Alzheimer's Disease Cooperative Study-Activities Of Daily Living Research Articles

Comparative Efficacy and Safety of Monoclonal Antibodies for Cognitive Decline in Patients with Alzheimer's Disease: A Systematic Review and Network Meta-Analysis.

Recent clinical trials of anti-Aβ monoclonal antibodies (mAbs) in the treatment of early Alzheimer's disease (AD) have produced encouraging cognitive and clinical results. The purpose of this network meta-analysis (NMA) was to compare and rank mAb drugs according to their efficacy and safety. PubMed, Embase, Web of Science, and the Cochrane Library were searched for randomized controlled trials testing various mAbs for the treatment of cognitive decline in patients with AD, up to March 31, 2023. R software (version 4.2.3) along with JAGS and STATA software (version 15.0) were used for statistical analysis. Odds ratio (OR) for binary variables, mean difference (MD) for continuous variables, and their 95% confidence intervals (CI) were utilized to estimate treatment effects and rank probabilities for each mAb in terms of safety and efficacy outcomes. We calculated the surface under the cumulative ranking area (SUCRA) to evaluate each mAb, with higher SUCRA values indicating better efficacy or lower likelihood of adverse events. Thirty-three randomized controlled trials with a total of 21,087 patients were included in the current NMA, involving eight different mAbs. SUCRA values showed that aducanumab (87.01% and 99.37%, respectively) was the most likely to achieve the best therapeutic effect based on the changes of Mini-Mental State Examination (MMSE) and Clinical Dementia Rating scale Sum of Boxes (CDR-SB) scores. Donanemab (88.50% and 99.00%, respectively) performed better than other therapies for Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Positron Emission Tomography-Standardized Uptake Value ratio (PET-SUVr). Lecanemab (87.24%) may be the most promising way to slow down the decrease of Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) score. In the analysis of the incidence of adverse events (subjects with any treatment-emergent adverse event), gantenerumab (89.12%) had the least potential for adverse events, while lecanemab (0.79%) may cause more adverse events. Solanezumab (95.75% and 80.38%, respectively) had the lowest incidence of amyloid-related imaging abnormalities characterized by edema and effusion (ARIA-E) and by cerebral microhemorrhages (ARIA-H) of the included immunotherapies. While SUCRA values provided a comprehensive measure of treatment efficacy, the inherent statistical uncertainty required careful analysis in clinical application. Despite immunotherapies significantly increasing the risks of adverse events and ARIA, the data suggest that mAbs can effectively improve the cognitive function of patients with mild and moderate AD. According to the NMA, aducanumab was the most likely to achieve significant improvements in different cognitive and clinical assessments (statistically improved MMSE and CDR-SB), followed by donanemab (statistically improved ADAS-Cog, and PET-SUVr) and lecanemab (statistically improved ADCS-ADL).

Effects of informant replacement in Alzheimer's disease clinical trials.

Alzheimer's disease (AD) trials require enrollment with an informant. We assessed relationships between informant replacement and Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) scores across four AD trials. Using generalized estimating equations, we examined associations between replacement and change in ADCS-ADL between successive visits. We used analysis of covariance to estimate the association between replacement and 18-month change from baseline, and an F-test to compare the variance of this change. Among 1336 participants, 63 (≈5%) experienced replacement. Between-visit mean change in ADCS-ADL was 2.44 points lower comparing replacement to stable informants (95% confidence interval [CI]: -3.91, -0.98). The difference in between-visit mean absolute change was 2.38 points (95% CI: 1.24, 3.52). Replacement was not significantly associated with an 18-month change from baseline. The ratio of variances (replacement/stable) was 1.80 (95% CI: 1.19, 2.99). Informant replacement is associated with bias and increased variability between visits and increased variance for overall ADCS-ADL.

Evidence of Clinical Efficacy and Pharmacological Mechanisms of Resveratrol in the Treatment of Alzheimer's Disease.

