Protocol for a seamless phase 2A-phase 2B randomized double-blind placebo-controlled trial to evaluate the safety and efficacy of benfotiamine in patients with early Alzheimer's disease (BenfoTeam).

BACKGROUND: Benfotiamine provides an important novel therapeutic direction in Alzheimer's disease (AD) with possible additive or synergistic effects to amyloid targeting therapeutic approaches. OBJECTIVE: To conduct a seamless phase 2A-2B proof of concept trial investigating tolerability, safety, and efficacy of benfotiamine, a prodrug of thiamine, as a first-in-class small molecule oral treatment for early AD. METHODS: This is the protocol for a randomized, double-blind, placebo-controlled 72-week clinical trial of benfotiamine in 406 participants with early AD. Phase 2A determines the highest safe and well-tolerated dose of benfotiamine to be carried forward to phase 2B. During phase 2A, real-time monitoring of pre-defined safety stopping criteria in the first approximately 150 enrollees will help determine which dose (600 mg or 1200 mg) will be carried forward into phase 2B. The phase 2A primary analysis will test whether the rate of tolerability events (TEs) is unacceptably high in the high-dose arm compared to placebo. The primary safety endpoint in phase 2A is the rate of TEs compared between active and placebo arms, at each dose. The completion of phase 2A will seamlessly transition to phase 2B without pausing or stopping the trial. Phase 2B will assess efficacy and longer-term safety of benfotiamine in a larger group of participants through 72 weeks of treatment, at the selected dose. The co-primary efficacy endpoints in phase 2B are CDR-Sum of Boxes and ADAS-Cog13. Secondary endpoints include safety and tolerability measures; pharmacokinetic measures of thiamine and its esters, erythrocyte transketolase activity as blood markers of efficacy of drug delivery; ADCS-ADL-MCI; and MoCA. CONCLUSION: The BenfoTeam trial utilizes an innovative seamless phase 2A-2B design to achieve proof of concept. It includes an adaptive dose decision rule, thus optimizing exposure to the highest and best-tolerated dose. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT06223360, registered on January 25, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06223360.

Comparing the Boston Naming Test With the Neuropsychological Assessment Battery-Naming Subtest in a Neurodegenerative Disease Clinic Population.

The Boston Naming Test-Second edition (BNT-2) and the Neuropsychological Assessment Battery-Naming (NAB-N) subtest are two commonly used confrontation naming tests used to evaluate word-finding ability in individuals suspected of neurodegenerative disease. The BNT-2 and NAB-N are designed to measure the same construct; however, observations in practice suggest these two tests provide divergent estimates of naming ability. This study sought to systematically investigate the level of agreement between performance on the BNT-2 and NAB-N. Records from 105 consecutive referrals seen for neuropsychological evaluation as part of routine care in an outpatient memory disorders clinic were reviewed. Discrepancy scores, concordance correlation coefficients, and root mean squared differences were calculated between demographically adjusted T-scores on the BNT-2 and NAB-N. Results indicated that estimates of word finding ability generated by the BNT-2 and NAB-N have a strong linear relationship but systematically generate scores that are inconsistent. Despite similar task demands, the BNT-2 and NAB-N provide different information about naming ability and further research is needed to understand these differences and inform clinicians on interpreting the naming estimates provided by each test.

Regression-based formulas for predicting change in memory test scores in healthy older adults: Comparing use of raw versus standardized scores.

INTRODUCTION: Standardized regression based (SRB) methods can be used to determine whether meaningful changes in performance on cognitive assessments occur over time. Both raw and standardized scores have been used in SRB models but it is unclear which score metric is most appropriate for predicting follow-up performance. The aim of the present study was to examine differences in SRB prediction formulas using raw versus standard scores on two memory tests commonly used in assessment of older adults. METHOD: The sample consisted of 135 healthy older adults who underwent baseline and 1-year follow-up neuropsychological assessment including the Hopkins Verbal Learning Test-Revised and Brief Visuospatial Memory Test-Revised. Regression models were fit to predict Time 2 scores from Time 1 scores and demographic variables. Separate models were fit using raw scores and standardized scores. Akaike's information criterion (AIC) was used to determine whether models using raw or standardized scores resulted in best fit. Pearson correlation and intraclass correlation coefficients were calculated between observed and predicted scores. Mean differences between observed and predicted scores were examined using pairwise t tests. To investigate whether a similar pattern of results would be evident using prediction formulas for nonmemory tests, all analyses were also conducted for nonmemory tests. RESULTS: All regression models were significant, and R2 values for memory test raw score models were larger than those generated by standardized score models. Memory test raw score models were also a better fit based on smaller AIC values. For nonmemory tests, raw score models did not consistently outperform standardized score models. All correlations between observed and predicted Time 2 scores were significant, and none of the predicted scores significantly differed from their respective observed score. CONCLUSION: For each memory measure, raw score models outperformed standardized score models. For nonmemory tests, neither score metric model consistently outperformed the other.

