Aging and Disease Course: Contributions to Lifespan Neurobiology of Schizophrenia

NCT04951700 | Active Not Recruiting

• 2 other identifiers: STU-2021-0413R01MH127317
• Study Type: observational
• Target: 194
• Locations: 1 country
• Sites: 1

Brief Summary

The 2020 NIMH Strategic Plan for Research calls for investigations targeting neurobiology of mental illness across the lifespan. Growing evidence suggests that lifespan neurobiology of schizophrenia (SZ) incorporates two distinct dimensions: aging and disease course. However, their clinical correlates, associated biomarker trajectories, and implications for treatment are unknown. This study will investigate differential aspects of SZ neurobiology captured by aging and disease course, in order to develop specific biomarkers which may offer actionable targets for SZ stage-dependent intervention. The study is predicated on a novel mechanistic Model of SZ Trajectories across the Adult Lifespan, positing distinct biological fingerprints within the anterior limbic system for aging and disease course in SZ: (1) alterations in the circuit's function and structure that occur earlier in the lifespan and are larger in magnitude than the alterations expected with normal aging (accelerated aging dimension); and (2) regionally-specific anterior limbic "hyperactivity" in early SZ, with a subsequent transformation into "hypoactivity" in advanced SZ (disease course dimension). In a sample of SZ and matched healthy controls (n=168, 84/group) aged 18-75 years the investigators will ascertain a broad panel of biomarkers \[via multimodal brain imaging: optimized 1H-MRS, high-resolution task-based fMRI, perfusion (Vascular Space Occupancy) and structural MRI\], along with comprehensive cognitive and clinical assessments. All measures will be acquired at baseline and repeated at 2-year longitudinal follow-up. Using cutting-edge computational approaches, the study will examine (i) effects of aging and SZ course on anterior limbic system biomarkers; (ii) lifespan trajectories for different biomarkers; (iii) patterns of limbic system biomarkers in age- and SZ course-based subgroups (e.g., Younger vs. Older, Early-Course vs. Advanced SZ), as well as in data-driven subgroups (e.g., those with vs. without accelerated aging profiles); and (iv) associations between biomarkers and cognitive and clinical outcomes. This research will advance the field by providing novel biomarkers that capture unique neurobiological contributions of aging and disease course in SZ, and will motivate future studies on SZ mechanisms across the lifespan and development of precision treatments.

Conditions

Schizophrenia; Aging; Disease Course; Biomarker; Neuroimaging; Cognitive Dysfunction

Outcome Measures

Primary Outcomes (5)

• Effects of aging and disease course on excitatory and inhibitory biomarkers in the anterior limbic system in schizophrenia (SZ) and healthy controls (CON) (Aim1 Outcomes).

  SZ and CON (n=84/group) will undergo novel triple-refocusing Magnetic Resonance Spectroscopy (1H-MRS) with Glutamate, GABA and broader metabolite measures from the anterior limbic system structures (bilateral hippocampi (Hipp) and medial prefrontal cortex (mPFC)), at baseline and 2-year longitudinal follow-up. Hypothesis 1.1: SZ will show declines in Glutamate and GABA in the Hipp and mPFC along the lifespan, with significantly earlier and larger reductions than those observed in CON. Hypothesis 1.2: SZ will show distinct Hipp-mPFC Glutamate and GABA markers along the disease course, with significantly elevated or equivalent Glutamate, and reduced GABA levels, in early SZ, and reduced Glutamate and GABA in advanced SZ, compared to CON.

  2 years

• Effects of aging and disease course on intrinsic activity biomarkers [VASO-based Cerebral Blood Volume (CBV)] in the anterior limbic circuit in SZ and CON (Aim2 Outcome).

  SZ and CON will undergo high-resolution brain perfusion imaging (VASO) at baseline and 2-year longitudinal follow-up. Hypothesis 2.1: SZ will show declines in Hipp-mPFC CBV along the lifespan, with significantly earlier and larger reductions than those observed in CON. Hypothesis 2.2: SZ will show distinct Hipp-mPFC CBV signatures across the disease course, with significantly elevated or equivalent CBV in early SZ, and reduced CBV in advanced SZ, compared to CON.

  2 years

• Effects of aging and disease course on memory task-driven activation biomarkers [fMRI with Pattern Separation task] in the anterior limbic circuit in SZ and CON (Aim2 Outcome).

  SZ and CON will undergo high-resolution brain fMRI with associational memory (Pattern Separation) task at baseline and 2-year longitudinal follow-up. Hypothesis 2.1: SZ will show declines in regional activation (BOLD signal) with Lure\>Repetition contrast along the lifespan, with significantly earlier and larger reductions than those in CON. Hypothesis 2.2: Within the disease course dimension, early SZ will show increased activation with a loss of activation modulation (e.g., increased BOLD signal with both Lures and Repetitions), with a subsequent decline in activation in mid-course and advanced SZ, compared to CON. We predict that these activation effects will be preset in the Hipp DG/CA3 and in a broader circuit supporting pattern separation operations (i.e., mPFC, parahippocampal, retrosplenial cortex).

