Mild Cognitive Impairment Clinical Trials Research Articles

Estimating attrition in mild-to-moderate Alzheimer’s disease and mild cognitive impairment clinical trials

BackgroundParticipant retention is a key factor that affects clinical trial integrity. Trial protocols estimate attrition as a function of sample size calculations. Alzheimer’s disease (AD) is an area of active treatment development. We aimed to quantify the association between trial duration and completion rates and provide guidance for estimating attrition in AD trial protocols.MethodsUsing the Alzforum and ClinicalTrials.gov databases, we analyzed retention data from 125 mild-to-moderate AD and 12 mild cognitive impairment (MCI) clinical trials. We compared the rates of completion between trial arms (active vs. control) and ran regression models to test the hypothesis that trials with longer study duration have lower trial completion using all available data and restricting to placebo data. Our primary outcome was the odds of trial completion for a 6-month increase in trial duration. From the regression model, we estimated the proportion of participants completing 6-, 12-, and 18-month trials.ResultsWe found that 21 (17%) mild-to-moderate AD trials and 1 (8%) MCI trial demonstrated greater dropout in treatment compared to placebo arms. For every 6-month increase in trial duration, there was a 27% decrease in the odds of trial completion (OR = 0.73; 95% CI 0.66, 0.81; p < 0.001) among participants in mild-to-moderate AD trials and a 55% decrease (OR = 0.45; 95% CI 0.36, 0.57; p < 0.001) among participants in MCI trials. The proportion of participants in the placebo group completing 6-, 12-, and 18-month trials were estimated to be 85.2%, 80.0%, and 73.3% for mild-to-moderate AD trials and 91.9%, 84.2%, and 71.3% for MCI trials, respectively.ConclusionsLonger duration trials may be underpowered to demonstrate estimated treatment effects and may suffer from a greater risk of bias than do shorter trials.

Dyadic retention in a phase 3 mild cognitive impairment clinical trial

AbstractBackgroundExiting a study early (dropout) may bias treatment effect estimates, while dropout and missing visits reduces study power. Simply increasing planned sample sizes cannot remove bias due to non‐ignorable missingness (Fleming, 2011). Preventing missing data is best (National Research Council, 2010). Hence, quantifying associations with missingness may identify ways to improve retention. Alzheimer’s disease (AD) clinical trials require study participation by a participant and study partner. Previous research examined dyadic retention in AD dementia trials (Grill et al., 2013; Bernstein, Grill &amp; Gillen, 2021), yet less is understood in mild cognitive impairment (MCI) trials. Here, we examined MCI trial dropout rates and missingness patterns by dyad type.MethodWe performed retrospective analyses of the Alzheimer’s Disease Cooperative Study phase 3 MCI trial of donepezil and vitamin E. Scheduled study visits occurred at baseline, month 3, and semi‐annually until month 36. Study completion included the progression to a possible or probable AD diagnosis or month 36 visit. Dropout was withdrawal of consent or lost‐to‐follow‐up. Deaths and study completions were censored. Dyad types were spousal, adult child, or other. We estimated Kaplan‐Meier‐based dropout rates and summarized frequencies of on‐study missing visit patterns by baseline dyad type and stratified by randomized treatment (placebo, donepezil, vitamin E).ResultFigure 1 displays cumulative dropout rates by dyad type and treatment (panels A, B, C). Among 259 participants randomized to placebo, estimated study dropout rates were 24% for spousal, 16% for adult child, and 14% for other dyads. Table 1 summarizes on‐study missing visit patterns by dyad type and treatment; Figure 2 displays placebo data for specific patterns of missing data. While on study, 21% of spousal, 23% of adult child, and 27% of other dyads missed at least one scheduled visit, primarily monotonic missingness.ConclusionDyad type may be associated with some types of missingness in MCI clinical trials. Implementing dyad‐type‐specific strategies that encourage staying on study and attending all scheduled visits may improve retention, thus reducing bias, in future MCI trials.