Comparing the Electronic and Standard Versions of the Montreal Cognitive Assessment in an Outpatient Memory Disorders Clinic: A Validation Study.

The Montreal Cognitive Assessment (MoCA) has become widely used as a brief test of cognitive function in patients with neurological disease. More convenient application of the MoCA might increase its use and enhance its utility. An electronic version of the MoCA has recently been developed. To establish validity of the electronic version (eMoCA), discrepancy scores, concordance correlation coefficients (CCC), and root mean squared differences (RMSD) were calculated between each administration method in a sample of 43 new adult patients presenting with primary memory complaints. The CCC was 0.84 and the RMSD was 2.27, with 76% of the sample having a difference score within 2 points. Overall, this study establishes adequate convergent validity between the MoCA and eMoCA among an adult population presenting with memory concerns.

Comparing the test of practical judgment with the neuropsychological assessment battery judgment subtest in a neurodegenerative disease clinic population.

The Test of Practical Judgment (TOP-J) and the Judgment subtest from the Neuropsychological Assessment Battery (NAB-JDG) are both brief interview-based measures that assess judgment. This study compared estimates of judgment obtained from these measures in a neurodegenerative disease population. Records from 61 referrals seen for neuropsychological evaluation in a neurodegenerative disorders clinic were reviewed. Measures of interest included the TOP-J and NAB-JDG. Concordance correlation coefficients (CCC) and root mean square differences (RMSD) were calculated between judgment T-scores. Discrepancy scores were calculated by subtracting NAB-JDG scores from TOP-J scores. CCC showed poor agreement between the judgment measures, with evidence of fixed bias, such that the NAB-JDG systematically generates higher scores than the TOP-J. This fixed bias was present whether NAB-JDG scores are demographically adjusted or unadjusted. There was no evidence of proportional bias. In a neurodegenerative disease clinic population, the TOP-J and NAB-JDG provide estimates of judgment ability that are systematically different. These two measures may be assessing different aspects within the larger construct of judgment and the inconsistency between measures would contraindicate using them interchangeably. Clinicians will need to carefully consider patient characteristics, clinical needs, and review specific item content when selecting between these measures.

Relationship between the Activities of Daily Living Questionnaire and the Montreal Cognitive Assessment.

INTRODUCTION: The Activities of Daily Living Questionnaire (ADL-Q) is an informant report questionnaire assessing functional impairment in daily living skills. Previous research has demonstrated correlations between ADL-Q and cognitive screening measures among patients with dementia. This study examined the relationship between ADL-Q and the Montreal Cognitive Assessment (MoCA), a brief cognitive screening. METHODS: Records of 448 individuals from an outpatient neurology clinic were reviewed. Pearson correlations were calculated between ADL-Q scores and MoCA scores. Linear regression models were fit using demographic information to predict ADL-Q scores. MoCA scores were then added to the models to determine the increase in predictive value of the MoCA. RESULTS: Lower MoCA scores were associated with higher levels of functional impairment. For each model, adding the MoCA significantly improved model fit. DISCUSSION: Low scores on the MoCA, among patient's presenting for memory complaints, should raise concerns about functional decline and prompt for further assessment of functional ability.

Estimates of premorbid ability in a neurodegenerative disease clinic population: comparing the Test of Premorbid Functioning and the Wide Range Achievement Test, 4th Edition.

OBJECTIVE: Two frequently used measures to assess premorbid intellectual ability include the Wide Range Achievement Test, 4th Edition Reading Subtest (WRAT-4 READ) and the Test of Premorbid Functioning (TOPF). The present study compared estimates obtained from these measures in a neurodegenerative disease population. METHOD: Records from 85 referrals seen for neuropsychological evaluation in a neurodegenerative disorders clinic were reviewed. Evaluations included TOPF, WRAT-4 READ, and measures of memory, reasoning, language, and executive functioning. Pairwise correlations and concordance correlation coefficients (CCC) were calculated between raw scores and predicted intelligence estimates. Discrepancy scores were calculated between estimates and data were divided into three groups based on size of standardized discrepancy score: Equal, WRAT-4 READ > TOPF, and TOPF > WRAT-4 READ. analysis of variances compared groups on demographic characteristics and cognitive performance. RESULTS: Despite strong Pearson correlation, CCC between predicted IQ estimates showed poor agreement between measures, with evidence of both fixed and proportional bias. Discrepancies ranged from -24.0 to 22.0 (M = 1.78, SD = 6.65), with TOPF generating higher estimates on average. Individuals performing better on WRAT-4 READ were significantly older (M age = 76.26, SD = 7.53) than those performing similarly on both measures and those performing better on TOPF (F (2, 82) = 7.31, p < .001). All other comparisons between groups on demographic variables and cognitive measures were non-significant. CONCLUSIONS: Estimates of premorbid intelligence obtained from the TOPF and WRAT-4 READ have a strong linear relationship, but systematically generate inconsistent estimates in a neurodegenerative disease clinical sample and should not be used interchangeably.