Ahead of print articles
THE SARS-COV-2 PANDEMIC AND THE BRAVE NEW DIGITAL WORLD OF ENVIRONMENTAL ENRICHMENT TO PREVENT BRAIN AGING AND COGNITIVE DECLINE
H. Hampel, A. Vergallo
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Individuals experiencing brain aging, cognitive decline, and dementia are currently confronted with several more complex challenges due to the current Sars-Cov-2 pandemic as compared to younger and cognitively healthy people. During the first six months of the pandemic, we are experiencing critical issues related to the management of mild cognitive impairment (MCI) and dementia. The evolving, highly contagious global viral spread has created a pressure test of unprecedented proportions for the existing brain health care infrastructure and related services for management, diagnosis, treatment, and prevention. Social distancing and lock-down measures are catalyzing and accelerating a technological paradigm shift, away from a traditional model of brain healthcare focused on late symptomatic disease stages and towards optimized preventive strategies to slow brain aging and increase resilience at preclinical asymptomatic stages. Digital technologies transform global healthcare for accessible equality of opportunities in order to generate better outcomes for brain aging aligned with the paradigm of preventive medicine.
H. Hampel ; A. Vergallo (2020): The Sars-Cov-2 Pandemic and the Brave New Digital World of Environmental Enrichment to Prevent Brain Aging and Cognitive Decline. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.39
THE COMPUTERIZED COGNITIVE COMPOSITE (C3) IN A4, AN ALZHEIMER’S DISEASE SECONDARY PREVENTION TRIAL
K.V. Papp, D.M. Rentz, P. Maruff, C.-K. Sun, R. Raman, M.C. Donohue, A. Schembri, C. Stark, M.A. Yassa, A.M. Wessels, R. Yaari, K.C. Holdridge, P.S. Aisen, R.A. Sperling, on behalf of the A4 Study Team
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Background: Computerized cognitive assessments may improve Alzheimer’s disease (AD) secondary prevention trial efficiency and accuracy. However, they require validation against standard outcomes and relevant biomarkers.
Objective: To assess the feasibility and validity of the tablet-based Computerized Cognitive Composite (C3).
Design: Cross-sectional analysis of cognitive screening data from the A4 study (Anti-Amyloid in Asymptomatic AD).
Setting: Multi-center international study.
Participants: Clinically normal (CN) older adults (65-85; n=4486)
Measurements: Participants underwent florbetapir-Positron Emission Tomography for Aβ+/- classification. They completed the C3 and standard paper and pencil measures included in the Preclinical Alzheimer’s Cognitive Composite (PACC). The C3 combines memory measures sensitive to change over time (Cogstate Brief Battery-One Card Learning) and measures shown to be declining early in AD including pattern separation (Behavioral Pattern Separation Test- Object- Lure Discrimination Index) and associative memory (Face Name Associative Memory Exam- Face-Name Matching). C3 acceptability and completion rates were assessed using qualitative and quantitative methods. C3 performance was explored in relation to Aβ+/- groups (n=1323/3163) and PACC.
Results: C3 was feasible for CN older adults to complete. Rates of incomplete or invalid administrations were extremely low, even in the bottom quartile of cognitive performers (PACC). C3 was moderately correlated with PACC (r=0.39). Aβ+ performed worse on C3 compared with Aβ- [unadjusted Cohen’s d=-0.22 (95%CI: -0.31,-0.13) p<0.001] and at a magnitude comparable to the PACC [d=-0.32 (95%CI: -0.41,-0.23) p<0.001]. Better C3 performance was observed in younger, more educated, and female participants.
Conclusions: These findings provide support for both the feasibility and validity of C3 and computerized cognitive outcomes more generally in AD secondary prevention trials.
K.V. Papp ; D.M. Rentz ; P. Maruff ; C.-K. Sun ; R. Raman ; M.C. Donohue ; A. Schembri ; C. Stark ; M.A. Yassa ; A.M. Wessels ; R. Yaari ; K.C. Holdridge ; P.S. Aisen ; R.A. Sperling ; on behalf of the A4 Study Team ; (2020): The Computerized Cognitive Composite (C3) in A4, an Alzheimer’s Disease Secondary Prevention Trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.38
IS RELUCTANCE TO SHARE ALZHEIMER’S DISEASE BIOMARKER STATUS WITH A STUDY PARTNER A BARRIER TO PRECLINICAL TRIAL RECRUITMENT?
C.G. Cox, M.M. Ryan, D.L. Gillen, J.D. Grill
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Background: Preclinical Alzheimer’s disease clinical trials test candidate treatments in individuals with biomarker evidence but no cognitive impairment. Participants are required to co-enroll with a knowledgeable study partner, to whom biomarker information is disclosed.
Objective: We investigated whether reluctance to share biomarker results is associated with viewing the study partner requirement as a barrier to preclinical trial enrollment.
Design: We developed a nine-item assessment on views toward the study partner requirement and performed in-person interviews based on a hypothetical clinical trial requiring biomarker testing and disclosure.
Setting: We conducted interviews on campus at the University of California, Irvine.
Participants: Two hundred cognitively unimpaired older adults recruited from the University of California, Irvine Consent-to-Contact Registry participated in the study.
Measurements: We used logistic regression models, adjusting for potential confounders, to examine potential associations with viewing the study partner requirement as a barrier to preclinical trial enrollment.