Impact of Study Partner Replacement in Mild Cognitive Impairment Clinical Trials

AbstractBackgroundIn Alzheimer’s disease (AD) clinical trials, including trials enrolling patients with Mild Cognitive Impairment (MCI), participants must enroll with a study partner (SP). SPs ensure compliance and provide study data, including assessments of the participant’s cognition and function. Thus, consistency in SP reporting is essential to trial integrity. We quantified the impact of SP replacement on bias and variance of SP‐reported AD Cooperative Study Activities of Daily Living (ADCS‐ADL‐MCI) scores in a large Phase 3 MCI trial.MethodWe analyzed data from the ADCS Donepezil/Vitamin E MCI Trial. We used logistic regression to estimate the association between SP type (spouse or non‐spouse) and the odds of experiencing an SP change. We used generalized estimating equations (GEE) to longitudinally model the differences in ADL scores recorded at consecutive visits as a function of whether an SP change occurred. All models adjusted for confounding factors, including SP type, participant age, time (in months) since baseline visit, gender, and ADL score at previous visit.ResultAmong the 768 participants, 41 (5%) experienced at least one SP change (Table 1). We estimated that the odds of experiencing an SP change were 60% lower for spousal SP dyads when compared to non‐spousal SP dyads (OR = 0.40; 95% CI: [0.18, 0.88]). Compared to those with consistent SP, participants who experienced SP replacement had, on average, a consecutive visit absolute score difference that was 1.76 points larger in magnitude (95% CI: [0.24, 3.29]; Figure 1). ADL scores were neither systematically larger nor smaller, on average, when a participant experienced a SP change (‐0.60; 95% CI: [‐2.61, 1.41]; Figure 2). The difference in the variance for end‐of‐study change from baseline ADL was higher for those who experienced an SP change compared to those who did not (110.35 vs 86.78; p‐value = 0.25).ConclusionOur results suggests that while SP replacement may not result in systematic bias on functional outcomes, it does increase variability. Efforts to reduce replacement or otherwise account for variability may be necessary.

Treatment effects on event-related EEG potentials and oscillations in Alzheimer's disease

Alzheimer's disease dementia (ADD) is the most diffuse neurodegenerative disorder belonging to mild cognitive impairment (MCI) and dementia in old persons. This disease is provoked by an abnormal accumulation of amyloid-beta and tauopathy proteins in the brain. Very recently, the first disease-modifying drug has been licensed with reserve (i.e., Aducanumab). Therefore, there is a need to identify and use biomarkers probing the neurophysiological underpinnings of human cognitive functions to test the clinical efficacy of that drug. In this regard, event-related electroencephalographic potentials (ERPs) and oscillations (EROs) are promising candidates. Here, an Expert Panel from the Electrophysiology Professional Interest Area of the Alzheimer's Association and Global Brain Consortium reviewed the field literature on the effects of the most used symptomatic drug against ADD (i.e., Acetylcholinesterase inhibitors) on ERPs and EROs in ADD patients with MCI and dementia at the group level. The most convincing results were found in ADD patients. In those patients, Acetylcholinesterase inhibitors partially normalized ERP P300 peak latency and amplitude in oddball paradigms using visual stimuli. In these same paradigms, those drugs partially normalize ERO phase-locking at the theta band (4–7 Hz) and spectral coherence between electrode pairs at the gamma (around 40 Hz) band. These results are of great interest and may motivate multicentric, double-blind, randomized, and placebo-controlled clinical trials in MCI and ADD patients for final cross-validation.

Dyadic Enrollment in a Phase 3 Mild Cognitive Impairment Clinical Trial.

Dyadic enrollment of a participant and study partner is required in mild cognitive impairment (MCI) clinical trials, despite participants being functionally independent. Research examining how the study partner requirement impacts MCI trials remains limited. Using the Alzheimer's Disease Cooperative Study donepezil and vitamin E MCI trial data, we quantified the proportions of enrolled spouse, adult child, and other dyads. We used multinomial regression to identify which baseline participant characteristics (age, sex, race and ethnicity, apolipoprotein E ε4 status, education, residence type) were associated with dyad type. Among 769 randomized dyads, 73% were spousal, 14% adult child, and 13% other dyads. Adjusting for multiple comparisons, underrepresented racial and ethnic background (eg, comparing Hispanic to non-Hispanic White participants: adult child vs. spouse odds ratio = 5.86; 95% confidence interval: 2.09, 16.5; other vs. spouse odds ratio = 4.95; 95% confidence interval: 1.83, 13.4), female sex, age, nonhouse residence, and apolipoprotein E ε4 noncarriage were each associated with a higher odds of having an adult child, as well as an other, study partner at enrollment. Increasing participation among nonspousal dyads may facilitate more inclusive and representative MCI trial samples.

