Stress Response Testing for Alzheimer's Risk

(Stress-AD Trial)

Overseen By Nicholas Bienko, MS

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Johns Hopkins University

Must not be taking: Neuroleptics, sedative hypnotics, glucocorticoids

Disqualifiers: Smoking, psychiatric illness, neurological disorder, immune disorder, drug dependence, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 3

240 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this clinical trial is to learn about how genetics and the response to stress predicts cognitive decline in individuals with mild cognitive impairment. The main question\[s\] it aims to answer are: * Does the hormone response to acute stress predict the degree of cognitive impairment following acute stress? * Do genes associated with the risk for Alzheimer's disease influence the relationship between stress hormone response to stress and cognitive impairment following stress? * Do cognitive impairment following acute stress and genes associated with the risk for Alzheimer's disease predict cognitive decline and change in biomarkers for Alzheimer's disease 2 years later? Participants will have 3 in-person study visits. The first 2 will occur at baseline and the 3rd visit will occur 2 years later. During the visits, participants will provide blood and saliva samples, undergo a 10-minute social stress procedure, complete questionnaires, and take tests of memory and other thinking skills. Someone who knows the participant (a "study partner") will be asked questions about the participant's daily functioning at the first and 3rd study visits.

Will I have to stop taking my current medications?

The trial requires that participants have not been treated with neuroleptics, sedative hypnotics, or glucocorticoids in the last six months. If you are currently taking these medications, you may need to stop them to participate.

What data supports the effectiveness of the treatment Trier Social Stress Test (TSST) for Alzheimer's risk?

The research suggests that higher stress responses, as measured by the TSST, may indicate a preclinical sign of cognitive impairment, which is related to Alzheimer's risk. This implies that the TSST could be useful in identifying individuals at risk for cognitive decline. ^{1 2 3 4 5}

Is the Trier Social Stress Test (TSST) safe for humans?

The TSST is generally considered safe for humans, as it has been used in various studies to assess stress responses without reports of significant adverse effects. However, it can cause temporary increases in stress hormones like cortisol, which are typically well-tolerated. ^{1 2 6 7 8}

How does the treatment in the Stress Response Testing for Alzheimer's Risk trial differ from other treatments for Alzheimer's?

This treatment is unique because it uses the Trier Social Stress Test (TSST) to assess stress response, which may help identify individuals at risk for cognitive impairment before symptoms appear. Unlike traditional Alzheimer's treatments that focus on managing symptoms, this approach aims to understand the role of stress in the disease's development. ^{2 9 10 11 12}

Research Team

Cynthia A Munro, PhD

Principal Investigator

Johns Hopkins School of Medicine

Eligibility Criteria

This trial is for English-speaking individuals aged 60 or older with mild cognitive impairment (MCI), who can consent to the study and have a 'study partner' available. They must be able to return for follow-up after two years, have a BMI between 17 and 30, and meet specific clinical criteria for MCI.

Inclusion Criteria

I am a native English speaker with Mild Cognitive Impairment.

I have mild cognitive impairment and my BMI is between 17 and 30.

Subjects with Mild Cognitive Impairment (MCI) must be willing and able to return for 2-year-followup visit

Exclusion Criteria

I have MCI and no history of major psychiatric illnesses.

I have MCI and have never had a severe head injury, stroke, or seizure.

Study Partners must be willing and able to attend study visits

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Participants and their study partners answer questions about daily functioning, and participants take paper-and-pencil tests and provide a blood sample.

1 day

1 visit (in-person)

Stress Procedure

Participants undergo a stress procedure involving public speaking and mental math, with stress hormone levels measured through saliva samples.

1 day

1 visit (in-person)

Follow-up

Participants and their study partners return for assessments, including blood samples and cognitive tests, to evaluate cognitive decline and neurodegeneration.

2 years

1 visit (in-person)

Treatment Details

Interventions

• Trier Social Stress Test

Trial Overview The study uses the Trier Social Stress Test to understand if stress hormones predict cognitive decline in those at risk for Alzheimer's. It explores how genes linked to Alzheimer's affect this relationship and whether they forecast changes in cognition and biomarkers over two years.

Participant Groups

Group I: Trier Social Stress Test Experimental Treatment 1 Intervention

All participants in the study will get undergo the same stress procedure

Who Is Running the Clinical Trial?