Results: Eighteen percent of participants reported strong agreement that the study partner requirement was a barrier to enrollment. Ten participants (5%) agreed at any level that they would be reluctant to share their biomarker result with a study partner. The estimated odds of viewing the study partner requirement as a barrier to enrollment were 26 times higher for these participants (OR=26.3, 95% CI 4.0, 172.3), compared to those who strongly disagreed that they would be reluctant to share their biomarker result. Overall, participants more frequently agreed with positive statements than negative statements about the study partner requirement, including 76% indicating they would want their study partner with them when they learned biomarker results.
Conclusions: This is one of the first studies to explore how potential preclinical Alzheimer’s disease trial participants feel about sharing their personal biomarker information with a study partner. Most participants viewed the study partner as an asset to trial enrollment, including having a partner present during biomarker disclosure.
C.G. Cox ; M.M. Ryan ; D.L. Gillen ; J.D. Grill (2020): Is Reluctance to Share Alzheimer’s Disease Biomarker Status with a Study Partner a Barrier to Preclinical Trial Recruitment?. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.36
A FRAMEWORK FOR DEVELOPING PHARMACOTHERAPY FOR AGITATION IN ALZHEIMER’S DISEASE: RECOMMENDATIONS OF THE ISCTM* WORKING GROUP
C. O’Gorman, R. Khoury, A. Anderson, M. Carter, F. DiCesare, S. Dubé, L. Ereshefsky, G. Grossberg, N. Hefting, S. Khan, S. Lind, H. Moebius, T. Shiovitz, P. Rosenberg
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C. O’Gorman ; R. Khoury ; A. Anderson ; M. Carter ; F. DiCesare ; S. Dubé ; L. Ereshefsky ; G. Grossberg ; N. Hefting ; S. Khan ; S. Lind ; H. Moebius ; T. Shiovitz ; P. Rosenberg (2020): A Framework for Developing Pharmacotherapy for Agitation in Alzheimer’s disease: Recommendations of the ISCTM* Working Group . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.37
INTEGRATING BIOMARKER OUTCOMES INTO CLINICAL TRIALS FOR ALZHEIMER’S DISEASE IN DOWN SYNDROME
M.S. Rafii, S. Zaman, B.L. Handen
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The NIH-funded Alzheimer’s Biomarker Consortium Down Syndrome (ABC-DS) and the European Horizon 21 Consortium are collecting critical new information on the natural history of Alzheimer’s Disease (AD) biomarkers in adults with Down syndrome (DS), a population genetically predisposed to developing AD. These studies are also providing key insights into which biomarkers best represent clinically meaningful outcomes that are most feasible in clinical trials. This paper considers how these data can be integrated in clinical trials for individuals with DS. The Alzheimer’s Clinical Trial Consortium - Down syndrome (ACTC-DS) is a platform that brings expert researchers from both networks together to conduct clinical trials for AD in DS across international sites while building on their expertise and experience.
M.S. Rafii ; S. Zaman ; B.L. Handen (2020): Integrating Biomarker Outcomes into Clinical Trials for Alzheimer’s Disease in Down Syndrome. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.35
AUTHORS RESPONSE TO UMBRICHT D, LETTER TO THE EDITOR REFERRING FUTILITY ANALYSES IN ALZHEIMER’S DISEASE (AD) CLINICAL TRIALS: A RISKY BUSINESS. THE JOURNAL OF PREVENTION OF ALZHEIMER’S DISEASE, 2020
P.S. Aisen, R. Raman
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P.S. Aisen ; R. Raman (2020): Authors response to Umbricht D, letter to the editor referring Futility Analyses in Alzheimer’s Disease (AD) Clinical Trials: A Risky Business. The Journal of Prevention of Alzheimer’s Disease, 2020. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.33
LETTER TO THE EDITOR REFERRING TO AISEN, P.S. AND R. RAMAN, FUTILITY ANALYSES IN ALZHEIMER’S DISEASE (AD) CLINICAL TRIALS: A RISKY BUSINESS. THE JOURNAL OF PREVENTION OF ALZHEIMER’S DISEASE, 2020
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D. Umbricht ; (2020): Letter to the editor referring to Aisen, P.S. and R. Raman, Futility Analyses in Alzheimer’s Disease (AD) Clinical Trials: A Risky Business. The Journal of Prevention of Alzheimer’s Disease, 2020. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.34
TOULOUSE ALZHEIMER’S CLINICAL RESEARCH CENTER RECOVERY AFTER THE COVID-19 CRISIS: TELEMEDICINE AN INNOVATIVE SOLUTION FOR CLINICAL RESEARCH DURING THE CORONAVIRUS PANDEMIC
C. Takeda, S. Guyonnet, P.J. Ousset, M. Soto, B. Vellas
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C. Takeda ; S. Guyonnet ; P.J. Ousset ; M. Soto ; B. Vellas (2020): Toulouse Alzheimer’s Clinical Research Center Recovery after the COVID-19 Crisis: Telemedicine an Innovative Solution for Clinical Research during the Coronavirus Pandemic. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.32
THE ALZHEIMER’S PREVENTION REGISTRY: A LARGE INTERNET-BASED PARTICIPANT RECRUITMENT REGISTRY TO ACCELERATE REFERRALS TO ALZHEIMER’S-FOCUSED STUDIES
J.B. Langbaum, N. High, J. Nichols, C. Kettenhoven, E.M. Reiman, P.N. Tariot
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Background: Recruitment for Alzheimer’s disease (AD)-focused studies, particularly prevention studies, is challenging due to the public’s lack of awareness about study opportunities coupled with studies’ inclusion and exclusion criteria, resulting in a high screen fail rate.