Cognitive Reserve and Mild Cognitive Impairment: Predictors and Rates of Reversion to Intact Cognition vs Progression to Dementia.

Background and ObjectivesLittle is known about the effect of education or other indicators of cognitive reserve on the rate of reversion from mild cognitive impairment (MCI) to normal cognition (NC) or the relative rate (RR) of reversion from MCI to NC vs progression from MCI to dementia. Our objectives were to (1) estimate transition rates from MCI to NC and dementia and (2) determine the effect of age, APOE, and indicators of cognitive reserve on the RR of reversion vs progression using multistate Markov modeling.MethodsWe estimated instantaneous transition rates between NC, MCI, and dementia after accounting for transition to death across up to 12 assessments in the Nun Study, a cohort study of religious sisters aged 75+ years. We estimated RRs of reversion vs progression for age, APOE, and potential cognitive reserve indicators: education, academic performance (high school grades), and written language skills (idea density, grammatical complexity).ResultsOf the 619 participants, 472 were assessed with MCI during the study period. Of these 472, 143 (30.3%) experienced at least one reverse transition to NC, and 120 of the 143 (83.9%) never developed dementia (mean follow-up = 8.6 years). In models adjusted for age group and APOE, higher levels of education more than doubled the RR ratio of reversion vs progression. Novel cognitive reserve indicators were significantly associated with a higher adjusted RR of reversion vs progression (higher vs lower levels for English grades: RR ratio = 1.83; idea density: RR ratio = 3.93; and grammatical complexity: RR ratio = 5.78).DiscussionKnowledge of frequent reversion from MCI to NC may alleviate concerns of inevitable cognitive decline in those with MCI. Identification of characteristics predicting the rate of reversion from MCI to NC vs progression from MCI to dementia may guide population-level interventions targeting these characteristics to prevent or postpone MCI and dementia. Research on cognitive trajectories would benefit from incorporating predictors of reverse transitions and competing events, such as death, into statistical modeling. These results may inform the design and interpretation of MCI clinical trials, given that a substantial proportion of participants may experience improvement without intervention.

The Dyad Dilemma: Strategies to Recruit Study Partners for Mild Cognitive Impairment Clinical Trials

Mild cognitive impairment (MCI) research faces challenges to successful enrollment, especially with clinical trial studies. This study explores researchers’ experiences recruiting from a U.S. Alzheimer’s Disease Center for a pilot, platform trial of biopsychosocial interventions for MCI dyads. Individuals with MCI that met the inclusion criteria for the study were invited to participate (n=39). Thematic analysis of recruitment case notes was utilized to track participants’ and study partners’ interest in participation. In most cases, participants with MCI were interested and willing to enroll and study partners were not. Recruiting persons with MCI and their study partners for clinical trials research may require specialized communication messaging such as education about how interventions address the needs of MCI, along with training on the relationship of MCI to cognitive decline. This presentation highlights effective strategies to engage study partners into recruitment for MCI research such as creating more flexible participation roles and offerings.

