VR Pupillometry in Cognitive Impairment

NCT07402356 | Recruiting

• 1 other identifier: 23-0991
• Study Type: observational
• Target: 140
• Locations: 1 country
• Sites: 1

Brief Summary

With disease-modifying therapies emerging for dementia and related conditions, identifying cognitive decline as early as possible is increasingly important. This prospective, single-center, repeated-measures study evaluates whether VR-based eye-tracking pupillometry can provide a practical, non-invasive biomarker of cognitive impairment and its progression over time. Pupil responses are linked to brain arousal systems relevant to cognitive dysfunction, including the locus coeruleus, which is affected early in Alzheimer's disease. Adults aged 18-80 years will be assigned to one of four cohorts (n=35 per cohort): i) Alzheimer's disease (supported by CSF biomarkers), ii) mild cognitive impairment (MCI) without Alzheimer's Disease, iii) depressive disorder with cognitive impairment, iv) healthy controls. Participants will undergo initial assessments at baseline and follow-up visits after 3 and 6 months. At each visit, pupil responses and behavioral metrics are recorded during a pupillary light reflex paradigm, a resting-state fixation block, a working-memory task (N-back), and a reward task. Pupillometric and behavioral metrics will be compared across cohorts and related to routine neuropsychological measures (MoCA, CERAD) and available clinical biomarkers (CSF markers; blood biomarkers). The primary objective is to determine whether task-evoked pupil response profiles sensitively quantify cognitive impairment, differ between cohorts, and track change over time. The long-term goal is to validate an easy-to-use, outpatient-compatible assessment to support objective characterization and monitoring of cognitive disorders.

Conditions

Alzheimer s Disease; Major Depressive Disorder (MDD); Mild Cognitive Impairment; Dementia

Keywords

Alzheimer's Disease; Major Depressive Disorder; Mild Cognitive Impairment; Dementia; Pupillometry; Biomarkers; Amyloid beta-Peptides; Tau Proteins

Outcome Measures

Primary Outcomes (1)

• Task-evoked pupil dilation during N-Back

  Pupil response metrics (mean relative pupil diameter in each condition) recorded with VR eye tracking during the N-back task for each condition (fixation, 0-back, 1-back, 2-back).

  Baseline

Secondary Outcomes (12)

• Resting-state pupil dynamics

  Baseline, 3 months, 6 months.

• Reward-task pupil response

  Baseline, 3 months, 6 months.

• N-back behavioral performance

  Baseline, 3 months, 6 months.

• Montreal Cognitive Assessment (MoCA)

  Baseline, 3 months, 6 months.

• CERAD cognitive battery (CERAD-Plus), norm-referenced z-scores

  Baseline, 6 months.

Other Outcomes (4)

• Between-group differences in N-back pupil metrics

  Baseline, 3 months, 6 months.

• Association between task-evoked pupil responses and cognitive test performance

  Baseline, 6 months.

• Association between task-evoked pupil responses and AD pathology markers

  Baseline through 6 months, using biomarker time points available

Study Arms (4)

Alzheimer's Disease

Participants with complaints of cognitive deficits and a diagnosis of Alzheimer's disease (AD) supported by cerebrospinal fluid (CSF) biomarker profile, where available.

Mild Cognitive Impairment without Alzheimer's Disease

Participants with complaints of cognitive deficits meeting criteria for mild cognitive impairment without evidence of Alzheimer's disease (CSF biomarkers not consistent with AD).

Depressive Disorder With Cognitive Impairment

Participants with complaints of cognitive impairment and no evidence of Alzheimer's pathology; deficits most consistent with depressive disorder.

Healthy Controls

Age-matched healthy volunteers.

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Adults aged 18-80 years will be recruited at the Max Planck Institute of Psychiatry (Munich, Germany) from inpatient wards and outpatient clinics. Patients have a suspected or confirmed clinical diagnosis of Alzheimer's disease, mild cognitive impairment, or depressive disorder with cognitive impairment. Routine clinical measures (neuropsychological testing and, CSF biomarkers, blood biomarkers, imaging) will be linked to study pupillometry outcomes.

You may qualify if:

• Written informed consent.
• Age 18-80 years.
• Ability to read and understand German.
• For patient cohorts: suspected or confirmed diagnosis of AD/MCI/depressive disorder with cognitive impairment according to clinical assessment and routine documentation.

You may not qualify if:

• Acute suicidality (e.g. BDI suicidality item \> 1).
• Change of psychotropic medication within the last 4 weeks.
• Lifetime psychotic disorder (ICD-10 F20-29).
• Lack of capacity to consent.
• Lifetime bipolar disorder (ICD-10 F31).
• Acute substance abuse or harmful use of alcohol or other psychoactive substances.
• Parkinson's syndrome (ICD-10 G20).
• Multiple sclerosis (ICD-10 G35).
• Stroke within the last 12 months.

Sponsors & Collaborators

• Max-Planck-Institute of Psychiatry: lead

Study Sites (1)

Max Planck Institute of Psychiatry

München, Bavaria, 80804, Germany

RECRUITING

Related Publications (5)

• Murphy PR, O'Connell RG, O'Sullivan M, Robertson IH, Balsters JH. Pupil diameter covaries with BOLD activity in human locus coeruleus. Hum Brain Mapp. 2014 Aug;35(8):4140-54. doi: 10.1002/hbm.22466. Epub 2014 Feb 7.

  PMID: 24510607 BACKGROUND

• Megemont M, McBurney-Lin J, Yang H. Pupil diameter is not an accurate real-time readout of locus coeruleus activity. Elife. 2022 Feb 2;11:e70510. doi: 10.7554/eLife.70510.

  PMID: 35107419 BACKGROUND

• Fietz J, Pohlchen D; BeCOME Working Group; Bruckl TM, Brem AK, Padberg F, Czisch M, Samann PG, Spoormaker VI. Data-Driven Pupil Response Profiles as Transdiagnostic Readouts for the Detection of Neurocognitive Functioning in Affective and Anxiety Disorders. Biol Psychiatry Cogn Neurosci Neuroimaging. 2024 Jun;9(6):580-587. doi: 10.1016/j.bpsc.2023.06.005. Epub 2023 Jun 20.

  PMID: 37348604 BACKGROUND

• Fietz J, Pohlchen D, Binder FP; BeCOME Working Group; Czisch M, Samann PG, Spoormaker VI. Pupillometry tracks cognitive load and salience network activity in a working memory functional magnetic resonance imaging task. Hum Brain Mapp. 2022 Feb 1;43(2):665-680. doi: 10.1002/hbm.25678. Epub 2021 Oct 8.

  PMID: 34622518 BACKGROUND

• Aston-Jones G, Cohen JD. An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance. Annu Rev Neurosci. 2005;28:403-50. doi: 10.1146/annurev.neuro.28.061604.135709.

  PMID: 16022602 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Blood and CSF; for marker analyses + control/calibration; Optional biobank opt-in (Munich Mental Health Biobank)

MeSH Terms

Conditions

Depressive Disorder, Major; Cognitive Dysfunction; Dementia; Alzheimer Disease; Plaque, Amyloid

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Cognition Disorders; Neurocognitive Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms

Study Officials

• Victor I. Spoormaker, PhD

  Max-Planck-Institute of Psychiatry

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Eva Vidovic, MD

CONTACT

089-30622-1402; eva_vidovic@psych.mpg.de

Victor I. Spoormaker, PhD

CONTACT

089-30622-1402; ambulanz@psych.mpg.de

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: January 12, 2026
• First Posted: February 11, 2026
• Study Start: May 1, 2025
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027
• Last Updated: February 17, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1)