Objectives: To develop an internet-based participant recruitment registry for efficiently and effectively raising awareness about AD-focused study opportunities and connecting potentially eligible volunteers to studies in their communities.
Methods: Individuals age 18 and older are eligible to join the Alzheimer’s Prevention Registry (APR). Individuals provide first and last name, year of birth, country, and zip/postal code to join the APR; for questions regarding race, ethnicity, sex, family history of AD or other dementia, and diagnosis of cognitive impairment, individuals have the option to select “prefer not to answer.” The APR website maintains a list of recruiting studies and contacts members who have opted in by email when new studies are available for enrollment.
Results: As of December 1, 2019, 346,661 individuals had joined the APR. Members had a mean age of 63.3 (SD 11.7) years and were predominately women (75%). 94% were cognitively unimpaired, 50% reported a family history of AD or other dementia, and of those who provided race, 76% were white. 39% joined the APR as a result of a paid social media advertisement. To date, the APR helped recruit for 82 studies.
Conclusions: The APR is a large, internet-based participant recruitment registry designed to raise awareness about AD prevention research and connect members with enrolling studies in their communities. It has demonstrated the ability to recruit and engage a large number of highly motivated members and assist researchers in meeting their recruitment goals. Future publications will report on the effectiveness of APR for accelerating recruitment and enrollment into AD-focused studies.
J.B. Langbaum ; N. High ; J. Nichols ; C. Kettenhoven ; E.M. Reiman ; P.N. Tariot (2020): The Alzheimer’s Prevention Registry: A Large Internet-Based Participant Recruitment Registry to Accelerate Referrals to Alzheimer’s-Focused Studies. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.31
THE ROLE OF CLINICAL TRIALS IN PRECLINICAL ALZHEIMER’S DISEASE DRUG DEVELOPMENT PROGRAMS
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J. Cummings (2020): The Role of Clinical Trials in Preclinical Alzheimer’s Disease Drug Development Programs. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.28
SELF-ADMINISTERED COGNITIVE TESTING BY OLDER ADULTS AT-RISK FOR COGNITIVE DECLINE
E. Tsoy, K.L. Possin, N. Thompson, K. Patel, S.K. Garrigues, I. Maravilla, S.J. Erlhoff, C.S. Ritchie
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Self-administered computerized cognitive testing could effectively monitor older individuals at-risk for cognitive decline at home. In this study, we tested the feasibility and reliability of 3 tablet-based executive functioning measures and an executive composite score in a sample of 30 older adults (age 80±6) with high multimorbidity. The tests were examiner-administered at baseline and then self-administered by the participants at home across 2 subsequent days. Eight of the participants reported no prior experience with touchscreen technology. Twenty-seven participants completed both self-administered assessments, and 28 completed at least one. Cronbach’s alpha (individual tests: .87-.89, composite: .93) and correlations between examiner-administered and self-administered performances (individual tests: .72-.91, composite: .93) were high. The participants who had never used a smartphone or a tablet computer showed comparable consistency. Remote self-administered tablet-based testing in older adults at-risk for cognitive decline is feasible and reliable, even among participants without prior technology experience.
E. Tsoy ; K.L. Possin ; N. Thompson ; K. Patel ; S.K. Garrigues ; I. Maravilla ; S.J. Erlhoff ; C.S. Ritchie (2020): Self-Administered Cognitive Testing by Older Adults At-Risk for Cognitive Decline. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.25
A MISSED OPPORTUNITY FOR DEMENTIA PREVENTION? CURRENT CHALLENGES FOR EARLY DETECTION AND MODERN-DAY SOLUTIONS
R. Isaacson, N. Saif
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R. Isaacson ; N. Saif (2020): A Missed Opportunity for Dementia Prevention? Current Challenges for Early Detection and Modern-Day Solutions. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.23
EFFECTIVENESS OF THE OPEN SCREENING PROGRAMS IN RECRUITING SUBJECTS TO PRODROMAL AND MILD ALZHEIMER’S DISEASE CLINICAL TRIALS
D. Wójcik, K. Szczechowiak, M. Zboch, M. Pikala
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BACKGROUND AND OBJECTIVES: Due to the lack of scientific data comparing the success and cost-effectiveness of trial recruiting strategies, the main goal of this paper is to present our results and experiences in recruiting participants to prodromal and mild AD clinical trials from an open-access screening program.
DESIGN: The screening procedure includes the interview, and combined tests administration conducted by experienced neuropsychologist: Mini-Mental State Examination (MMSE) and Auditory-Verbal Learning Test (AVLT). The clinical evaluation was based on test scores, patient and/or caregiver interview, and the health questionnaire.
SETTINGS AND PARTICIPANTS: The open-access screening program was conducted in Wroclaw Alzheimer’s Center for 18 months (2018-2019). We invited individuals age 50 or older with the caregivers. The total number of subjects was 730 (N=730).