Estimating attrition in mild‐to‐moderate Alzheimer’s disease and mild cognitive impairment clinical trials

AbstractBackgroundParticipant retention directly affects the validity and generalizability of clinical trial results. Investigators need information about expected attrition when planning trials of varying durations.MethodUsing the Alzforum and clinicaltrials.gov databases we reviewed 351 phase 2 and 3 placebo‐controlled trials conducted since 1998. Eighty‐six mild‐to‐moderate Alzheimer’s disease (AD) and eleven Mild Cognitive Impairment (MCI) trials met criteria for inclusion in this study. We first assessed the frequency with which trial arms differed in overall retention. When trials included more than one active arm, we combined those arms into a single group. To model associations between trial duration and retention, we used binomial regression.ResultFigure 1 illustrates differences in the observed proportion of participants completing in each trial between active and placebo arms for mild‐to‐moderate AD (Figure 1A) and MCI trials (Figure 1B). For each trial, a 95% confidence interval for the true difference between arms is provided. Since there was no consistent difference between arms, subsequent analyses combined active and placebo arms. Figure 2 illustrates the completion rate by trial duration for mild‐to‐moderate AD (Figure 2A) and MCI trials (Figure 2B). A local smoother along with uncertainty regions is added for visual aid. In general, trials with longer study duration had lower retention rates. Using binomial regression with robust variance estimates to account for within‐trial correlation, we estimated that a 6‐month increase in trial duration is associated with a 34% decrease in the odds of trial completion (OR=0.66; 95% CI: 0.58, 0.75; p&lt;0.001) among mild‐to‐moderate AD trials and a 20% decrease (OR=0.80; 95% CI: 0.68, 0.93; p=0.004) among MCI trials. From the binomial regression model, the proportion of participants completing 6, 12, and 18‐month trials were estimated to be 82.9%, 76.3%, and 68.0% for mild‐to‐moderate AD trials and 82.6%, 79.1%, and 75.2% for MCI trials, respectively.ConclusionWhile decisions related to expected trial attrition are guided by several factors, these estimates may assist investigators designing trials and suggest that trial attrition is frequent and related to trial duration.

Lessons learned on recruiting dyads for mild cognitive impairment clinical trials

AbstractBackgroundPrevious research has shown that up to one‐third of patients diagnosed with mild cognitive impairment (MCI) demonstrate resistance to acceptance of the diagnosis, which may contribute to reduced engagement in clinical research activities including interventional trials.MethodThis study explored researchers’ experiences to recruit 18 dyads from a U.S. Alzheimer’s Research Center to participate in a nine‐month duration, pilot, platform trial of biopsychosocial interventions for persons with MCI and their study partner. Thirty‐nine individuals with MCI met the inclusion criteria for the study. The MCI‐study partner dyads were contacted by mail and phone solicitation for recruitment. Thematic analysis of recruitment case notes was used to track the number of telephone contacts, reasons for interest/disinterest in participation, and questions about the study.ResultWhereas many participants with MCI were interested and willing to enroll (92.3%), frequently study partners were not willing to enroll (53.8%). Study partners primarily consisted of male spouses with a mean age of 67. Study partners reported reasons for disinterest including being unavailable to participate in research sessions (due to availability or geographical distance) and lack of knowledge on MCI or the benefit of research involvement. Further data on the characteristics of study partners in regards to their willingness to engage in research will be presented.ConclusionRecruiting persons with MCI and their study partners for clinical trials research may require specialized communication messaging and strategies for dyad engagement. Strategies should target study partners by promoting the opportunities and potential benefits of MCI clinical trials while considering challenges to involvement due to availability (e.g., weekend meetings, remote offerings, and attempting to lessen the burden of research engagement), rather than focusing recruitment efforts solely on the participant. Further studies exploring strategies to educate and engage study partners to enhance recruitment into MCI research is warranted.

On the design of early-phase Alzheimer's disease clinical trials with cerebrospinal fluid tau outcomes.

