Characterizing Heterogeneity in Neuroimaging, Cognition, Clinical Symptoms, and Genetics among Patients with Late-Life Depression

iSTAGING consortium, ADNI, BIOCARD, and BLSA

doi:10.1001/jamapsychiatry.2022.0020

Characterizing Heterogeneity in Neuroimaging, Cognition, Clinical Symptoms, and Genetics among Patients with Late-Life Depression

iSTAGING consortium, ADNI, BIOCARD, and BLSA

Center for Systems Genomics, Pennsylvania State University, University Park, Pennsylvania, USA.
Research Department of Epidemiology and Public Health, University College London, UK; School of Psychology, University of East London, London, UK.
Health Psychology Section, Psychology Department, Institute of Psychology, Psychiatry and Neuroscience, King's College London, United Kingdom.
1Department of Hepatology, Imperial College London, London, UK. 2Institute of Liver Studies at King's College School of Medicine at King's College Hospital, London, UK. 3Institute of Human Health and Performance, University College London, London, UK. 4Department of Asthma Allergy and Lung Biology, King's College London, London, UK. 5Division of Critical Care Medicine, University of Alberta, Edmonton, Canada.
California State University
Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
1] Department of Medical Genetics, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3 [2] Biomedical Research Centre, The University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
1] Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA. [2] Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri, USA. [3] Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA.
Department of Pediatrics, Indiana University School of Medicine
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Cognitive Science Department, Johns Hopkins University, Baltimore, MD USA.
Laboratory of Genetics and Genomics, National Institute on Aging, National Institute of Health, Baltimore, 20892, MD, USA.

Research output: Contribution to journal › Article › peer-review

71 Citations (Scopus)

Abstract

Importance: Late-life depression (LLD) is characterized by considerable heterogeneity in clinical manifestation. Unraveling such heterogeneity might aid in elucidating etiological mechanisms and support precision and individualized medicine. Objective: To cross-sectionally and longitudinally delineate disease-related heterogeneity in LLD associated with neuroanatomy, cognitive functioning, clinical symptoms, and genetic profiles. Design, Setting, and Participants: The Imaging-Based Coordinate System for Aging and Neurodegenerative Diseases (iSTAGING) study is an international multicenter consortium investigating brain aging in pooled and harmonized data from 13 studies with more than 35000 participants, including a subset of individuals with major depressive disorder. Multimodal data from a multicenter sample (N = 996), including neuroimaging, neurocognitive assessments, and genetics, were analyzed in this study. A semisupervised clustering method (heterogeneity through discriminative analysis) was applied to regional gray matter (GM) brain volumes to derive dimensional representations. Data were collected from July 2017 to July 2020 and analyzed from July 2020 to December 2021. Main Outcomes and Measures: Two dimensions were identified to delineate LLD-associated heterogeneity in voxelwise GM maps, white matter (WM) fractional anisotropy, neurocognitive functioning, clinical phenotype, and genetics. Results: A total of 501 participants with LLD (mean [SD] age, 67.39 [5.56] years; 332 women) and 495 healthy control individuals (mean [SD] age, 66.53 [5.16] years; 333 women) were included. Patients in dimension 1 demonstrated relatively preserved brain anatomy without WM disruptions relative to healthy control individuals. In contrast, patients in dimension 2 showed widespread brain atrophy and WM integrity disruptions, along with cognitive impairment and higher depression severity. Moreover, 1 de novo independent genetic variant (rs13120336; chromosome: 4, 186387714; minor allele, G) was significantly associated with dimension 1 (odds ratio, 2.35; SE, 0.15; P = 3.14 ×10⁸) but not with dimension 2. The 2 dimensions demonstrated significant single-nucleotide variant-based heritability of 18% to 27% within the general population (N = 12518 in UK Biobank). In a subset of individuals having longitudinal measurements, those in dimension 2 experienced a more rapid longitudinal change in GM and brain age (Cohen f²= 0.03; P =.02) and were more likely to progress to Alzheimer disease (Cohen f²= 0.03; P =.03) compared with those in dimension 1 (N = 1431 participants and 7224 scans from the Alzheimer's Disease Neuroimaging Initiative [ADNI], Baltimore Longitudinal Study of Aging [BLSA], and Biomarkers for Older Controls at Risk for Dementia [BIOCARD] data sets). Conclusions and Relevance: This study characterized heterogeneity in LLD into 2 dimensions with distinct neuroanatomical, cognitive, clinical, and genetic profiles. This dimensional approach provides a potential mechanism for investigating the heterogeneity of LLD and the relevance of the latent dimensions to possible disease mechanisms, clinical outcomes, and responses to interventions..

