Family Medicine and Public Health (Y.Z., S.D.E.), University of California, San Diego; and VA San Diego Healthcare System (D.G., R.R., A.H.), CA.
Gabriel C LégerFrom the Departments of Neurosciences (D.S.S., D.P.S., D.G., G.C.L., G.M.P., D.M.J., R.R., A.H.), Pathology (V.S.G., L.A.H., D.P.P., A.H.), and Family Medicine and Public Health (Y.Z., S.D.E.), University of California, San Diego; and VA San Diego Healthcare System (D.G., R.R., A.H.), CA.ORCID 0000-0001-7900-3957
Guerry M PeavyFrom the Departments of Neurosciences (D.S.S., D.P.S., D.G., G.C.L., G.M.P., D.M.J., R.R., A.H.), Pathology (V.S.G., L.A.H., D.P.P., A.H.), and Family Medicine and Public Health (Y.Z., S.D.E.), University of California, San Diego; and VA San Diego Healthcare System (D.G., R.R., A.H.), CA.
Diane M JacobsFrom the Departments of Neurosciences (D.S.S., D.P.S., D.G., G.C.L., G.M.P., D.M.J., R.R., A.H.), Pathology (V.S.G., L.A.H., D.P.P., A.H.), and Family Medicine and Public Health (Y.Z., S.D.E.), University of California, San Diego; and VA San Diego Healthcare System (D.G., R.R., A.H.), CA.
Robert RissmanFrom the Departments of Neurosciences (D.S.S., D.P.S., D.G., G.C.L., G.M.P., D.M.J., R.R., A.H.), Pathology (V.S.G., L.A.H., D.P.P., A.H.), and Family Medicine and Public Health (Y.Z., S.D.E.), University of California, San Diego; and VA San Diego Healthcare System (D.G., R.R., A.H.), CA.ORCID 0000-0001-9245-8278
Donald P PizzoFrom the Departments of Neurosciences (D.S.S., D.P.S., D.G., G.C.L., G.M.P., D.M.J., R.R., A.H.), Pathology (V.S.G., L.A.H., D.P.P., A.H.), and Family Medicine and Public Health (Y.Z., S.D.E.), University of California, San Diego; and VA San Diego Healthcare System (D.G., R.R., A.H.), CA.
Annie HinikerFrom the Departments of Neurosciences (D.S.S., D.P.S., D.G., G.C.L., G.M.P., D.M.J., R.R., A.H.), Pathology (V.S.G., L.A.H., D.P.P., A.H.), and Family Medicine and Public Health (Y.Z., S.D.E.), University of California, San Diego; and VA San Diego Healthcare System (D.G., R.R., A.H.), CA. ahiniker@health.ucsd.edu.
University of California System · US

Funding

UCSD Shiley-Marcos Alzheimer's Disease Research Center P30P30AG062429 · NIA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI JAMES B BREWER · 2019 to 2026
$34.9M
Chemical-Genetic Approaches to Define Lrrk2 Kinase Function in Parkinson DiseaseK08NS090633 · NINDS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI HINIKER, ANNIE E · 2014 to 2018
$1.1M
Repetition Priming Deficits and Locus Coeruleus Dysfunction in Alzheimer's DiseaseF30AG063440 · NIA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI SMIRNOV, DENIS · 2019 to 2022
$179k
NIA NIH HHS F30 AG063440NIA NIH HHS P30 AG062429NINDS NIH HHS K08 NS090633
6 · The paper itself

Abstract

BACKGROUND AND

objectivePatients with earlier age at onset of sporadic Alzheimer disease (AD) are more likely than those with later onset to present with atypical clinical and cognitive features. We sought to determine whether this age-related clinical and cognitive heterogeneity is mediated by different topographic distributions of tau-aggregate neurofibrillary tangles (NFTs) or by variable amounts of concomitant non-AD neuropathology.

methodsThe relative distribution of NFT density in hippocampus and midfrontal neocortex was calculated, and α-synuclein, TAR DNA binding protein 43 (TDP-43), and microvascular copathologies were staged, in patients with severe AD and age at onset of 51-60 (n = 40), 61-70 (n = 41), and >70 (n = 40) years. Regression, mediation, and mixed effects models examined relationships of pathologic findings with clinical features and longitudinal cognitive decline.

resultsPatients with later age at onset of AD were less likely to present with nonmemory complaints (odds ratio [OR] 0.46 per decade, 95% confidence interval [CI] 0.22-0.88), psychiatric symptoms (β = -0.66, 95% CI -1.15 to -0.17), and functional impairment (β = -1.25, 95% CI -2.34 to -0.16). TDP-43 (OR 2.00, 95% CI 1.23-3.35) and microvascular copathology (OR 2.02, 95% CI 1.24-3.40) were more common in later onset AD, and α-synuclein copathology was not related to age at onset. NFT density in midfrontal cortex (β = -0.51, 95% CI -0.72 to -0.31) and midfrontal/hippocampal NFT ratio (β = -0.18, 95% CI -0.26 to -0.10) were lower in those with later age at onset. Executive function (β = 0.48, 95% CI 0.09-0.90) and visuospatial cognitive deficits (β = 0.97, 95% CI 0.46-1.46) were less impaired in patients with later age at onset. Mediation analyses showed that the effect of age at onset on severity of executive function deficits was mediated by midfrontal/hippocampal NFT ratio (β = 0.21, 95% CI 0.08-0.38) and not by concomitant non-AD pathologies. Midfrontal/hippocampal NFT ratio also mediated an association between earlier age at onset and faster decline on tests of global cognition, executive function, and visuospatial abilities. DISCUSSION: Worse executive dysfunction and faster cognitive decline in people with sporadic AD with earlier rather than later age at onset is mediated by greater relative midfrontal neocortical to hippocampal NFT burden and not by concomitant non-AD neuropathology.

Indexed as

Alzheimer DiseaseNeocortexAge of OnsetAutopsyHumansNeurofibrillary Tanglestau Proteinstau Proteins

Identifiers

PMID34810247
PMCPMC8826459
OpenAlexW3216929962

What OpenQuestion holds

Textmetadata
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Registered trials

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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.