Johns Hopkins University

Lead Sponsor

Trials

2,366

Recruited

15,160,000+

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

Findings from Research

The novel cognitive stress test, LASSI-L, effectively identifies subtle cognitive impairments in older adults, with 89% of participants with mild cognitive impairment (MCI) showing deficits, compared to only 13% of cognitively normal individuals.

The test's ability to measure recovery from proactive semantic interference (PSI) is linked to amyloid load in the brain, suggesting it could be a valuable tool for detecting early cognitive decline and Alzheimer's disease risk in individuals who appear cognitively normal.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Novel Cognitive Stress Test for the Detection of Preclinical Alzheimer Disease: Discriminative Properties and Relation to Amyloid Load. Loewenstein, DA., Curiel, RE., Greig, MT., et al.[2022]

In a study of 129 older adults, higher cortisol levels in response to acute stress were linked to a 26.1% incidence of cognitive impairment not dementia (CIND) after five years, suggesting that stress may play a role in cognitive decline.

Participants who later developed CIND showed greater cortisol responsiveness to stress and a lower cortisol awakening response five years prior to diagnosis, indicating that these stress responses could be early indicators of cognitive impairment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cortisol reactivity to a psychosocial stressor significantly increases the risk of developing Cognitive Impairment no Dementia five years later. de Souza-Talarico, JN., Alves, AR., Brucki, SMD., et al.[2021]

In a study of 98 elderly individuals, including 46 Alzheimer's disease patients and 52 healthy controls, it was found that stress markers like cortisol levels and state anxiety did not affect memory performance in Alzheimer's patients.

In contrast, healthy elderly individuals showed significant relationships between cortisol and anxiety levels with their memory performance, indicating that emotional memory in Alzheimer's patients may operate differently than in healthy older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of stress on emotional memory in patients with Alzheimer's disease and in healthy elderly. Gómez-Gallego, M., Gómez-García, J.[2019]

In a study of 268 participants, including 122 Alzheimer's disease patients and 146 healthy controls, it was found that stressful life events did not significantly impact financial capacity in either group.

Despite healthy controls reporting more stressful events than Alzheimer's patients, the study concluded that recent life events do not play a causal role in the financial deficits observed in Alzheimer's patients, suggesting that cognitive assessments like the MMSE are more relevant for evaluating financial capacity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stressful life events, general cognitive performance, and financial capacity in healthy older adults and Alzheimer's disease patients. Giannouli, V., Tsolaki, M.[2023]

In a study using the TgF344-AD rat model for Alzheimer's disease, chronic stress did not significantly increase anxiety or fear-like behaviors in transgenic rats compared to wild-type rats, suggesting that short-term stress may not exacerbate these symptoms in this model.

Non-stressed Tg+ rats exhibited higher anxiety-like behavior than non-stressed WT rats, indicating that the presence of Alzheimer's-related pathology may influence anxiety levels, but chronic stress alone did not further impact these behaviors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential effects of chronic stress on anxiety-like behavior and contextual fear conditioning in the TgF344-AD rat model of Alzheimer's disease. Pentkowski, NS., Bouquin, SJ., Maestas-Olguin, CR., et al.[2022]

The scopolamine challenge test (SCT) was shown to effectively identify older adults at risk for Alzheimer's disease (AD) by correlating baseline cognitive performance with changes in cognitive function and amyloid levels over a 27-month period.

In a study of 63 older adults with memory difficulties, those who failed the SCT exhibited significant cognitive decline and higher amyloid burden on PET imaging, suggesting that the SCT could be a valuable tool for early detection of AD-related changes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Disruption of cholinergic neurotransmission, within a cognitive challenge paradigm, is indicative of Aβ-related cognitive impairment in preclinical Alzheimer's disease after a 27-month delay interval. Alber, J., Maruff, P., Santos, CY., et al.[2021]

The SKT (Syndrom Kurztest) effectively assesses treatment responses in dementia, showing strong test-retest reliability with scores of .90 for the total score and .75 to .93 for factor scores in a study of 265 patients with mild to moderate Alzheimer's disease.

The analysis confirmed two main factors—memory and attention—demonstrating that the SKT is valid and correlates well with established dementia assessments like the MMSE and ADAS, indicating its effectiveness in evaluating cognitive dysfunction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Factor structure and scoring of the SKT test battery. Kim, YS., Nibbelink, DW., Overall, JE.[2019]

In a study involving 80 Alzheimer's disease (AD) patients and 104 healthy controls, higher cortisol levels were linked to poorer verbal memory performance in healthy individuals, but this negative effect was less pronounced in AD patients.