MEASUREMENTS AND RESULTS: Due to our research, the detection rates in the screened population were 0,7% for severe dementia, 4,1% for moderate dementia, 18,6% for mild dementia, and 28,9% for mild cognitive impairment (MCI). From 347 individuals classified in our open-access screening programs as MCI or mild dementia patients, as many as 248 patients were screened in Alzheimer’s disease clinical trials, which is 71,47%. Moreover, 63 from 347 individuals selected from our program as MCI or mild dementia patients were randomized into the clinical trials, which is 18,16%. Furthermore, 63 from total 730 (8,6%) patients were randomized in clinical trials.
CONCLUSIONS: Open-access screening programs can improve detection of MCI and dementia in society, help to distinguish demented from non-demented elderly, and improve recruitment of prodromal AD patients who would probably not have come to the memory clinic otherwise.
D. Wójcik ; K. Szczechowiak ; M. Zboch ; M. Pikala (2020): Effectiveness of the Open Screening Programs in Recruiting Subjects to Prodromal and Mild Alzheimer’s Disease Clinical Trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.15
THE INTERRELATIONSHIP BETWEEN INSULIN-LIKE GROWTH FACTOR 1, APOLIPOPROTEIN E Ε4, LIFESTYLE FACTORS, AND THE AGING BODY AND BRAIN
S.A. Galle, I.K. Geraedts, J.B. Deijen, M.V. Milders, M.L. Drent
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Aging is associated with a decrease in body and brain function and with a decline in insulin-like growth factor 1 levels. The observed associations between alterations in insulin-like growth factor 1 levels and cognitive functioning and Mild Cognitive Impairment suggest that altered insulin-like growth factor 1 signaling may accompany Alzheimer’s disease or is involved in the pathogenesis of the disease. Recent animal research has suggested a possible association between insulin-like growth factor 1 levels and the Apolipoprotein E ε4 allele, a genetic predisposition to Alzheimer’s disease. It is therefore hypothesized that a reduction in insulin-like growth factor 1 signaling may moderate the vulnerability to Alzheimer’s disease of human Apolipoprotein E ε4 carriers. We address the impact of age-related decline of insulin-like growth factor 1 levels on physical and brain function in healthy aging and Alzheimer’s disease and discuss the links between insulin-like growth factor 1 and the Apolipoprotein E ε4 polymorphism. Furthermore, we discuss lifestyle interventions that may increase insulin-like growth factor 1 serum levels, including physical activity and adherence to a protein rich diet and the possible benefits to the physical fitness and cognitive functioning of the aging population.
S.A. Galle ; I.K. Geraedts ; J.B. Deijen ; M.V. Milders ; M.L. Drent (2020): The Interrelationship between Insulin-Like Growth Factor 1, Apolipoprotein E ε4, Lifestyle Factors, and the Aging Body and Brain. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.11
PTI-125 REDUCES BIOMARKERS OF ALZHEIMER’S DISEASE IN PATIENTS
H.-Y. Wang, Z. Pei, K.-C. Lee, E. Lopez-Brignoni, B. Nikolov, C.A. Crowley, M.R. Marsman, R. Barbier, N. Friedmann, L.H. Burns
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BACKGROUND: The most common dementia worldwide, Alzheimer’s disease is often diagnosed via biomarkers in cerebrospinal fluid, including reduced levels of Aβ1–42, and increases in total tau and phosphorylated tau-181. Here we describe results of a Phase 2a study of a promising new drug candidate that significantly reversed all measured biomarkers of Alzheimer’s disease, neurodegeneration and neuroinflammation. PTI-125 is an oral small molecule drug candidate that binds and reverses an altered conformation of the scaffolding protein filamin A found in Alzheimer’s disease brain. Altered filamin A links to the α7-nicotinic acetylcholine receptor to allow Aβ42’s toxic signaling through this receptor to hyperphosphorylate tau. Altered filamin A also links to toll-like receptor 4 to enable Aβ-induced persistent activation of this receptor and inflammatory cytokine release. Restoring the native shape of filamin A prevents or reverses filamin A’s linkages to the α7-nicotinic acetylcholine receptor and toll-like receptor 4, thereby blocking Aβ42’s activation of these receptors. The result is reduced tau hyperphosphorylation and neuroinflammation, with multiple functional improvements demonstrated in transgenic mice and postmortem Alzheimer’s disease brain.
OBJECTIVES: Safety, pharmacokinetics, and cerebrospinal fluid and plasma biomarkers were assessed following treatment with PTI-125 for 28 days. Target engagement and mechanism of action were assessed in patient lymphocytes by measuring 1) the reversal of filamin A’s altered conformation, 2) linkages of filamin A with α7-nicotinic acetylcholine receptor or toll-like receptor 4, and 3) levels of Aβ42 bound to α7-nicotinic acetylcholine receptor or CD14, the co-receptor for toll-like receptor 4.
DESIGN: This was a first-in-patient, open-label Phase 2a safety, pharmacokinetics and biomarker study.
SETTING: Five clinical trial sites in the U.S. under an Investigational New Drug application.
PARTICIPANTS: This study included 13 mild-to-moderate Alzheimer’s disease patients, age 50-85, Mini Mental State Exam ≥16 and ≤24 with a cerebrospinal fluid total tau/Aβ42 ratio ≥0.30.
INTERVENTION: PTI-125 oral tablets (100 mg) were administered twice daily for 28 consecutive days.
