Nevin Manimala

Alzheimers Dement. 2024 Dec;20 Suppl 6:e087120. doi: 10.1002/alz.087120.

ABSTRACT

BACKGROUND: Donepezil, an acetylcholinesterase inhibitor (AChEI), is an FDA-approved drug to treat these neurodegenerative diseases, e.g., Alzheimer’s Disease (AD) and Mild Cognitive Impairment (MCI). AChEIs are able to stabilize or slow decline in cognition, function, and behavior. Our objective is to investigate whether Donepezil is able to significantly reduce the rate of hippocampal (Hip) atrophy in neurodegenerative diseases.

METHODS: We followed the PRISMA statement guidelines during the preparation of this systematic review. We searched in MEDLINE (PubMed), CENTRAL (Cochrane Library, November 2023), SCOPUS, and Web of Science and included randomized clinical trials (RCTs) comparing 10 mg donepezil-treated with donepezil-untreated (placebo) and/without control in terms of magnetic resonance imaging (MRI) follow up visits’ results.

RESULTS: A total of four studies out of 174 met our inclusion criteria (599 participants; donepezil = 281, placebo = 318), two of them were ADs and the others were MCIs. 323 participants were female (representing 53.92% of included study population). Follow up between baseline and endpoint results was 12 months. Available outcome data cover reduction of hippocampal atrophy rate in patients with neurodegenerative diseases, but data on several outcome dimensions were either unavailable or not consistently reported across all studies. Results concluded from studies been conducted on MCI patients were statistically insignificant (P > 0.05) annual percentage of change (APC) of Hip volume at 12 months compared to placebo, but studies on AD patients indicated statistically significant APC of Hip volume at 24 and 50 weeks (P < 0.001), but one of these studies also reported no significant difference in neuropsychological performance between treatment groups.

CONCLUSION: The findings of this review suggest that donepezil reducing hippocampal atrophy rate was statistically insignificant for MCI and statistically significant for AD, but its clinical significance is questionable until further investigations. It is also important to note that while the data provided insights into the impact of donepezil, there were limitations, such as incomplete reporting of outcome dimensions in some studies.

PMID:39782575 | DOI:10.1002/alz.087120

Alzheimers Dement. 2024 Dec;20 Suppl 6:e086844. doi: 10.1002/alz.086844.

ABSTRACT

BACKGROUND: Clinical trials should strive to yield results that are clinically meaningful rather than solely relying on statistical significance. However, the determination of clinical meaningfulness of dementia clinical trials lacks standardization and varies based on the trial’s nature. To tackle this issue, a proposed approach involves assessing the time saved before reaching a specific threshold in cognitive status. In this study, we investigated the time saved in cognitive decline among the top responders based on the individual-level treatment responses (ITR) analysis, using data from the Internet-based Conversational Engagement Clinical Trial (I-CONECT; NCT02871921).

METHOD: I-CONECT is a randomized controlled trial to examine the effects of conversational interactions on cognition among socially isolated participants aged ≥ 75 years old. The experiment group engaged in video chats with study staff 4 times/week for 6 months; the control groups received weekly check-in phone calls. We focused on cognitive outcomes that exhibited significant treatment effects at 6-month follow-up: the Montreal Cognitive Assessment (MoCA) for global cognition and Category Fluency Animals (CFA) for semantic fluency. To assess ITR, we employed 300 iterations of 3-fold cross-validated random forest models. We estimated treatment heterogeneity by conducting permutation tests on the area between curves (ABC) statistics derived from the ITR scores. We estimated time saved in cognitive decline as the difference in the number of months required for the top responders (top 25%; 33%) and the remaining participants to reach the same cognitive level at 6-months follow-up.

RESULT: ABC statistics showed substantial heterogeneity in treatment response with MoCA but modest heterogeneity in treatment response with CFA. For global cognition, assuming a treatment effect size between 30-50%, the top 25% and 33% of responders exhibited potential cognitive delays ranging from 4.1 to 10.8 months and 5.9 to 13.9 months, respectively (Figure 1). For semantic fluency, large effect sizes (70-100%) are required to show potential cognitive delays ranging from 0.5 to 6.7 months.

CONCLUSION: Individual differences in the time saved for cognitive decline through the ITR analysis are meaningful outcomes in clinical trials. Future trial outcomes should consider both quantity and quality concepts such as quality-adjusted time saved.