Interestingly, moderate levels of anxiety were associated with improved memory performance in both AD patients and healthy older adults, suggesting that anxiety may have a complex role in memory function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stress and verbal memory in patients with Alzheimer's disease: different role of cortisol and anxiety. Gómez-Gallego, M., Gómez-García, J.[2020]

The Trier Social Stress Test (TSST) is a reliable method for inducing acute stress in experimental settings, revealing significant differences in stress responses across genders and age groups, as well as insights into genetic and epigenetic factors influencing these responses.

The TSST has been adapted for various contexts, including group settings and brain imaging, and continues to be the gold standard for studying the neurobiology of acute stress, although alternative stress paradigms may be useful in specific scenarios.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Trier Social Stress Test: Principles and practice. Allen, AP., Kennedy, PJ., Dockray, S., et al.[2022]

The study validated a remote version of the Trier Social Stress Test (TSST-Online) for children, demonstrating that it effectively activates the stress response similar to in-person assessments, with 63% of participants showing a significant increase in cortisol levels.

The TSST-Online allows for safe and effective assessment of stress reactivity in children and adolescents without the need for in-person visits, making it particularly useful during situations like the COVID-19 pandemic or for participants living far from research facilities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Validation of an online version of the Trier Social Stress Test in a study of adolescents. Gunnar, MR., Reid, BM., Donzella, B., et al.[2023]

The Trier Social Stress Test in group format (TSST-G) effectively induces a psychobiological stress response, as shown by significant increases in negative affect, heart rate (HR), and salivary alpha-amylase (sAA) in a study with 294 participants during the first test.

When comparing two different protocols for the second test, the defensive speech protocol resulted in a stronger autonomic stress response (higher HR and lower heart rate variability) than a neutral presentation, indicating that ego-involving tasks may be more effective for studying stress reactivity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mood and autonomic responses to repeated exposure to the Trier Social Stress Test for Groups (TSST-G). Boesch, M., Sefidan, S., Ehlert, U., et al.[2014]

The review analyzed 49 studies on the Trier Social Stress Test (TSST) and found that about 25% of them showed significant correlations between cortisol levels (a physiological stress marker) and perceived emotional stress, indicating a link between physical and emotional responses to stress.

The study highlighted that differences in assessment methods, stress protocol variations, and individual differences may contribute to the inconsistent relationship between physiological and psychological stress responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute psychosocial stress: does the emotional stress response correspond with physiological responses? Campbell, J., Ehlert, U.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

A Novel Cognitive Stress Test for the Detection of Preclinical Alzheimer Disease: Discriminative Properties and Relation to Amyloid Load. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Cortisol reactivity to a psychosocial stressor significantly increases the risk of developing Cognitive Impairment no Dementia five years later. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Effects of stress on emotional memory in patients with Alzheimer's disease and in healthy elderly. [2019]

4. Germany pubmed.ncbi.nlm.nih.gov

Stressful life events, general cognitive performance, and financial capacity in healthy older adults and Alzheimer's disease patients. [2023]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Differential effects of chronic stress on anxiety-like behavior and contextual fear conditioning in the TgF344-AD rat model of Alzheimer's disease. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Disruption of cholinergic neurotransmission, within a cognitive challenge paradigm, is indicative of Aβ-related cognitive impairment in preclinical Alzheimer's disease after a 27-month delay interval. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Factor structure and scoring of the SKT test battery. [2019]

8. England pubmed.ncbi.nlm.nih.gov

Stress and verbal memory in patients with Alzheimer's disease: different role of cortisol and anxiety. [2020]

9. United States pubmed.ncbi.nlm.nih.gov

The Trier Social Stress Test: Principles and practice. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Validation of an online version of the Trier Social Stress Test in a study of adolescents. [2023]

11. England pubmed.ncbi.nlm.nih.gov

Mood and autonomic responses to repeated exposure to the Trier Social Stress Test for Groups (TSST-G). [2014]

12. England pubmed.ncbi.nlm.nih.gov

Acute psychosocial stress: does the emotional stress response correspond with physiological responses? [2022]