To evaluate the efficacy and pharmacological mechanisms of resveratrol in Alzheimer's disease (AD) patients. We conducted a thorough exploration of existing randomized controlled trials concerning the treatment of Alzheimer's disease patients using resveratrol, utilizing accessible open databases. Quantitative variables were represented as a standardized mean difference (SMD), accompanied by a 95% confidence interval (CI). Additionally, we examined the potential targets and plausible pathways associated with the impact of resveratrol on Alzheimer's disease using network pharmacology techniques. Our meta-analysis comprised five trials involving 271 AD patients, of whom 139 received resveratrol treatment and 132 received placebo treatment. Compared with placebo therapy, resveratrol treatment resulted in a significant improvement in Alzheimer's Disease Cooperative Study- Activities of Daily Living (ADAS-ADL) scores (SMD=0.51; 95% CI, 0.24 to 0.78) and cerebrospinal fluid (CSF) Aβ40 (SMD=0.84; 95% CI, 0.21 to 1.47) and plasma Aβ40 levels (SMD=0.43; 95% CI, 0.07 to 0.79). However, the improvement in the resveratrol-treated group compared with the placebo treatment group on the Mini-Mental State Examination (MMSE) score, CSF Aβ42 and plasma Aβ42 levels, and brain volume was not significant. There were no noteworthy statistical variances in the occurrence of adverse effects noted between the two groups. The outcomes of network pharmacology divulged that the principal enriched interaction pathway between resveratrol and Alzheimer's disease is primarily concentrated within the PI3K signaling pathways. Resveratrol's potential key targets for the treatment of AD include MAKP1, HRAS, EGFR, and MAPK2K1. While having a high safety profile, resveratrol has efficacy in AD patients to a certain extent, and more data are required to validate the efficacy of resveratrol for the treatment of AD in the future. Suppression of the PI3K signaling pathways could hold significant importance in the treatment of AD patients using resveratrol.

Cross-sectional and longitudinal assessments of function in prodromal-to-mild Alzheimer's disease: A comparison of the ADCS-ADL and A-IADL-Q scales.

Prior observational work in a heterogeneous cohort of participants with mild cognitive impairment suggests the Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q) may have greater sensitivity for functional decline than the more established Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale. However, the relative utility of the A-IADL-Q versus the ADCS-ADL for clinical trials in early Alzheimer's disease (AD) remains uncertain. We compared baseline and longitudinal performance of the A-IADL-Q and ADCS-ADL in participants with biomarker-confirmed prodromal (pAD; n=158) or mild (mAD; n=283) AD enrolled in the 18-month Tauriel study of semorinemab (NCT03289143). The A-IADL-Q exhibited numerically stronger discrimination between pAD and mAD participants at baseline per Cohen's d analyses and similar sensitivity to longitudinal decline across cohorts over 18 months relative to the ADCS-ADL. The comparable performance of the ADCS-ADL and A-IADL-Q supports the utility of the A-IADL-Q in early AD clinical trials. The Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q) may be more sensitive than the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL) for distinguishing prodromal and mild Alzheimer's disease (AD).A-IADL-Q and ADCS-ADL are similarly sensitive to decline in early AD over 18 months.Comparable performance of these indices supports A-IADL-Q use in future AD trials.Additional AD clinical trial data could extend findings across more diverse cohorts.

The Fifth Bioelectronic Medicine Summit Hosted by the Feinstein Institutes for Medical Research (Manhasset, NY) and Columbia Engineering (NY, NY) at The Garden City Hotel, Garden City, NY 11530 on October 11-12th, 2022- Bioelectronic Medicine: Today’s Tools, Tomorrow’s Therapies

The Fifth Bioelectronic Medicine Summit Hosted by the Feinstein Institutes for Medical Research (Manhasset, NY) and Columbia Engineering (NY, NY) at The Garden City Hotel, Garden City, NY 11530 on October 11-12th, 2022- Bioelectronic Medicine: Today’s Tools, Tomorrow’s Therapies

Effects of Orally Administered Nicotinamide Riboside on Bioenergetic Metabolism, Oxidative Stress and Cognition in Mild Cognitive Impairment and Mild Alzheimer's Disease