PMID:39782573 | DOI:10.1002/alz.086844

Alzheimers Dement. 2024 Dec;20 Suppl 6:e086330. doi: 10.1002/alz.086330.

ABSTRACT

BACKGROUND: Iron is vital for metabolism but can act as a catalyst for oxidative damage. Elevated brain iron, determined from biomarkers of iron (CSF ferritin and quantitative susceptibility mapping MRI) and from post-mortem measurement of brain iron, has been associated with accelerated cognitive decline in multiple Alzheimer’s disease (AD) clinical, cohorts. These findings supported the hypothesis that treatment with the brain-permeable iron chelator deferiprone may be associated clinical benefit in AD.

METHODS: A multicentre, phase II, double-blind, randomized, placebo controlled clinical trial of deferiprone (15 mg/kg administered orally twice a day) was conducted in people with amyloid-confirmed MCI and mild AD (MMSE≥20) over 12 months. The primary outcome was cognition, assessed at baseline, 6 months, 12 months using neuropsychological test battery of memory (3), executive function (3) and attention (2). Secondary outcomes included adverse events (safety analysis), change in brain iron burden measured by quantitative susceptibility mapping MRI (target engagement), and brain volume changes (secondary efficacy measure).

RESULTS: 81 participants were recruited and randomized in a 2:1 ratio (53 drug:28 placebo). Baseline characteristics were equivalent between arms. 54 participants completed the study (withdrawals = 7 placebo and 20 deferiprone arm). Quantitative susceptibility mapping of the hippocampus at baseline and 12 months confirmed a significant (β[95%CI]:-6.7 [-11.0,-2.5]; P = 0.004) lowering of brain iron in the deferiprone arm (mean change:-3.71 ppb, 95% CI:-7.24, -0.18) compared to placebo, whose iron levels increased during this timeframe (+3.03 ppb, 95%CI: 0.27, 5.80). Participants in the Deferiprone arm showed large statistically significant cognitive decline (β[95%CI]:-0.295 [-0.456, -0.135], P<0.001, Cohen’s d: -0.704) compared to placebo (deferiprone mean change, [95%CI]:-0.86, [-1.12, -0.61]; placebo mean change, [95%CI]:-0.27, [-0.55, 0.00]).

CONCLUSION: Deferiprone (30 mg/kg/day) treatment markedly accelerated cognitive decline in people with amyloid-confirmed MCI and mild AD. These findings highlight the importance of iron for cognition in AD, and provoke new questions. It is possible that iron elevation in AD is protective, or represents iron being sequestered inappropriately (e.g. deposited in pathology) leading to functional iron deficiency; or the chosen dose of deferiprone was too high for this condition.

PMID:39782553 | DOI:10.1002/alz.086330

Alzheimers Dement. 2024 Dec;20 Suppl 6:e086486. doi: 10.1002/alz.086486.

ABSTRACT

BACKGROUND: Pivotal Alzheimer’s Disease (AD) trials typically require thousands of participants, resulting in long enrollment timelines and substantial costs. We leverage deep learning predictive models to create prognostic scores (forecasted control outcome) of trial participants and in combination with a linear statistical model to increase statistical power in randomized clinical trials (RCT). This is a straightforward extension of the traditional RCT analysis, allowing for ease of use in any clinical program. We demonstrate the application of these methods retrospectively on 3 pivotal Phase III clinical trials in mild-to-moderate AD (NCT00236431, NCT00574132, and NCT00575055).

METHOD: A probabilistic deep learning model was trained on the trajectories of nearly 7000 participants who had varying degrees of cognitive impairment, ranging from mild cognitive impairment (MCI) to moderate AD. These trajectories were collected observational studies and the control arms of RCTs. This trained model was used to forecast the control outcomes of participants in the three trials retrospectively, by entering their individual trial baseline data. The resultant forecasts are known as prognostic scores and represent comprehensive predictions across a broad range of AD outcomes. We evaluated the potential reduction in estimated variance and how this could translate to required sample size by incorporating the prognostic score as a covariate in the primary linear statistical model of each study, analyzing the 11-component Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) and the Clinical Dementia Rating Sum-of-Boxes (CDR-SB) endpoints as applicable.

RESULT: Prognostic scores have the potential to decrease estimated variance between 5% to 10% and placebo arm sample size between 7% and 17% in the 3 studies when comparing standard + prognostic score vs. standard adjustment.