Original language	English
Pages (from-to)	464-474
Number of pages	11
Journal	JAMA Psychiatry
Volume	79
Issue number	5
DOIs	https://doi.org/10.1001/jamapsychiatry.2022.0020
Publication status	Published - 1 May 2022

Keywords

Alzheimer Disease/diagnostic imaging
Brain/diagnostic imaging
Cognition
Depression
Depressive Disorder, Major/diagnostic imaging
Female
Humans
Longitudinal Studies
Magnetic Resonance Imaging/methods
Male
Neuroimaging

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10.1001/jamapsychiatry.2022.0020

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@article{c4f177e11f9444daa5af48899326f5c7,

title = "Characterizing Heterogeneity in Neuroimaging, Cognition, Clinical Symptoms, and Genetics among Patients with Late-Life Depression",

abstract = "Importance: Late-life depression (LLD) is characterized by considerable heterogeneity in clinical manifestation. Unraveling such heterogeneity might aid in elucidating etiological mechanisms and support precision and individualized medicine. Objective: To cross-sectionally and longitudinally delineate disease-related heterogeneity in LLD associated with neuroanatomy, cognitive functioning, clinical symptoms, and genetic profiles. Design, Setting, and Participants: The Imaging-Based Coordinate System for Aging and Neurodegenerative Diseases (iSTAGING) study is an international multicenter consortium investigating brain aging in pooled and harmonized data from 13 studies with more than 35000 participants, including a subset of individuals with major depressive disorder. Multimodal data from a multicenter sample (N = 996), including neuroimaging, neurocognitive assessments, and genetics, were analyzed in this study. A semisupervised clustering method (heterogeneity through discriminative analysis) was applied to regional gray matter (GM) brain volumes to derive dimensional representations. Data were collected from July 2017 to July 2020 and analyzed from July 2020 to December 2021. Main Outcomes and Measures: Two dimensions were identified to delineate LLD-associated heterogeneity in voxelwise GM maps, white matter (WM) fractional anisotropy, neurocognitive functioning, clinical phenotype, and genetics. Results: A total of 501 participants with LLD (mean [SD] age, 67.39 [5.56] years; 332 women) and 495 healthy control individuals (mean [SD] age, 66.53 [5.16] years; 333 women) were included. Patients in dimension 1 demonstrated relatively preserved brain anatomy without WM disruptions relative to healthy control individuals. In contrast, patients in dimension 2 showed widespread brain atrophy and WM integrity disruptions, along with cognitive impairment and higher depression severity. Moreover, 1 de novo independent genetic variant (rs13120336; chromosome: 4, 186387714; minor allele, G) was significantly associated with dimension 1 (odds ratio, 2.35; SE, 0.15; P = 3.14 ×108) but not with dimension 2. The 2 dimensions demonstrated significant single-nucleotide variant-based heritability of 18% to 27% within the general population (N = 12518 in UK Biobank). In a subset of individuals having longitudinal measurements, those in dimension 2 experienced a more rapid longitudinal change in GM and brain age (Cohen f2= 0.03; P =.02) and were more likely to progress to Alzheimer disease (Cohen f2= 0.03; P =.03) compared with those in dimension 1 (N = 1431 participants and 7224 scans from the Alzheimer's Disease Neuroimaging Initiative [ADNI], Baltimore Longitudinal Study of Aging [BLSA], and Biomarkers for Older Controls at Risk for Dementia [BIOCARD] data sets). Conclusions and Relevance: This study characterized heterogeneity in LLD into 2 dimensions with distinct neuroanatomical, cognitive, clinical, and genetic profiles. This dimensional approach provides a potential mechanism for investigating the heterogeneity of LLD and the relevance of the latent dimensions to possible disease mechanisms, clinical outcomes, and responses to interventions..",

keywords = "Alzheimer Disease/diagnostic imaging, Brain/diagnostic imaging, Cognition, Depression, Depressive Disorder, Major/diagnostic imaging, Female, Humans, Longitudinal Studies, Magnetic Resonance Imaging/methods, Male, Neuroimaging",