  2 years

• Effects of aging and disease course on cortical thickness biomarkers in the anterior limbic system in SZ and CON (Aim3 Outcomes).

  SZ and CON will undergo high-resolution structural brain MRI, at baseline and 2-year longitudinal follow-up. Hypothesis 3.1: SZ will show declines in FreeSurfer-based cortical thickness in Hipp, mPFC and broader fronto-temporal regions across the lifespan, with significantly earlier and larger reductions than those in CON. Hypothesis 3.2: SZ will show distinct fronto-temporal alterations along the disease course, with modestly reduced cortical thickness in early SZ and larger reductions in advanced SZ, compared to CON.

  2 years

• Effects of aging and disease course on gray matter volume biomarkers in the anterior limbic system in SZ and CON (Aim3 Outcomes).

  SZ and CON will undergo high-resolution structural brain MRI, at baseline and 2-year longitudinal follow-up. Hypothesis 3.1: SZ will show declines in gray matter volumes (measured with FreeSurfer and Voxel-Based Morphometry) in Hipp, mPFC and broader fronto-temporal regions across the lifespan, with significantly earlier and larger reductions than those in CON. Hypothesis 3.2: SZ will show distinct fronto-temporal alterations along the disease course, with modestly reduced gray matter volume in early SZ and larger reductions in advanced SZ, compared to CON.

  2 years

Other Outcomes (1)

• Associations between brain MRI and cognitive and clinical measures.

  2 years

Study Arms (2)

Schizophrenia

Women and men, all races and ethnicities, aged 18-65 years, meeting diagnostic DSM-5 criteria for schizophrenia or schizoaffective disorder.

Other: Other

Healthy Controls

Women and men, all races and ethnicities, aged 18-75 years, without personal history of lifetime psychiatric disorders, or a family history of psychotic disorders in 1st- or 2nd-degree relatives.

Other: Other

Interventions

Other OTHER

This is not an intervention study

Healthy Controls; Schizophrenia

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Study population will include individuals with psychotic disorders (schizophrenia or schizoaffective disorder) and healthy comparison participants (individuals without personal history of lifetime psychiatric disorders, or a family history of psychotic disorders in 1st- or 2nd-degree relatives). Participants will be women and men, all races and ethnicities. Participants with schizophrenia/schizoaffective disorder will be aged 18-65 years, healthy comparison participants will be aged 18-75 years.

You may qualify if:

• years of age (SZ); 18-75 years of age (CON)
• Women and men
• All races and ethnicities
• Psychiatric diagnoses:
• Patient participants (SZ): Meet DSM-5 criteria for schizophrenia or schizoaffective disorder Healthy control participants (CON): No personal history of lifetime psychiatric disorders, or a family history of psychotic disorders in 1st-or 2nd- degree relatives
• Able to read, speak, and understand English
• Able and willing to provide written informed consent; and willing to commit to the study protocol, including 2-year longitudinal follow-up

You may not qualify if:

• Compromised cognitive function: Both SZ and CON participants: Estimated premorbid intellectual ability \<75 age-corrected score on Wide Range Achievement Test-4/Word Reading Subtest (WRAT-4) CON participants: \<26 score on the Montreal Cognitive Assessment (MoCA)
• Neurological or medical disorder that may affect brain function (history of stroke, head injury with a loss of consciousness \>10 min, seizure disorder, AIDS, poorly controlled hypertension, poorly controlled diabetes, decompensated lung disease, etc.)
• Co-morbid DSM-5 diagnosis of drug/alcohol use disorder in prior 3 months
• Current treatment with benzodiazepine or non-benzodiazepine sedatives/hypnotics, and/or anticonvulsants
• Presence of ferromagnetic objects in body
• Weight or body size exceeding MRI scanner capacity \[\>300 lbs\]
• Claustrophobia in MRI scanner
• Pregnant women
• Breastfeeding women (VASO scan will not be administered. All other imaging modalities are safe to administer.)
• Impaired kidney function: Glomerular Filtration Rate (GFR) \< 30 ml/min/1.73m2 (VASO scan will not be administered due to an association between Gadolinium-based MR contrast use and Nephrogenic Systemic Fibrosis in individuals with severely impaired renal function. All other imaging modalities are safe to administer.)
• History of hypersensitivity to any MRI contrast agent (VASO scan will not be administered. All other imaging modalities are safe to administer.)

Sponsors & Collaborators

• University of Texas Southwestern Medical Center: lead
• National Institute of Mental Health (NIMH): collaborator

Study Sites (1)

UT Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

MeSH Terms

Conditions

Schizophrenia; Disease Progression; Cognitive Dysfunction

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Cognition Disorders; Neurocognitive Disorders

Study Officials

• Elena I. Ivleva, MD, PhD

  UT Southwestern Medical Center, Department of Psychiatry

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Target Duration: 2 Years
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: ASSOC PROFESSOR

Study Record Dates

• First Submitted: June 1, 2021
• First Posted: July 7, 2021
• Study Start: July 1, 2021
• Primary Completion: April 30, 2026
• Study Completion (Estimated): April 30, 2027
• Last Updated: August 21, 2025

Record last verified: 2025-08

Locations

US (1)