MEASUREMENTS: Safety was assessed by electrocardiograms, clinical laboratory analyses and adverse event monitoring. Plasma levels of PTI-125 were measured in blood samples taken over 12 h after the first and last doses; cerebrospinal fluid levels were measured after the last dose. Commercial enzyme linked immunosorbent assays assessed levels of biomarkers of Alzheimer’s disease in cerebrospinal fluid and plasma before and after treatment with PTI-125. The study measured biomarkers of pathology (pT181 tau, total tau and Aβ42), neurodegeneration (neurofilament light chain and neurogranin) and neuroinflammation (YKL-40, interleukin-6, interleukin-1β and tumor necrosis factor α). Plasma levels of phosphorylated and nitrated tau were assessed by immunoprecipitation of tau followed by immunoblotting of three different phospho-epitopes elevated in AD (pT181-tau, pS202-tau and pT231-tau) and nY29-tau. Changes in conformation of filamin A in lymphocytes were measured by isoelectric focusing point. Filamin A linkages to α7-nicotinic acetylcholine receptor and toll-like receptor 4 were assessed by immunoblot detection of α7-nicotinic acetylcholine receptor and toll-like receptor 4 in anti-filamin A immunoprecipitates from lymphocytes. Aβ42 complexed with α7-nicotinic acetylcholine receptor or CD14 in lymphocytes was also measured by co-immunoprecipitation. The trial did not measure cognition.
RESULTS: Consistent with the drug’s mechanism of action and preclinical data, PTI-125 reduced cerebrospinal fluid biomarkers of Alzheimer’s disease pathology, neurodegeneration and neuroinflammation from baseline to Day 28. All patients showed a biomarker response to PTI-125. Total tau, neurogranin, and neurofilament light chain decreased by 20%, 32% and 22%, respectively. Phospho-tau (pT181) decreased 34%, evidence that PTI-125 suppresses tau hyperphosphorylation induced by Aβ42’s signaling through α7-nicotinic acetylcholine receptor. Cerebrospinal fluid biomarkers of neuroinflammation (YKL-40 and inflammatory cytokines) decreased by 5-14%. Biomarker effects were similar in plasma. Aβ42 increased slightly – a desirable result because low Aβ42 indicates Alzheimer’s disease. This increase is consistent with PTI-125’s 1,000-fold reduction of Aβ42’s femtomolar binding affinity to α7-nicotinic acetylcholine receptor. Biomarker reductions were at least p ≤ 0.001 by paired t test. Target engagement was shown in lymphocytes by a shift in filamin A’s conformation from aberrant to native: 93% was aberrant on Day 1 vs. 40% on Day 28. As a result, filamin A linkages with α7-nicotinic acetylcholine receptor and toll-like receptor 4, and Aβ42 complexes with α7-nicotinic acetylcholine receptor and CD14, were all significantly reduced by PTI-125. PTI-125 was safe and well-tolerated in all patients. Plasma half-life was 4.5 h and approximately 30% drug accumulation was observed on Day 28 vs. Day 1.
CONCLUSIONS: PTI-125 significantly reduced biomarkers of Alzheimer’s disease pathology, neurodegeneration, and neuroinflammation in both cerebrospinal fluid and plasma. All patients responded to treatment. The magnitude and consistency of reductions in established, objective biomarkers imply that PTI-125 treatment counteracted disease processes and reduced the rate of neurodegeneration. Based on encouraging biomarker data and safety profile, approximately 60 patients with mild-to-moderate AD are currently being enrolled in a Phase 2b randomized, placebo-controlled confirmatory study to assess the safety, tolerability and efficacy of PTI-125.
H.-Y. Wang ; Z. Pei ; K.-C. Lee ; E. Lopez-Brignoni ; B. Nikolov ; C.A. Crowley ; M.R. Marsman ; R. Barbier ; N. Friedmann ; L.H. Burns (2020): PTI-125 Reduces Biomarkers of Alzheimer’s Disease in Patients. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.6
JPAD Volume 7, N°03 - 2020
NEXT-GENERATION ALZHEIMER’S THERAPEUTICS: LEVERAGING DEEP BIOLOGY
F.M. Longo, S.M. Massa
J Prev Alz Dis 2020;3(7):138-139Show summaryHide summary
F.M. Longo ; S.M. Massa (2020): Next-generation Alzheimer’s Therapeutics: Leveraging Deep Biology. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.30
A IS FOR AMYLOID
J Prev Alz Dis 2020;3(7):140-141Show summaryHide summary
D.J. Selkoe (2020): A Is for Amyloid. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.27
AN INDUSTRY PERSPECTIVE: FUTURE OF ANTI-AMYLOID TRIALS
J Prev Alz Dis 2020;3(7):142-143Show summaryHide summary
L.D. Kramer (2020): An Industry Perspective: Future of Anti-Amyloid Trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.26
SCREENING FOR MILD COGNITIVE IMPAIRMENT: THERE IS THE WILL BUT IS THERE A WAY?