<h3>Introduction</h3> Alzheimer's Disease (AD) is a neurodegenerative disease affecting millions of people worldwide, representing significant health and economic burdens. There has been a recent drive to develop more effective AD treatments. A potential strategy involves enhancing brain bioenergetics, or the metabolism of fuel molecules to create and use energy through glycolysis and oxidative phosphorylation (OxPhos). The regulation of mitochondrial turnover and function in the brain declines as we age, and it has become increasingly accepted that these metabolic alterations precede hallmark AD pathology, including amyloid-beta (Aβ) plaques and neurofibrillary tangles. An overlapping set of mechanisms involving redox dysregulation, oxidative stress, and mitochondrial dysfunction may be related to mild cognitive impairment (MCI) and AD. Nicotinamide adenine dinucleotide (NAD) has been identified as a promising molecular target for bioenergetic treatments as it is requisite for many redox reactions. The redox ratio (RR, i.e., NAD+/NADH) is a mark of the system's ability to carry out ATP synthesis. NAD+ levels decrease as we age, which compromises energy production in the mitochondria, impairs clearance of damaged mitochondria, and impacts our brain's capacity to react to oxidative stress. Since mitochondrial dysfunction and oxidative stress are believed to play a role in the pathophysiology of age-related diseases, boosting NAD levels could be an effective AD treatment. Nicotinamide Riboside (NR) is a naturally occurring, over the counter, commercially available, and safe vitamin B3-based NAD+ precursor supplement. Several lines of evidence suggest that NR is a mitochondrially-favored NAD+ precursor. Data supports the safety and efficacy of using NR to increase NAD+ levels in humans, but these studies have not measured the RR at critical tissue sites, such as the brain, to determine the therapeutic potential of oral NR supplementation. This study proposes a novel intervention strategy for patients with MCI or mild AD that targets redox dysregulation and oxidative stress in the brain using NR. Our primary objective is to validate the effect of NR supplementation on NAD+ levels and RR in the brain of patients with MCI or mild AD. Our secondary aim is to quantify the impact of NR supplementation on ensuing markers of mitochondrial function and oxidative stress in MCI and mild AD patients. Our third, exploratory aim, is to correlate neuroimaging measurements with clinical assessments. <h3>Methods</h3> A 12-week open-label, clinical trial of NR supported by the National Institute on Aging (R01AG066670, Du/Forester), we plan to enroll a total of 50 participants - 25 with MCI and 25 with mild AD, all with at least one copy of the APOE ε4 allele. Participants will be asked to take 1,000 mg NR daily over 12-weeks, and to come in for three scanning visits. We will use novel neuroimaging methods —spectroscopy on a 4T scanner to enable in vivo measurement of NAD+, NADH and RR, along with markers of mitochondrial function tied to NAD, including creatine kinase (CK), ATPase, and glutathione (GSH)—a molecule essential for cellular repair. Our primary outcome measures are NAD+ levels and RR. Our secondary outcome measures are CK/ATPase activity and GSH levels. Our exploratory outcome measures include the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) for cognition and the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) for daily functioning. <h3>Results</h3> Previous clinical trials of NR pharmacokinetics in humans support the safety and efficacy of using NR to increase NAD+ levels in the plasma. Emerging data also highlights important health benefits this supplement may have. We recently received preliminary spectroscopic data following a course of NR supplementation in healthy volunteers (N=4) which observed elevations in NAD+ and RR after two weeks. Only a small difference of downstream effects, CK/ATPase activity and GSH levels, were observed, which could be due to the short period of NR treatment. We hypothesize that oral NR will increase NAD+ and RR in the medial prefrontal cortex and will increase GSH levels and CK/ATPase activity in the brain. For our exploratory aim, we hypothesize that oral NR will improve cognitive status and functional abilities, as measured by the RBANS and ADCS-ADL. <h3>Conclusions</h3> We are investigating NR to target redox dysregulation and oxidative stress in the brain in those with MCI or mild AD. We aim to document and quantify the neurobiological and clinical effects of NR supplementation in MCI and mild AD using in vivo brain imaging. This novel intervention strategy of brain bioenergetics has thus far received minute empirical attention and may represent an alternative strategy for treating MCI and mild AD. Early detection and repair of neural dysfunction at this critical stage could significantly alter disease course and improve functional outcomes. <h3>This research was funded by</h3> National Institutes of Health

A Multinational, Multicenter, Randomized, Double-Blind, Active Comparator, Phase III Clinical Trial to Evaluate the Efficacy and Safety of Donepezil Transdermal Patch in Patients With Alzheimer's Disease.

Background and PurposeOral administration of cholinesterase inhibitors is often associated with adverse gastrointestinal effects, and so developing an alternative administration route, such as transdermal, is urgently needed. The primary objective of this study was to determine the efficacy and safety of the IPI-301 donepezil transdermal patch compared with donepezil tablets (control) in mild-to-moderate probable Alzheimer’s disease (AD).MethodsThis prospective, randomized, double-blind, double-dummy, two-arm parallel, multicenter trial included 399 patients, among whom 303 completed the trial. For randomization, the patients were stratified based on previous treatment and donepezil dose; patients in each stratum were randomized to the test and control groups at a 1:1 ratio.ResultsThe difference between the control group and the IPI-301 group, quantified as the Hodges–Lehmann estimate of location shift, was 0.00 (95% confidence interval: -1.00 to 1.33), with an upper limit of less than 2.02. The change in Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) score differed significantly between the IPI-301 and control groups (p=0.02). However, the changes in the full-itemized ADCS-ADL scores at week 24 did not differ significantly between the two groups. There were no differences between the two groups regarding the scores for the Clinician Interview-Based Impression of Change (p=0.9097), Mini-Mental State Examination (p=0.7018), Neuropsychiatric Inventory (p=0.7656), or Clinical Dementia Rating (p=0.9990). Adverse events, vital signs, and laboratory test results were comparable between the two groups.ConclusionsIPI-301 was safe and efficacious in improving cognitive function in patients with mild-to-moderate AD.