author = "{iSTAGING consortium, ADNI, BIOCARD, and BLSA} and Junhao Wen and Fu, {Cynthia H Y} and Duygu Tosun and Yogasudha Veturi and Zhijian Yang and Ahmed Abdulkadir and Elizabeth Mamourian and Dhivya Srinivasan and Ioanna Skampardoni and Ashish Singh and Hema Nawani and Jingxuan Bao and Guray Erus and Haochang Shou and Mohamad Habes and Jimit Doshi and Erdem Varol and Mackin, {R Scott} and Aristeidis Sotiras and Yong Fan and Saykin, {Andrew J} and Sheline, {Yvette I} and Li Shen and Ritchie, {Marylyn D} and Wolk, {David A} and Marilyn Albert and Resnick, {Susan M} and Christos Davatzikos",

note = "Funding Information: grants from the National Institutes of Health during the conduct of the study and outside the submitted work and support from Johnson and Johnson outside the submitted work. Dr Sotiras reported support from TheraPanacea Equity outside the submitted work. Dr Saykin reported grants from the National Institutes of Health paid to Indiana University during the conduct of the study. Dr Saykin receives support from multiple National Institutes of Health grants, has received support from Avid Radiopharmaceuticals, a subsidiary of Eli Lilly (in kind contribution of PET tracer precursor); Bayer Oncology (scientific advisory board); Siemens Medical Solutions (dementia advisory board); Springer-Nature Publishing (editorial office support as Editor-in-Chief, Brain Imaging and Behavior). Dr Wolk served as site principle investigator for studies by Biogen, Merck, and Eli Lilly/Avid; has received consulting fees from General Electric Healthcare and Neuronix; is on the DSMB for a trial sponsored by Functional Neuromodulation; and has consulted for Qynapse. Dr Albert reported grants from the National Institute on Aging during the conduct of the study and other support from Eli Lilly Consultant outside the submitted work. No other disclosures were reported. Funding/Support: This work was supported in part by National Institutes of Health grants 1RF1-AG054409-01 and U01-AG068057. Alzheimer{\textquoteright}s Disease Neuroimaging Initiative (ADNI) is supported by National Institutes of Health grants U01-AG024904 and RC2-AG036535. The Biomarkers for Older Controls at Risk for Dementia (BIOCARD) study is supported by National Institutes of Health grant U19-AG033655. The Baltimore Longitudinal Study of Aging (BLSA) is supported by the Intramural Research Program of the National Institute on Aging and research and development contract HHSN-260-2004-00012C. This research has been conducted using the UK Biobank Resource under application number 35148. Publisher Copyright: {\textcopyright} 2022 American Medical Association. All rights reserved.",

year = "2022",

month = may,

day = "1",

doi = "10.1001/jamapsychiatry.2022.0020",

language = "English",

volume = "79",

pages = "464--474",

journal = "JAMA Psychiatry",

issn = "2168-622X",

publisher = "American Medical Association",

number = "5",

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TY - JOUR

T1 - Characterizing Heterogeneity in Neuroimaging, Cognition, Clinical Symptoms, and Genetics among Patients with Late-Life Depression