J Prev Alz Dis 2020;3(7):144-145Show summaryHide summary
J.E. Galvin (2020): Screening for Mild Cognitive Impairment: There is the Will but Is There a Way?. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.16
CTAD Task Force
THE FUTURE OF ANTI-AMYLOID TRIALS
P.S. Aisen, J. Cummings, R. Doody, L. Kramer, S. Salloway, D.J. Selkoe, J. Sims, R.A. Sperling, B. Vellas, and the EU/US CTAD 2019 Task Force
J Prev Alz Dis 2020;3(7):146-151Show summaryHide summary
The termination of many clinical trials of amyloid-targeting therapies for the treatment of Alzheimer’s disease (AD) has had a major impact on the AD clinical research enterprise. However, positive signals in recent studies have reinvigorated support for the amyloid hypothesis and amyloid-targeting strategies. In December 2019, the EU-US Clinical Trials on Alzheimer’s Disease (CTAD) Task Force met to share learnings from these studies in order to inform future trials and promote the development of effective AD treatments. Critical factors that have emerged in studies of anti-amyloid monoclonal antibody therapies include developing a better understanding of the specific amyloid species targeted by different antibodies, advancing our insight into the mechanism by which those antibodies may reduce pathology, implementing more comprehensive repertoires of biomarkers into trials, and identifying appropriate doses. Studies suggest that Amyloid-Related Imaging Abnormalities – effusion type (ARIA-E) are a manageable safety concern and that caution should be exercised before terminating studies based on interim analyses. The Task Force concluded that opportunities for developing effective treatments include developing new biomarkers, intervening in early stages of disease, and use of combination therapies.
P.S. Aisen ; J. Cummings ; R. Doody ; L. Kramer ; S. Salloway ; D.J. Selkoe ; J. Sims ; R.A. Sperling ; B. Vellas ; and the EU/US CTAD 2019 Task Force (2020): The Future of Anti-Amyloid Trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.24
NON-AMYLOID APPROACHES TO DISEASE MODIFICATION FOR ALZHEIMER’S DISEASE: AN EU/US CTAD TASK FORCE REPORT
S. Gauthier, P.S. Aisen, J. Cummings, M.J. Detke, F.M. Longo, R. Raman, M. Sabbagh, L. Schneider, R. Tanzi, P. Tariot, M. Weiner, J. Touchon, B. Vellas, and the EU/US CTAD Task Force
J Prev Alz Dis 2020;3(7):152-157Show summaryHide summary
While amyloid-targeting therapies continue to predominate in the Alzheimer’s disease (AD) drug development pipeline, there is increasing recognition that to effectively treat the disease it may be necessary to target other mechanisms and pathways as well. In December 2019, The EU/US CTAD Task Force discussed these alternative approaches to disease modification in AD, focusing on tau-targeting therapies, neurotrophin receptor modulation, anti-microbial strategies, and the innate immune response; as well as vascular approaches, aging, and non-pharmacological approaches such as lifestyle intervention strategies, photobiomodulation and neurostimulation. The Task Force proposed a general strategy to accelerate the development of alternative treatment approaches, which would include increased partnerships and collaborations, improved trial designs, and further exploration of combination therapy strategies.
S. Gauthier ; P.S. Aisen ; J. Cummings ; M.J. Detke ; F.M. Longo ; R. Raman ; M. Sabbagh ; L. Schneider ; R. Tanzi ; P. Tariot ; M. Weiner ; J. Touchon ; B. Vellas ; and the EU/US CTAD Task Force ; ; (2020): Non-Amyloid Approaches to Disease Modification for Alzheimer’s Disease: An EU/US CTAD Task Force Report. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.18
RATIONALE FOR EARLY DIAGNOSIS OF MILD COGNITIVE IMPAIRMENT (MCI) SUPPORTED BY EMERGING DIGITAL TECHNOLOGIES
M.N. Sabbagh, M. Boada, S. Borson, M. Chilukuri, P.M. Doraiswamy, B. Dubois, J. Ingram, A. Iwata, A.P. Porsteinsson, K.L. Possin, G.D. Rabinovici, B. Vellas, S. Chao, A. Vergallo, H. Hampel
J Prev Alz Dis 2020;3(7):158-164Show summaryHide summary
Disease-modifying pharmacotherapies for Alzheimer’s Disease (AD) are currently in late-stage clinical development; once approved, new healthcare infrastructures and services, including primary healthcare, will be necessary to accommodate a huge demand for early and large-scale detection of AD. The increasing global accessibility of digital consumer electronics has opened up new prospects for early diagnosis and management of mild cognitive impairment (MCI) with particular regard to AD. This new wave of innovation has spurred research in both academia and industry, aimed at developing and validating a new “digital generation” of tools for the assessment of the cognitive performance. In light of this paradigm shift, an international working group (the Global Advisory Group on Future MCI Care Pathways) convened to elaborate on how digital tools may be optimally integrated in screening-diagnostic pathways of AD The working group developed consensus perspectives on new algorithms for large-scale screening, detection, and diagnosis of individuals with MCI within primary medical care delivery. In addition, the expert panel addressed operational aspects concerning the implementation of unsupervised at-home testing of cognitive performance. The ultimate intent of the working group’s consensus perspectives is to provide guidance to developers of cognitive tests and tools to facilitate the transition toward globally accessible cognitive screening aimed at the early detection, diagnosis, and management of MCI due to AD.