CONCLUSION: Prognostic scores have the potential to increase the statistical power in clinical trials; this would enable a reduced number of subjects required to detect a significant treatment effect. Potential sample size reduction during trial planning must be carefully estimated using independent validation studies to reduce the risk of under-powering the trial.

PMID:39782540 | DOI:10.1002/alz.086486

Alzheimers Dement. 2024 Dec;20 Suppl 6:e086988. doi: 10.1002/alz.086988.

ABSTRACT

BACKGROUND: The Mini-Mental State Examination (MMSE) is a common screening tool in Alzheimer’s disease (AD) clinical trials. MMSE score inflation at inclusionary visits poses challenges by potentially amplifying placebo responses and complicating the detection of treatment effects. Despite these concerns, prior research (e.g., Echevarria, 2023) has reported instances of MMSE score inflation when it is utilized as an inclusion criterion. Little is known, however, whether this phenomenon is observed universally in AD trials across geo-cultural regions. This study examined whether MMSE score changes from Screening to Baseline differ across geo-cultural regions in global AD trials. The regions compared included North America, Asia, Eastern Europe, Western Europe, Latin America, and the Middle East/Africa.

METHOD: Data from two multinational Phase 3 AD trials, where MMSE was an inclusionary criterion at Screening but not at Baseline, were analyzed. Both studies used the same MMSE cut-off for the inclusionary criterion. All raters underwent uniform training and certification for MMSE administration. An enhanced eMMSE scale was employed to minimize rater errors, and a data quality surveillance program included central audio review of eMMSE administration and scoring. Kruskal-Wallis and Dunn’s tests were used to compare score changes across regions.

RESULTS: Table 1 displays the mean score changes from MMSE Screening to Baseline for each region. A Kruskal-Wallis H-test revealed statistically significant heterogeneity in MMSE score changes across regions, χ2 (5) = 16.709, p<.001. Dunn’s tests indicated significantly smaller score changes in North America (p<.001) compared to other regions.

CONCLUSIONS: This study observed geo-cultural variances in MMSE score changes from Screening to Baseline in AD trials. North America demonstrated a significantly smaller score decrement than other regions, indicating potential lesser MMSE score inflation at inclusionary visits. The geo-cultural differences in MMSE score inflation might reflect cultural impacts on placebo responses. Previous research underscores cultural effects on placebo and nocebo phenomena as cultural factors impact therapeutic expectations, disease perceptions, and treatment interactions (Cundiff-O’Sullivan et al.). Further investigation is essential to comprehend the factors driving these geo-cultural disparities in MMSE Screening score inflation and their implications in AD trials.

PMID:39782533 | DOI:10.1002/alz.086988

Alzheimers Dement. 2024 Dec;20 Suppl 6:e084775. doi: 10.1002/alz.084775.

ABSTRACT

Numerous drugs (including disease-modifying therapies, cognitive enhancers and neuropsychiatric treatments) are being developed for Alzheimer’s and related dementias (ADRD). Emerging neuroimaging modalities, and genetic and other biomarkers potentially enhance diagnostic and prognostic accuracy. These advances need to be assessed in real-world studies (RWS). Currently, there are several national and two emerging international ADRD registries that differ in their data requirements. For instance, most existing registries do not routinely capture safety data. Outcome harmonisation would facilitate collaboration between international and national registries and, in turn, support interoperability, and enhance the statistical power and external validity of RWS. In response, the International Registry for Alzheimer’s Disease and other Dementias (InRAD) convened a Steering Committee of leaders and investigators from registries in Europe, Asia and Australia to define a harmonised minimum dataset (MDS) and extended dataset (EDS) that enables collaboration. A wider stakeholder group, including patient representatives, regulators, payors and industry, will validate the agreed MDS and EDS (Figure 1). The harmonised MDS and EDS will form the basis of data captured in InRAD, which can also form the foundation of collaboration in future RWS within and across registries (Figures 2 and 3). The harmonised MDS and EDS reflect the needs of two user levels. Firstly, the MDS and EDS should inform differential diagnosis and clinical decision making by presenting longitudinal data in a graphical dashboard summarising important outcomes at the point of care. The harmonised MDS will encompass demographics, functional and cognitive instruments, and rating scales. The harmonised EDS can answer specific questions and/or include additional functional and cognitive instruments to, for example, reflect local clinical practice and patient-reported outcomes. Secondly, harmonised MDS and EDS facilitate collaboration between registries to, for example, benchmark, assess efficacy and important safety outcomes, and to inform health technology assessments. The harmonised data sets will be as lean as practical, undergo comprehensive beta-testing by InRAD and the results shared with stakeholders. The presentation will explore the background to and need for data harmonisation across registries, the latest iteration of the harmonised MDS and EDS, and InRAD’s overall progress.