The focus of Alzheimer's disease studies has shifted to earlier disease stages, including mild cognitive impairment. Biomarker inclusion criteria are often incorporated into mild cognitive impairment clinical trials to identify individuals with "prodromal Alzheimer's disease" to ensure appropriate drug targets and enrich for participants likely to develop Alzheimer's disease dementia. The use of these eligibility criteria may affect study power. We investigated outcome variability and study power in the setting of proof-of-concept prodromal Alzheimer's disease trials that incorporate cerebrospinal fluid levels of total tau (t-tau) and phosphorylated (p-tau) as primary outcomes and how differing biomarker inclusion criteria affect power. We used data from the Alzheimer's Disease Neuroimaging Initiative to model trial scenarios and to estimate the variance and within-subject correlation of total and phosphorylated tau. These estimates were then used to investigate the differences in study power for trials considering these two surrogate outcomes. Patient characteristics were similar for all eligibility criteria. The lowest outcome variance and highest within-subject correlation were obtained when phosphorylated tau was used as an eligibility criterion, compared to amyloid beta or total tau, regardless of whether total tau or phosphorylated tau were used as primary outcomes. Power increased when eligibility criteria were broadened to allow for enrollment of subjects with either low amyloid beta or high phosphorylated tau. Specific biomarker inclusion criteria may impact statistical power in trials using total tau or phosphorylated tau as the primary outcome. In concert with other important considerations such as treatment target and population of clinical interest, these results may have implications to the integrity and efficiency of prodromal Alzheimer's disease trial designs.

Using practice effects for targeted trials or sub-group analysis in Alzheimer's disease: How practice effects predict change over time.

ObjectiveTo describe the presence of practice effects in persons with Alzheimer disease (AD) or mild cognitive impairment (MCI) and to evaluate how practice effects affect cognitive progression and the outcome of clinical trials.MethodsUsing data from a meta-database consisting of 18 studies including participants from the Alzheimer disease Cooperative Study (ADCS) and the Alzheimer Disease Neuroimaging Initiative (ADNI) with ADAS-Cog11 as the primary outcome, we defined practice effects based on the improvement in the first two ADAS-Cog11 scores and then estimated the presence of practice effects and compared the cognitive progression between participants with and without practice effects. The robustness of practice effects was investigated using CDR SB, an outcome independent the definition itself. Furthermore, we evaluated how practice effects can affect sample size estimation.ResultsThe overall percent of practice effects for AD participants was 39.0% and 53.3% for MCI participants. For AD studies, the mean change from baseline to 2 years was 12.8 points for the non-practice effects group vs 7.4 for the practice effects group; whereas for MCI studies, it was 4.1 for non-practice effects group vs 0.2 for the practice effects group. AD participants without practice effects progressed 0.9 points faster than those with practice effects over a period of 2 years in CDR-SB; whereas for MCI participants, the difference is 0.7 points. The sample sizes can be different by over 35% when estimated based on participants with/without practice effects.ConclusionPractice effects were prevalent and robust in persons with AD or MCI and affected the cognitive progression and sample size estimation. Planning of future AD or MCI clinical trials should account for practice effects to avoid underpower or considers target trials or stratification analysis based on practice effects.

Spotlight on the September 20 Issue

#### Notable in Neurology This issue features an article that evaluates the influence of heterogeneous underlying pathology in corticobasal syndrome by using multimodal neuroimaging, and another that investigates the effect of enriching mild cognitive impairment clinical trials using combined markers of amyloid pathology and neurodegeneration. A featured article evaluates the comparative safety and adjunctive efficacy of pregabalin and gabapentin in reducing seizure frequency in patients with partial-onset seizures. ### Influence of sodium consumption and associated knowledge on poststroke hypertension in Uganda![Graphic][1]</img> The authors assessed 24-hour urine sodium levels of Ugandan patients with and without a history of stroke as indicators of dietary salt consumption and its association with blood pressure control. The development of educational strategies that … [1]: /embed/inline-graphic-1.gif

Enrichment of clinical trials in MCI due to AD using markers of amyloid and neurodegeneration.

To investigate the effect of enriching mild cognitive impairment (MCI) clinical trials using combined markers of amyloid pathology and neurodegeneration. We evaluate an implementation of the recent National Institute for Aging-Alzheimer's Association (NIA-AA) diagnostic criteria for MCI due to Alzheimer disease (AD) as inclusion criteria in clinical trials and assess the effect of enrichment with amyloid (A+), neurodegeneration (N+), and their combination (A+N+) on the rate of clinical progression, required sample sizes, and estimates of trial time and cost. Enrichment based on an individual marker (A+ or N+) substantially improves all assessed trial characteristics. Combined enrichment (A+N+) further improves these results with a reduction in required sample sizes by 45% to 60%, depending on the endpoint. Operationalizing the NIA-AA diagnostic criteria for clinical trial screening has the potential to substantially improve the statistical power of trials in MCI due to AD by identifying a more rapidly progressing patient population.

