VR Pupillometry in Cognitive Impairment

Task-evoked Pupillometry in AD, MCI, and Depression-Related Cognitive Impairment

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.

Study Overview

• Status: Recruiting
• Conditions: Dementia; Mild Cognitive Impairment; Major Depressive Disorder (MDD); Alzheimer s Disease

Detailed Description

Cognitive performance typically declines with age and is usually accompanied by attention and memory deficits. While such changes can be consistent with normal ageing, they may also reflect affective disorders or early stages of neurodegenerative diseases (e.g. Alzheimer's Disease; AD). In clinical practice, neurocognitive tests are commonly used to distinguish age-appropriate change from pathological decline. As these tests quantify behavioral performance, they are better at detecting cognitive decline, once measurable deficits are manifested. However, they have limited sensitivity to subtle changes that can precede overt clinical symptoms by several years. This study evaluates a diagnostic approach based on pupil dilation measurements that may support earlier detection and longitudinal monitoring, potentially enabling earlier interventions.

Pupillometry provides a noninvasive index of pupil dynamics linked to arousal systems relevant to cognition, including the locus coeruleus-noradrenergic (LC-NA) system. LC-NA activity is coupled to pupil dilation via autonomic pathways, and this coupling has been demonstrated across animal and human studies. Given its widespread projections, the LC-NA system is implicated in psychiatric and neurological conditions through roles in arousal regulation, stress responsivity, attention, and memory. Pupillometry in Alzheimer's disease has often been examined using pupillary light reflex paradigms. However, simple light-flash measures may be less informative in early-stage impairment because pupil responses vary with cognitive state and task demands and do not provide a uniform, task-independent readout of LC-linked function. Accordingly, analyzing pupil responses during and immediately following cognitive tasks may be better suited to capturing subtle dysfunction relevant to prodromal processes, with light-reflex alterations potentially becoming more apparent once impairment is established. In prior work, the investigators observed pupil diameter increased with working-memory load during an N-back task. Most participants showed the expected increase in pupil dilation with task difficulty, whereas a subset exhibited pronounced atypical pupil responses despite only slight differences on standard neurocognitive measures. Building on these principles, this study uses a VR-based assessment to examine adults presenting with early, non-specific cognitive complaints. By systematically recording pupil dynamics during and following cognitive paradigms, the investigators aim to obtain readouts of LC-NA system function that may support differential diagnosis among conditions with overlapping clinical presentations (e.g. depression-related cognitive impairment vs. early dementia).

At each visit, participants are fitted with a VR headset by trained study personnel and complete VR-based assessments with concurrent eye tracking and behavioral performance recording. Assessments are conducted at baseline (T0) and repeated after 3 months (T1) and 6 months (T2). At each visit, pupil responses and task performance are recorded during a pupillary light reflex paradigm, a resting-state fixation block, a working-memory task (N-back), and a reward task. Participants also complete routine neuropsychological testing, including the Montreal Cognitive Assessment (MoCA) and the CERAD battery comprising semantic fluency, Boston Naming Test, Mini-Mental State Examination (MMSE), word list learning, word list delayed recall, word list recognition, figure copying, figure delayed recall, phonemic fluency, and Trail Making Test. Additional assessments include the Bayer Activities of Daily Living scale (Bayer-ADL) and the Geriatric Depression Scale (GDS), as well as questionnaires assessing subjective cognitive impairment (FLei) and childhood adversity (CTQ). Sociodemographic data are recorded, including age, sex, education (years of schooling), and occupation. Blood is collected for routine laboratory measures and blood-based biomarker analyses (including phosphorylated tau 217), and clinical data from routine care are linked where available. In some cases, cerebrospinal fluid biomarkers from routine clinical evaluation are available and linked, including AD pathology markers (amyloid-β and tau measures).

Pupillometric and behavioral measures will be compared across cohorts and evaluated longitudinally across follow-up visits. Measures will also be related to routine neuropsychological assessment, as well as available clinical biomarkers (CSF amyloid-β and tau measures blood-based biomarkers and anatomical neuroimaging sequences). Prior observations suggest that pupil dilation scales with cognitive load and that task-evoked pupil responses can differ, even when standard neurocognitive measures show only subtle differences. The investigators hypothesize that task-evoked pupil response patterns will differ between cohorts and may be sensitive to change over time.

• Study Type: Observational
• Enrollment (Estimated): 140

Contacts and Locations

• Study Contact: Name: Eva Vidovic, MD; Phone Number: 0049 089-30622-1402; Email: eva_vidovic@psych.mpg.de
• Study Contact Backup: Name: Victor I. Spoormaker, PhD; Phone Number: 0049 089-30622-1402; Email: ambulanz@psych.mpg.de

Study Locations

• Germany
  • Bavaria
    • München, Bavaria, Germany, 80804
      • Recruiting
      • Max Planck Institute of Psychiatry
      • Contact: Eva Vidovic, MD; Phone Number: 0049 089 30622 1402; Email: ambulanz@psych.mpg.de
      • Contact: Victor I. Spoormaker, PhD; Phone Number: 0049 089 30622 1402; Email: ambulanz@psych.mpg.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• 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.