AU - iSTAGING consortium, ADNI, BIOCARD, and BLSA

AU - Wen, Junhao

AU - Fu, Cynthia H Y

AU - Tosun, Duygu

AU - Veturi, Yogasudha

AU - Yang, Zhijian

AU - Abdulkadir, Ahmed

AU - Mamourian, Elizabeth

AU - Srinivasan, Dhivya

AU - Skampardoni, Ioanna

AU - Singh, Ashish

AU - Nawani, Hema

AU - Bao, Jingxuan

AU - Erus, Guray

AU - Shou, Haochang

AU - Habes, Mohamad

AU - Doshi, Jimit

AU - Varol, Erdem

AU - Mackin, R Scott

AU - Sotiras, Aristeidis

AU - Fan, Yong

AU - Saykin, Andrew J

AU - Sheline, Yvette I

AU - Shen, Li

AU - Ritchie, Marylyn D

AU - Wolk, David A

AU - Albert, Marilyn

AU - Resnick, Susan M

AU - Davatzikos, Christos

N1 - Funding Information: grants from the National Institutes of Health during the conduct of the study and outside the submitted work and support from Johnson and Johnson outside the submitted work. Dr Sotiras reported support from TheraPanacea Equity outside the submitted work. Dr Saykin reported grants from the National Institutes of Health paid to Indiana University during the conduct of the study. Dr Saykin receives support from multiple National Institutes of Health grants, has received support from Avid Radiopharmaceuticals, a subsidiary of Eli Lilly (in kind contribution of PET tracer precursor); Bayer Oncology (scientific advisory board); Siemens Medical Solutions (dementia advisory board); Springer-Nature Publishing (editorial office support as Editor-in-Chief, Brain Imaging and Behavior). Dr Wolk served as site principle investigator for studies by Biogen, Merck, and Eli Lilly/Avid; has received consulting fees from General Electric Healthcare and Neuronix; is on the DSMB for a trial sponsored by Functional Neuromodulation; and has consulted for Qynapse. Dr Albert reported grants from the National Institute on Aging during the conduct of the study and other support from Eli Lilly Consultant outside the submitted work. No other disclosures were reported. Funding/Support: This work was supported in part by National Institutes of Health grants 1RF1-AG054409-01 and U01-AG068057. Alzheimer’s Disease Neuroimaging Initiative (ADNI) is supported by National Institutes of Health grants U01-AG024904 and RC2-AG036535. The Biomarkers for Older Controls at Risk for Dementia (BIOCARD) study is supported by National Institutes of Health grant U19-AG033655. The Baltimore Longitudinal Study of Aging (BLSA) is supported by the Intramural Research Program of the National Institute on Aging and research and development contract HHSN-260-2004-00012C. This research has been conducted using the UK Biobank Resource under application number 35148. Publisher Copyright: © 2022 American Medical Association. All rights reserved.

PY - 2022/5/1

Y1 - 2022/5/1

N2 - Importance: Late-life depression (LLD) is characterized by considerable heterogeneity in clinical manifestation. Unraveling such heterogeneity might aid in elucidating etiological mechanisms and support precision and individualized medicine. Objective: To cross-sectionally and longitudinally delineate disease-related heterogeneity in LLD associated with neuroanatomy, cognitive functioning, clinical symptoms, and genetic profiles. Design, Setting, and Participants: The Imaging-Based Coordinate System for Aging and Neurodegenerative Diseases (iSTAGING) study is an international multicenter consortium investigating brain aging in pooled and harmonized data from 13 studies with more than 35000 participants, including a subset of individuals with major depressive disorder. Multimodal data from a multicenter sample (N = 996), including neuroimaging, neurocognitive assessments, and genetics, were analyzed in this study. A semisupervised clustering method (heterogeneity through discriminative analysis) was applied to regional gray matter (GM) brain volumes to derive dimensional representations. Data were collected from July 2017 to July 2020 and analyzed from July 2020 to December 2021. Main Outcomes and Measures: Two dimensions were identified to delineate LLD-associated heterogeneity in voxelwise GM maps, white matter (WM) fractional anisotropy, neurocognitive functioning, clinical phenotype, and genetics. Results: A total of 501 participants with LLD (mean [SD] age, 67.39 [5.56] years; 332 women) and 495 healthy control individuals (mean [SD] age, 66.53 [5.16] years; 333 women) were included. Patients in dimension 1 demonstrated relatively preserved brain anatomy without WM disruptions relative to healthy control individuals. In contrast, patients in dimension 2 showed widespread brain atrophy and WM integrity disruptions, along with cognitive impairment and higher depression severity. Moreover, 1 de novo independent genetic variant (rs13120336; chromosome: 4, 186387714; minor allele, G) was significantly associated with dimension 1 (odds ratio, 2.35; SE, 0.15; P = 3.14 ×108) but not with dimension 2. The 2 dimensions demonstrated significant single-nucleotide variant-based heritability of 18% to 27% within the general population (N = 12518 in UK Biobank). In a subset of individuals having longitudinal measurements, those in dimension 2 experienced a more rapid longitudinal change in GM and brain age (Cohen f2= 0.03; P =.02) and were more likely to progress to Alzheimer disease (Cohen f2= 0.03; P =.03) compared with those in dimension 1 (N = 1431 participants and 7224 scans from the Alzheimer's Disease Neuroimaging Initiative [ADNI], Baltimore Longitudinal Study of Aging [BLSA], and Biomarkers for Older Controls at Risk for Dementia [BIOCARD] data sets). Conclusions and Relevance: This study characterized heterogeneity in LLD into 2 dimensions with distinct neuroanatomical, cognitive, clinical, and genetic profiles. This dimensional approach provides a potential mechanism for investigating the heterogeneity of LLD and the relevance of the latent dimensions to possible disease mechanisms, clinical outcomes, and responses to interventions..