Alzheimer Disease Biomarkers as Outcome Measures for Clinical Trials in MCI.

The aim of this study was to compare the performance and power of the best-established diagnostic biological markers as outcome measures for clinical trials in patients with mild cognitive impairment (MCI). Magnetic resonance imaging, F-18 fluorodeoxyglucose positron emission tomography markers, and Alzheimer's Disease Assessment Scale-cognitive subscale were compared in terms of effect size and statistical power over different follow-up periods in 2 MCI groups, selected from Alzheimer's Disease Neuroimaging Initiative data set based on cerebrospinal fluid (abnormal cerebrospinal fluid Aβ1-42 concentration-ABETA+) or magnetic resonance imaging evidence of Alzheimer disease (positivity to hippocampal atrophy-HIPPO+). Biomarkers progression was modeled through mixed effect models. Scaled slope was chosen as measure of effect size. Biomarkers power was estimated using simulation algorithms. Seventy-four ABETA+ and 51 HIPPO+ MCI patients were included in the study. Imaging biomarkers of neurodegeneration, especially MR measurements, showed highest performance. For all biomarkers and both MCI groups, power increased with increasing follow-up time, irrespective of biomarker assessment frequency. These findings provide information about biomarker enrichment and outcome measurements that could be employed to reduce MCI patient samples and treatment duration in future clinical trials.

REVIEW AND ANALYSIS OF CROSS-CULTURAL NORMATIVE DATA FOR THE REPEATABLE BATTERY FOR THE ASSESSMENT OF NEUROPSYCHOLOGICAL STATUS (RBANS): IMPLICATIONS FOR MULTI-NATIONAL MCI CLINICAL TRIALS

The National Institute on Aging (NIA) and Alzheimer's Association Workgroup criteria for the diagnosis of mild cognitive impairment (MCI) includes “objective evidence of impairment in one or more cognitive domains, typically memory” that is “worse than that expected for age and education” (Albert et al. 2011), but no specific test has been identified. For multi-national clinical trials that use memory tests as a screening method for MCI, this diagnostic criterion relies on normative data, the availability of which varies depending on language and country. The purpose of this research is to review and analyze published normative RBANS data globally to determine the extent to which norms across cultures are similar to US based norms and to discuss associated implications of the use of the RBANS for clinical trials in MCI. A PubMed search using search terms including “RBANS”, “normative data”, “cross-cultural”, and specific language terms (e.g., Spanish, Chinese, etc.) was conducted, including a review of publication reference sections to identify potentially relevant datasets. RBANS normative data for healthy elderly and MCI have been published in several countries, including several US English samples and samples from Spain, Singapore, Australia, Greece, Armenia, Hungary, and France. Sample sizes across studies ranged from small (e.g., 28) to large (e.g., 718) and reporting of demographic and clinical features varied, limiting direct comparisons across studies. Studies provided differing level of details regarding RBANS translations and despite available translations, normative data in MCI or AD do not appear to have been published for several countries. Descriptive and graphical analyses were compiled across samples, comparing raw and Index scores according to demographic variables (i.e., age, education), highlighting key similarities and differences across countries and languages. The diagnosis of MCI requires cognitive (typically memory) test performance worse than expected for age and education, but no gold standard cognitive test has emerged for application in multi-national clinical trials. Implications of the strengths and limitations of the existing RBANS research will be discussed, including the need for research on educational influences on cognitive tests cross-culturally and consistent data reporting conventions to facilitate direct comparisons across countries.