M.N. Sabbagh ; M. Boada ; S. Borson ; M. Chilukuri ; P.M. Doraiswamy ; B. Dubois ; J. Ingram ; A. Iwata ; A.P. Porsteinsson ; K.L. Possin ; G.D. Rabinovici ; B. Vellas ; S. Chao ; A. Vergallo ; H. Hampel (2020): Rationale for Early Diagnosis of Mild Cognitive Impairment (MCI) supported by Emerging Digital Technologies. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.19
EARLY DETECTION OF MILD COGNITIVE IMPAIRMENT (MCI) IN PRIMARY CARE
M.N. Sabbagh, M. Boada, S. Borson, M. Chilukuri, B. Dubois, J. Ingram, A. Iwata, A.P. Porsteinsson, K.L. Possin, G.D. Rabinovici, B. Vellas, S. Chao, A. Vergallo, H. Hampel
J Prev Alz Dis 2020;3(7):165-170Show summaryHide summary
Mild cognitive impairment (MCI) is significantly misdiagnosed in the primary care setting due to multi-dimensional frictions and barriers associated with evaluating individuals’ cognitive performance. To move toward large-scale cognitive screening, a global panel of clinicians and cognitive neuroscientists convened to elaborate on current challenges that hamper widespread cognitive performance assessment. This report summarizes a conceptual framework and provides guidance to clinical researchers and test developers and suppliers to inform ongoing refinement of cognitive evaluation. This perspective builds upon a previous article in this series, which outlined the rationale for and potentially against efforts to promote widespread detection of MCI. This working group acknowledges that cognitive screening by default is not recommended and proposes large-scale evaluation of individuals with a concern or interest in their cognitive performance. Such a strategy can increase the likelihood to timely and effective identification and management of MCI. The rising global incidence of AD demands innovation that will help alleviate the burden to healthcare systems when coupled with the potentially near-term approval of disease-modifying therapies. Additionally, we argue that adequate infrastructure, equipment, and resources urgently should be integrated in the primary care setting to optimize the patient journey and accommodate widespread cognitive evaluation.
M.N. Sabbagh ; M. Boada ; S. Borson ; M. Chilukuri ; B. Dubois ; J. Ingram ; A. Iwata ; A.P. Porsteinsson ; K.L. Possin ; G.D. Rabinovici ; B. Vellas ; S. Chao ; A. Vergallo ; H. Hampel (2020): Early Detection of Mild Cognitive Impairment (MCI) in Primary Care. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.21
EARLY DETECTION OF MILD COGNITIVE IMPAIRMENT (MCI) IN AN AT-HOME SETTING
M.N. Sabbagh, M. Boada, S. Borson, P.M. Doraiswamy, B. Dubois, J. Ingram, A. Iwata, A.P. Porsteinsson, K.L. Possin, G.D. Rabinovici, B. Vellas, S. Chao, A. Vergallo, H. Hampel
J Prev Alz Dis 2020;3(7):171-178Show summaryHide summary
Emerging digital tools have the potential to enable a new generation of qualitative and quantitative assessment of cognitive performance. Moreover, the ubiquity of consumer electronics, such as smartphones and tablets, can be harnessed to support large-scale self-assessed cognitive screening with benefit to healthcare systems and consumers. A wide variety of apps, wearables, and new digital technologies are either available or in development for the detection of mild cognitive impairment (MCI), a risk factor for dementia. Two categories of novel methodologies may be considered: passive technologies (which monitor a user’s behavior without active user input) and interactive assessments (which require active user input). Such examinations can be self-administered, supervised by a caregiver, or conducted by an informant at home or outside of a clinical setting. These direct-to-consumer tools have the potential to sidestep barriers associated with cognitive evaluation in primary care, thus improving access to cognitive assessments. Although direct-to-consumer cognitive assessment is associated with its own barriers, including test validation, user experience, and technological concerns, it is conceivable that these issues can be addressed so that a large-scale, self-assessed cognitive evaluation that would represent an initial cognitive screen may be feasible in the future.
M.N. Sabbagh ; M. Boada ; S. Borson ; P.M. Doraiswamy ; B. Dubois ; J. Ingram ; A. Iwata ; A.P. Porsteinsson ; K.L. Possin ; G.D. Rabinovici ; B. Vellas ; S. Chao ; A. Vergallo ; H. Hampel (2020): Early Detection of Mild Cognitive Impairment (MCI) in an At-Home Setting. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.22
DEVELOPMENT OF AN UPSA SHORT FORM FOR USE IN LONGITUDINAL STUDIES IN THE EARLY ALZHEIMER’S DISEASE SPECTRUM
T.E. Goldberg, P.D. Harvey, D.P. Devanand, R.S.E. Keefe, J.J. Gomar
J Prev Alz Dis 2020;3(7):179-183Show summaryHide summary
BACKGROUND: In individuals with only mild or very mild cognitive attenuations (i.e., so-called pre-clinical AD), performance-based measures of function may be superior to informant-based measures because of increased sensitivity, greater reliability, and fewer ceiling effects.
Objective: We sought to determine if a performance-based measure of everyday function would demonstrate adequate psychometric properties and validity in the context of serial assessment over a one-year period in patients with Mild Cognitive Impairment (MCI) and early stage Alzheimer’s disease (AD).
Design: Participants were assessed with the performance-based measure at baseline, six weeks, and one year.
Setting: A specialized center for the assessment and treatment of AD.
Participants: Three groups of subjects participated: a healthy subjects (HS) older cognitively intact group (N=43), an MCI group (N=20), and an AD group (N=26).