PMID:39782525 | DOI:10.1002/alz.084775

Alzheimers Dement. 2024 Dec;20 Suppl 6:e086492. doi: 10.1002/alz.086492.

ABSTRACT

BACKGROUND: Alzheimer’s disease (AD) is a progressive neurodegenerative disease associated with neuroinflammation and heightened production of reactive oxygen species (ROS) in the brain from overactive NADPH Oxidase 2 (NOX2). The current study examines whether administration of a novel, brain-penetrant NOX2 inhibitor (CPP11G & CPP11H) reduces amyloid plaque load and improves AD-associated vascular dysfunction in a male APP-PS1 mouse model of AD.

METHOD: Intraperitoneal injections of CPP11G (n = 1) or CPP11H (n = 2) three times per week began at 9-10 months of age in the treatment APP-PS1 group (15 mg/kg). The control group of age-matched APP-PS1 mice received no treatment (n = 7). All mice were implanted with a 5mm cranial window for awake optical imaging at least 2 weeks prior to onset of treatment. Two-photon microscopy was performed to assess longitudinal changes in amyloid plaque deposition after weekly Methoxy-04 administration (1 mg/kg). Changes in plaque load were quantified weekly and averaged monthly. Additionally, wide-field optical imaging at 620nm was performed with a 90s, 8% CO2 hypercapnic challenge. This imaging wavelength is sensitive to changes in blood oxygenation (OIS-BOLD) to capture changes in vascular reactivity over time.

RESULT: Treatment with CPP11G/H shows a trend toward reduction in cortical plaque load when compared to an untreated cohort (Fig. 1). OIS-BOLD results for vascular reactivity studies show a slight trend of improved vascular function over time with CPP11G/H treatment (Fig. 2).

CONCLUSION: Our preliminary findings show a strong trend in amyloid plaque reduction with ongoing CPP11G/H treatment in older-aged AD mice and improved vascular function. Ongoing studies to increase the size of the treated cohort will reveal the reliability and statistical significance of CPP11G/H’s therapeutic benefits. We are also examining the impact of treatment on microglia activation and gliosis in APP-PS1::CX3CR1-GFP mice (Fig. 3).

PMID:39782524 | DOI:10.1002/alz.086492

Alzheimers Dement. 2024 Dec;20 Suppl 6:e086975. doi: 10.1002/alz.086975.

ABSTRACT

BACKGROUND: Randomized placebo-controlled trials (RCTs) are the gold standard to evaluate efficacy of new drug treatments for Alzheimer’s disease. For example, the United States FDA approved the brain amyloid-targeting drug lecanemab following CLARITY AD, Biogen and Eisai’s Phase 3 RCT. However, recruiting enough participants for a high-powered and demographically representative trial is difficult and expensive. Fortunately, historical patient data from existing external observational studies of a disease can help populate RCTs [Thorlund et al. (2020). https://doi.org/10.2147/CLEP.S242097]. We propose a new trial framework that uses an external study to source “digital twins” for each trial participant. Using computer-simulated trials mimicking CLARITY AD’s demographics and 18-month duration, we show that our digital twin trial (DTT) has increased power compared to a conventional RCT.

METHOD: A continuous time linear mixed model tracked CDRSB change-from-baseline (CDRSBΔbl) trajectories in 670 ADNI participants satisfying CLARITY AD inclusion criteria [clinicaltrials.gov/study/NCT03887455]. To simulate an RCT, we resampled and added noise to participants’ data, generating a desired sample size of “recruited” participants who we randomized 1:1 to “drug” and “placebo” groups. We calculated participants’ CDRSBΔbl scores at 18 months and simulated the drug effect as a 25% reduction in CDRSBΔbl. For each participant in our DTT, we used Gower’s distance on demographic and clinical baseline variables to identify 20 most-similar real ADNI participants (the digital twins) from our original 670. Each original ADNI participant’s 18-month CDRSBΔbl was calculated using the model. A z-score was then calculated for each DTT participant’s 18-month CDRSBΔbl relative to their digital twins. T-tests were used to evaluate DTT drug vs. placebo group difference in mean z-score and, separately, RCT group difference in mean 18-month CDRSBΔbl. We simulated each trial 1,000 times. Power is the proportion of simulations with a statistically significant treatment group difference.