Operationalizing hippocampal volume as an enrichment biomarker for amnestic mild cognitive impairment trials: effect of algorithm, test-retest variability, and cut point on trial cost, duration, and sample size

The objective of this study was to evaluate the effect of computational algorithm, measurement variability, and cut point on hippocampal volume (HCV)-based patient selection for clinical trials in mild cognitive impairment (MCI). We used normal control and amnestic MCI subjects from the Alzheimer's Disease Neuroimaging Initiative 1 (ADNI-1) as normative reference and screening cohorts. We evaluated the enrichment performance of 4 widely used hippocampal segmentation algorithms (FreeSurfer, Hippocampus Multi-Atlas Propagation and Segmentation (HMAPS), Learning Embeddings Atlas Propagation (LEAP), and NeuroQuant) in terms of 2-year changes in Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and Clinical Dementia Rating Sum of Boxes (CDR-SB). We modeled the implications for sample size, screen fail rates, and trial cost and duration. HCV based patient selection yielded reduced sample sizes (by ∼40%–60%) and lower trial costs (by ∼30%–40%) across a wide range of cut points. These results provide a guide to the choice of HCV cut point for amnestic MCI clinical trials, allowing an informed tradeoff between statistical and practical considerations.

Effect of APOE genotype status on targeted clinical trials outcomes and efficiency in dementia and mild cognitive impairment resulting from Alzheimer's disease

BackgroundThe apolipoprotein E (APOE) ε4 genotype has been recommended as a potential inclusion or exclusion criterion in targeted clinical trials for Alzheimer's disease (AD) and mild cognitive impairment (MCI) resulting from AD, and has been implemented in trials of immunotherapeutic agents. MethodsWe tested this recommendation with clinical trial simulations using participants from a meta-database of 19 studies to create trial samples with APOE ε4 proportions ranging from 0% (all noncarriers) to 100% (all carriers). For each percentage of APOE ε4 carriers, we resampled the database randomly for 1000 trials for each trial scenario, planning for 18- or 24-month trials with samples from 50 to 400 patients per treatment or placebo group, up to 40% dropouts, and outcomes on the Alzheimer's Disease Assessment Scale, cognitive subscale (ADAS-cog) with effect sizes from 0.15 to 0.75, and calculated statistical power. ResultsEnrichment of clinical trial participants based on APOE ε4 carrier status resulted in minimal increases in power compared with enrolling participants with the APOE ε3 genotype only or enrolling patients without regard to APOE genotype. Increased screening requirements to enhance the sample would offset gains in power. ConclusionsAlthough samples enriched for APOE ε4 carriers in AD or MCI clinical trials showed slightly more cognitive impairment and greater decline using the number APOE ε4 alleles as an inclusion criterion most likely would not result in more efficient trials, and trials would take longer because fewer patients would be available. The APOE ε4/εX (where X = 2, 3 or 4) genotype could be useful, however, as an explanatory variable or covariate if warranted by a drug's action.

A direct morphometric comparison of five labeling protocols for multi-atlas driven automatic segmentation of the hippocampus in Alzheimer's disease

Hippocampal volumetry derived from structural MRI is increasingly used to delineate regions of interest for functional measurements, assess efficacy in therapeutic trials of Alzheimer's disease (AD) and has been endorsed by the new AD diagnostic guidelines as a radiological marker of disease progression. Unfortunately, morphological heterogeneity in AD can prevent accurate demarcation of the hippocampus. Recent developments in automated volumetry commonly use multi-template fusion driven by expert manual labels, enabling highly accurate and reproducible segmentation in disease and healthy subjects. However, there are several protocols to define the hippocampus anatomically in vivo, and the method used to generate atlases may impact automatic accuracy and sensitivity - particularly in pathologically heterogeneous samples. Here we report a fully automated segmentation technique that provides a robust platform to directly evaluate both technical and biomarker performance in AD among anatomically unique labeling protocols. For the first time we test head-to-head the performance of five common hippocampal labeling protocols for multi-atlas based segmentation, using both the Sunnybrook Longitudinal Dementia Study and the entire Alzheimer's Disease Neuroimaging Initiative 1 (ADNI-1) baseline and 24-month dataset. We based these atlas libraries on the protocols of (Haller et al., 1997; Killiany et al., 1993; Malykhin et al., 2007; Pantel et al., 2000; Pruessner et al., 2000), and a single operator performed all manual tracings to generate de facto "ground truth" labels. All methods distinguished between normal elders, mild cognitive impairment (MCI), and AD in the expected directions, and showed comparable correlations with measures of episodic memory performance. Only more inclusive protocols distinguished between stable MCI and MCI-to-AD converters, and had slightly better associations with episodic memory. Moreover, we demonstrate that protocols including more posterior anatomy and dorsal white matter compartments furnish the best voxel-overlap accuracies (Dice Similarity Coefficient=0.87-0.89), compared to expert manual tracings, and achieve the smallest sample sizes required to power clinical trials in MCI and AD. The greatest distribution of errors was localized to the caudal hippocampus and the alveus-fimbria compartment when these regions were excluded. The definition of the medial body did not significantly alter accuracy among more comprehensive protocols. Voxel-overlap accuracies between automatic and manual labels were lower for the more pathologically heterogeneous Sunnybrook study in comparison to the ADNI-1 sample. Finally, accuracy among protocols appears to significantly differ the most in AD subjects compared to MCI and normal elders. Together, these results suggest that selection of a candidate protocol for fully automatic multi-template based segmentation in AD can influence both segmentation accuracy when compared to expert manual labels and performance as a biomarker in MCI and AD.