Measurements: A three subtest short form of the UCSD Performance-Based Skills Assessment (UPSA) (called the UPSA-3) was the measure of interest. It consisted of the Communication, Planning, and Finance subtests.
Results: Mixed model repeated measures were used to assess performance over time. Large group effects were present (HS>MCI>AD). Additionally, the AD and MCI groups demonstrated declines over one year, while the HS group remained stable (group x time interaction p=.11). The MCI/AD group demonstrated adequate test-retest reliability and did not demonstrate ceiling or floor effects.
Conclusion: Our data indicate that the UPSA-3 is suitable for clinical trials in that it has adequate ecological coverage and reasonable psychometric properties, and perhaps most importantly, demonstrates validity in serial assessments.
T.E. Goldberg ; P.D. Harvey ; D.P. Devanand ; R.S.E. Keefe ; J.J. Gomar (2019): Predictive factors of in-hospital mortality in older adults with community-acquired bloodstream infection. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2019.51
TARGETING LIFESTYLE BEHAVIOR TO IMPROVE BRAIN HEALTH: USER-EXPERIENCES OF AN ONLINE PROGRAM FOR INDIVIDUALS WITH SUBJECTIVE COGNITIVE DECLINE
L.M.P. Wesselman, A.K. Schild, A.M. Hooghiemstra, D. Meiberth, A.J. Drijver, M.v. Leeuwenstijn-Koopman, N.D. Prins, S. Brennan, P. Scheltens, F. Jessen, W.M. van der Flier, S.A.M. Sikkes
J Prev Alz Dis 2020;3(7):184-194Show summaryHide summary
Background: Online programs targeting lifestyle have the potential to benefit brain health. We aimed to develop such a program for individuals with subjective cognitive decline (SCD). These individuals were reported to be at increased risk for dementia, and report both an intrinsic need for brain health information and motivation to participate in prevention strategies. Co-creation and user-evaluation benefits the adherence to and acceptance of online programs. Previously, we developed a prototype of the online program in co-creation with the users .
Objectives: We now aimed to evaluate the user-experiences of our online lifestyle program for brain health.
Design: 30-day user test; multi-method.
Setting: Participants were recruited in a memory clinic and (online) research registries in the Netherlands (Alzheimer Center Amsterdam) and Germany (Center for memory disorders, Cologne).
Participants: Individuals with SCD (N=137, 65±9y, 57% female).
Measurements: We assessed user-experiences quantitatively with rating daily advices and usefulness, satisfaction and ease of use questionnaires as well as qualitatively using telephone interviews.
Results: Quantitative data showed that daily advices were rated moderately useful (3.5 ±1.5, range 1-5 points). Participants (n=101, 78%) gave moderate ratings on the programs’ usability (3.7±1.3, max 7), ease of learning (3.6±1.9) and satisfaction (4.0±1.5), and marginal ratings on the overall usability (63.7±19.0, max 100). Qualitative data collected during telephone interviews showed that participants highly appreciated the content of the program. They elaborated that lower ratings of the program were mainly due to technical issues that hindered a smooth walk through. Participants reported that the program increased awareness of lifestyle factors related to brain health.
Conclusions: Overall user-experience of the online lifestyle program was moderate to positive. Qualitative data showed that content was appreciated and that flawless, easy access technique is essential. The heterogeneity in ratings of program content and in program use highlights the need for personalization. These findings support the use of online self-applied lifestyle programs when aiming to reach large groups of motivated at-risk individuals for brain health promotion.
L.M.P. Wesselman ; A.K. Schild ; A.M. Hooghiemstra ; D. Meiberth ; A.J. Drijver ; M.v. Leeuwenstijn-Koopman ; N.D. Prins ; S. Brennan ; P. Scheltens ; F. Jessen ; W.M. van der Flier ; S.A.M. Sikkes (2020): Targeting Lifestyle Behavior to Improve Brain Health: User-Experiences of an Online Program for Individuals with Subjective Cognitive Decline. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.9
FUTILITY ANALYSES IN ALZHEIMER’S DISEASE (AD) CLINICAL TRIALS: A RISKY BUSINESS
P.S. Aisen, R. Raman
J Prev Alz Dis 2020;3(7):195-196Show summaryHide summary
P.S. Aisen ; R. Raman (2020): Futility Analyses in Alzheimer’s Disease (AD) Clinical Trials: A Risky Business. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.20
IMPACT OF THE COVID-19 OUTBREAK ON THE CLINICAL AND RESEARCH ACTIVITIES OF MEMORY CLINICS: AN ALZHEIMER’S DISEASE CENTER FACING THE COVID-19 CRISIS
P.J. Ousset, B. Vellas
J Prev Alz Dis 2020;3(7):197-198Show summaryHide summary
P.J. Ousset ; B. Vellas ; (2020): Impact of the Covid-19 Outbreak on the Clinical and Research Activities of Memory Clinics: An Alzheimer’s Disease Center Facing the Covid-19 Crisis. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.17
THE EU/US TASK FORCE’S FUTURE FOR ANTI-AMYLOID TRIALS: FAITES VOS JEUX
J Prev Alz Dis 2020;3(7):199-200Show summaryHide summary
L.S. Schneider (2020): The EU/US Task Force’s Future for Anti-Amyloid Trials: Faites Vos Jeux. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.29