Description

Inclusion Criteria:

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

Exclusion Criteria:

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

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Resting-state pupil dynamics	Mean and variability of pupil diameter during resting fixation.	Baseline, 3 months, 6 months.
Reward-task pupil response	Pupil response metrics (mean relative pupil diameter in each condition) recorded with VR eye tracking during each condition (reward, control).	Baseline, 3 months, 6 months.
Blood-based biomarkers	Blood biomarker concentrations assessed from collected blood samples, including phosphorylated tau 217 (p-tau217) and Aβ1-42/Aβ1-40 ratio.	Baseline, 6 months.
CSF Alzheimer's disease pathology markers	CSF biomarkers from routine clinical evaluation where available, including Aβ1-42, Aβ1-40, Aβ1-42/Aβ1-40 ratio, total tau, and phosphorylated tau.	Baseline.
N-back behavioral performance	Behavioral performance during the VR N-back task, quantified as accuracy and reaction time for each load condition ( 0-, 1-, 2-back).	Baseline, 3 months, 6 months.
Montreal Cognitive Assessment (MoCA)	Global cognitive screening tool used to quantify overall cognitive impairment. Range: 0-30; higher scores indicate better cognitive performance.	Baseline, 3 months, 6 months.
CERAD cognitive battery (CERAD-Plus), norm-referenced z-scores	CERAD-Plus subtests include semantic fluency, Boston Naming Test, word list learning, word list delayed recall, word list recognition, figure copying, figure delayed recall, phonemic fluency, and Trail Making Test. The subtests will be evaluated using age-/education-adjusted norm-referenced z-scores. A z-score of 0 corresponds to the normative mean; higher z-scores indicate better cognitive performance and lower z-scores indicate worse performance.	Baseline, 6 months.
Bayer Activities of Daily Living (Bayer-ADL)	Functional status measured using the Bayer-ADL mean item score (quotient). Range: 1.00-10.00. Higher scores indicate worse functional impairment (more difficulty with activities of daily living).	Baseline, 6 months.
Geriatric Depression Scale	Geriatric Depression Scale, 30-item version (GDS-30), total score (depressive symptoms). Range: 0-30; higher scores indicate more depressive symptoms.	Baseline, 6 months.
Subjective cognitive impairment (Fragebogen zur geistigen Leistungsfähigkeit; FLei), total score	35-item self-report assessing cognitive difficulties over the last 6 months (0-4 per item). Range: 0-140. Higher scores indicate greater subjective cognitive impairment (more perceived difficulties).	Baseline, 6 months.
Childhood Trauma Questionnaire (CTQ)	Retrospective recall-based measures administered to adults. Used to determine experiences of childhood trauma. Higher scores indicate greater childhood adversity.	Baseline.
Task-evoked pupil dilation during N-Back	Pupil response metrics (mean relative pupil diameter in each condition; load-dependent slope across conditions) recorded with VR eye tracking during the N-back task for each condition (fixation, 0-back, 1-back, 2-back).	3 months, 6 months.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Between-group differences in N-back pupil metrics	Comparison of the primary N-back pupil load metric across the four cohorts (Alzheimer's disease, mild cognitive impairment, depressive disorder with cognitive impairment, healthy controls).	Baseline, 3 months, 6 months.
Association between task-evoked pupil responses and AD pathology markers	Association between the N-back pupil metrics and available biomarkers of AD pathology (CSF and blood-based biomarkers).	Baseline through 6 months, using biomarker time points available
Change from baseline in N-back pupil metrics	Within-participant change from baseline in the prespecified N-back pupil load metric	Baseline, 3 months, 6 months.
Association between task-evoked pupil responses and cognitive test performance	Association between the N-back pupil metrics and cognitive performance measures (MoCA total score; CERAD-Plus subtest z-scores).	Baseline, 6 months.

Collaborators and Investigators

• Sponsor: Max-Planck-Institute of Psychiatry
• Investigators: Principal Investigator: Victor I. Spoormaker, PhD, Max-Planck-Institute of Psychiatry

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2025
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: January 12, 2026
• First Submitted That Met QC Criteria: February 3, 2026
• First Posted (Actual): February 11, 2026

Study Record Updates

• Last Update Posted (Actual): February 17, 2026
• Last Update Submitted That Met QC Criteria: February 12, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Alzheimer's Disease; Mild Cognitive Impairment; Dementia; Biomarkers; Major Depressive Disorder; Pupillometry; Amyloid beta-Peptides; Tau Proteins
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Pathological Conditions, Anatomical; Neurocognitive Disorders; Cognition Disorders; Tauopathies; Neurodegenerative Diseases; Mood Disorders; Depressive Disorder; Pathological Conditions, Signs and Symptoms; Cognitive Dysfunction; Alzheimer Disease; Depressive Disorder, Major; Dementia; Plaque, Amyloid
• Other Study ID Numbers: 23-0991

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No