AB - Importance: Late-life depression (LLD) is characterized by considerable heterogeneity in clinical manifestation. Unraveling such heterogeneity might aid in elucidating etiological mechanisms and support precision and individualized medicine. Objective: To cross-sectionally and longitudinally delineate disease-related heterogeneity in LLD associated with neuroanatomy, cognitive functioning, clinical symptoms, and genetic profiles. Design, Setting, and Participants: The Imaging-Based Coordinate System for Aging and Neurodegenerative Diseases (iSTAGING) study is an international multicenter consortium investigating brain aging in pooled and harmonized data from 13 studies with more than 35000 participants, including a subset of individuals with major depressive disorder. Multimodal data from a multicenter sample (N = 996), including neuroimaging, neurocognitive assessments, and genetics, were analyzed in this study. A semisupervised clustering method (heterogeneity through discriminative analysis) was applied to regional gray matter (GM) brain volumes to derive dimensional representations. Data were collected from July 2017 to July 2020 and analyzed from July 2020 to December 2021. Main Outcomes and Measures: Two dimensions were identified to delineate LLD-associated heterogeneity in voxelwise GM maps, white matter (WM) fractional anisotropy, neurocognitive functioning, clinical phenotype, and genetics. Results: A total of 501 participants with LLD (mean [SD] age, 67.39 [5.56] years; 332 women) and 495 healthy control individuals (mean [SD] age, 66.53 [5.16] years; 333 women) were included. Patients in dimension 1 demonstrated relatively preserved brain anatomy without WM disruptions relative to healthy control individuals. In contrast, patients in dimension 2 showed widespread brain atrophy and WM integrity disruptions, along with cognitive impairment and higher depression severity. Moreover, 1 de novo independent genetic variant (rs13120336; chromosome: 4, 186387714; minor allele, G) was significantly associated with dimension 1 (odds ratio, 2.35; SE, 0.15; P = 3.14 ×108) but not with dimension 2. The 2 dimensions demonstrated significant single-nucleotide variant-based heritability of 18% to 27% within the general population (N = 12518 in UK Biobank). In a subset of individuals having longitudinal measurements, those in dimension 2 experienced a more rapid longitudinal change in GM and brain age (Cohen f2= 0.03; P =.02) and were more likely to progress to Alzheimer disease (Cohen f2= 0.03; P =.03) compared with those in dimension 1 (N = 1431 participants and 7224 scans from the Alzheimer's Disease Neuroimaging Initiative [ADNI], Baltimore Longitudinal Study of Aging [BLSA], and Biomarkers for Older Controls at Risk for Dementia [BIOCARD] data sets). Conclusions and Relevance: This study characterized heterogeneity in LLD into 2 dimensions with distinct neuroanatomical, cognitive, clinical, and genetic profiles. This dimensional approach provides a potential mechanism for investigating the heterogeneity of LLD and the relevance of the latent dimensions to possible disease mechanisms, clinical outcomes, and responses to interventions..

KW - Alzheimer Disease/diagnostic imaging

KW - Brain/diagnostic imaging

KW - Cognition

KW - Depression

KW - Depressive Disorder, Major/diagnostic imaging

KW - Female

KW - Humans

KW - Longitudinal Studies

KW - Magnetic Resonance Imaging/methods

KW - Male

KW - Neuroimaging

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U2 - 10.1001/jamapsychiatry.2022.0020

DO - 10.1001/jamapsychiatry.2022.0020

M3 - Article

C2 - 35262657

AN - SCOPUS:85125837552

SN - 2168-622X

VL - 79

SP - 464

EP - 474

JO - JAMA Psychiatry

JF - JAMA Psychiatry

IS - 5

ER -

Characterizing Heterogeneity in Neuroimaging, Cognition, Clinical Symptoms, and Genetics among Patients with Late-Life Depression

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Keywords

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