RESULT: Figure 1 shows that 90% power is reached with approximately 500 fewer recruited participants in simulated DTTs (∼1,600 participants) compared to RCTs (∼2,100 participants).

CONCLUSION: DTTs might require substantially fewer recruited participants to achieve the same power as conventional RCTs. This sample size reduction could facilitate recruitment for trials on Alzheimer’s and in rare diseases with low patient numbers.

PMID:39782519 | DOI:10.1002/alz.086975

Alzheimers Dement. 2024 Dec;20 Suppl 6:e085863. doi: 10.1002/alz.085863.

ABSTRACT

BACKGROUND: Cognitive impairment, a common aging-related pathology, is a risk factor for dementia. Echinacoside (ECH), derived from the traditional Chinese medicine Cistanche deserticola, shows anti-aging properties including anti-inflammation, oxidative stress reduction, and neuronal protection. Despite its benefits, the beneficial impact of ECH on age-related cognitive decline remains unclear. Senescence accelerated mouse-prone 8 (SAMP8) mice, known for rapid aging and related pathologies in the brain like glial activation, neuro-inflammation, neuron loss, and cognitive decline, are ideal for this study. The purpose of this study is to investigate the effect of ECH effects on cognitive functions in SAMP8 mice.

METHODS: Six-month-old male SAMP8 mice (n = 8∼9) were used as the model group, while age-matched senescence-accelerated mouse resistant 1 (SAMR1) mice were used as normal controls. After adaptation in the specific pathogen free (SPF) room for one week, we administered ECH intragastrically to the SAMP8 mice daily for two months, and the control group was administered with saline. Behavioral tests, including open field test and Morris water maze, were performed to assess the mood and memory function of the SAMP8 mice. After that, all mice were sacrificed by intraperitoneal perfusion to extract brain tissues for western blotting and immunofluorescence.

RESULTS: ECH-treated SAMP8 mice showed significantly reduced escape latency in the Morris water maze compared to controls, indicating improved cognitive abilities (P<0.05). ECH also tended to lower beta-amyloid and phosphorylated Tau levels in the hippocampus of SAMP8 mice, though not statistically significant due to small sample sizes (n = 3). SAMP8 mice had higher microglia and astroglia activation than SAMR1 mice, but ECH notably inhibited this in SAMP8 mice (Figure 1).

CONCLUSIONS: Our study demonstrates that ECH intervention can markedly enhance the memory function in SAMP8 mice and inhibits microglial and astroglial activation. These findings suggest a beneficial role of ECH in alleviating cognitive decline in SAMP8 mice by reducing glia-related inflammation.

PMID:39782511 | DOI:10.1002/alz.085863

Alzheimers Dement. 2024 Dec;20 Suppl 6:e083432. doi: 10.1002/alz.083432.

ABSTRACT

An overview is given of surrogate marker evaluation, starting from the original definition of Prentice and his criteria, the estimation framework of Freedman, the meta-analytic framework, and the evaluation of surrogate endpoints from a causal inference point of view. Attention will be given, in particular, to evaluating tau-PET as a reasonably likely surrogate in Alzheimer’s Disease. A meta-analytic surrogate marker evaluation approach will be followed, for a continuous surrogate and a continuous true endpoint. Provisions are made to use both clinical trial data as well as natural history (real world) data. The statistical analysis consists of two steps: (1) a federated step where every site analyzes its own data, according to this protocol and the software provided; (2) a central step where the data hub processes the model outputs from the first step. The federated data analysis is a framework. As such, it can be applied based on a variety of choices made. Such choices pertain to patient population (e.g., early versus later stage), cognitive scale used (or, alternatively, sub-scale or custom-made item set), and particular tau PET measurement used (e.g., with variation over region of interest). A number of possible extensions are discussed too, as well as a single-trial evaluation method to complement the federated meta-analysis.

PMID:39782495 | DOI:10.1002/alz.083432