Spotlight on the September 20 Issue

#### Notable in Neurology This issue features an article that evaluates the influence of heterogeneous underlying pathology in corticobasal syndrome by using multimodal neuroimaging, and another that investigates the effect of enriching mild cognitive impairment clinical trials using combined markers of amyloid pathology and neurodegeneration. A featured article evaluates the comparative safety and adjunctive efficacy of pregabalin and gabapentin in reducing seizure frequency in patients with partial-onset seizures. ### Influence of sodium consumption and associated knowledge on poststroke hypertension in Uganda![Graphic][1] The authors assessed 24-hour urine sodium levels of Ugandan patients with and without a history of stroke as indicators of dietary salt consumption and its association with blood pressure control. The development of educational strategies that … [1]: /embed/inline-graphic-1.gif

Cerebrospinal Fluid Profiles and Prospective Course and Outcome in Patients With Amnestic Mild Cognitive Impairment

To examine the effect of specific cerebrospinal fluid (CSF) profiles on the rate of cognitive decline, disease progression, and risk of conversion to Alzheimer disease (AD) dementia in patients with amnestic mild cognitive impairment (MCI). Total tau (T-tau), tau phosphorylated at threonine 181, and β-amyloid 1-42 peptide (Aβ42) were immunoassayed in CSF samples obtained from patients with MCI enrolled in the Alzheimer's Disease Neuroimaging Initiative. Patients were then stratified by CSF profiles: (1) normal T-tau and normal Aβ42 (ie, normal-T-tauAβ42), (2) normal T-tau but abnormal Aβ42 (ie, abnormal-Aβ42), (3) abnormal T-tau but normal Aβ42 (ie, abnormal-T-tau), and (4) abnormal T-tau and abnormal Aβ42 (ie, abnormal-T-tauAβ42). Fifty-eight sites in the United States and Canada. One hundred ninety-five patients with MCI. A composite cognitive measure, the Clinical Dementia Rating Scale-sum of boxes subscale, and conversion to AD dementia. Patients with MCI with a CSF profile of abnormal-Aβ42 or abnormal-T-tauAβ42 experienced a faster rate of decline on the composite cognitive measure and the Clinical Dementia Rating Scale-sum of boxes subscale compared with those with normal-T-tauAβ42. They also had a greater risk of converting to AD dementia relative to the normal-T-tauAβ42 group. In contrast, those with a CSF profile of abnormal-T-tau did not differ from the normal-T-tauAβ42 group on any outcome. These findings were generally replicated when the sample was reclassified by patterns of tau phosphorylated at threonine 181 and Aβ42 abnormalities. β-Amyloid abnormalities but not tau alterations are associated with cognitive deterioration, disease progression, and increased risk of conversion to AD dementia in patients with MCI. Patients with abnormal Aβ42 may be prime candidates for drug treatment and clinical trials in MCI.