Masitinib in mild to moderate Alzheimer’s disease: Results from study AB09004

AbstractBackgroundMasitinib is a small molecule drug targeting KIT, LYN, FYN and CSF1R. Proof‐of‐concept that masitinib slowed cognitive decline in Alzheimer's disease (AD) was previously demonstrated [doi:10.1186/alzrt75; doi:10.3233/JAD‐200466]. Study AB09004 assessed oral masitinib administered as an add‐on therapy to standard care for the treatment of mild to moderate AD.MethodPhase 2B/3 study AB09004 comprised two independent, double‐blinded, placebo‐controlled, sub‐studies: masitinib at 4.5mg/kg/day versus placebo (randomized 1:1), and a titrated masitinib dose of 6.0 mg/kg/day versus matched placebo (randomized 2:1). Eligible patients that had a clinical diagnosis of AD with baseline mini‐mental state examination (MMSE) score ≥12–≤25, and had received a stable dose of cholinesterase inhibitor (donepezil, rivastigmine or galantamine) and/or memantine for ≥6 months, were treated for 24 weeks. Primary endpoint was overall change from baseline at week‐24 (analysis of covariance model) in the Alzheimer's Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog) or the Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS‐ADL) score. The study was successful if a significant improvement was reached on either ADAS‐Cog or ADCS‐ADL at a 2.5% level of statistical significance, in either sub‐study.ResultMasitinib (4.5mg/kg/day) (n=182, median (age=73 years, MMSE=19, ADCS‐ADL=55.0, ADAS‐Cog=25.5)) showed significant benefit over placebo (n=176, median (age=73 years, MMSE=19, ADCS‐ADL=53.5, ADAS‐Cog=24.8)) with a least‐squares mean difference in ADAS‐Cog from baseline (δCog) of ‐1.46 versus 0.69, respectively, and corresponding least‐squares mean difference between groups (ΔCog) of ‐2.15 (97.5%CI[‐3.48,‐0.81]);p=0.0003. All ADAS‐Cog sensitivity analyses were convergent with the primary outcome, including the conservative jump‐to‐reference approach with ΔCog of ‐1.89 (95%CI[‐3.06,‐0.72];p=0.0016). Considering ADCS‐ADL, δADL was 1.01 for masitinib (4.5mg/kg/day) versus ‐0.81 for placebo, with a ΔADL of 1.82 (97.5%CI[‐0.15,3.79]);p=0.038. Safety was consistent with the known profile for masitinib. The proportion of patients presenting at least one adverse event (AE) or severe AE was respectively, 87.0% and 26.5% for masitinib (4.5mg/kg/day, n=185) versus 77.5% and 19.3% for placebo (pooled, n=280). Efficacy results from the titrated masitinib 6.0 mg/kg/day sub‐study were inconclusive and no new safety signal was observed.ConclusionMasitinib (4.5mg/kg/day), a tyrosine kinase inhibitor targeting mast cell and microglia activity, may provide a new treatment option for mild to moderate AD.

Randomized controlled trial of gamma sensory stimulation treatment maintains functional ability and decreases sleep fragmentation in Alzheimer’s disease patients

AbstractBackgroundDaily, at‐home gamma sensory stimulation consisting of EEG‐calibrated auditory and visual stimuli is a new therapeutic approach for the treatment of Alzheimer’s Disease (AD). Based on experimental studies demonstrating that sensory‐evoked gamma oscillation halts or reverses AD‐related pathology, improves cognitive function, and normalizes circadian rhythm in transgenic mice carrying human AD pathological genes, this clinical trial evaluated the effects of 40Hz sensory stimulation on functional ability and sleep quality of AD patients.MethodPatients with mild‐to‐moderate AD (MMSE 14‐26, inclusive; n=74) were randomized to receive either 40Hz noninvasive audio‐visual stimulation or sham stimulation over a 6‐month period. Functional abilities of patients were measured by Alzheimer's Disease Cooperative Study ‐ Activities of Daily Living (ADCS‐ADL) scale at baseline and every four weeks during the study and follow‐up period. Sleep quality was assessed from nighttime activities of a subgroup of patients (n=7 in treatment, n=6 in sham groups) who were monitored continuously via a wrist worn actigraphy watch throughout the 6‐month period.ResultAdjusted ADCS‐ADL scores from beginning and end of the trial were compared in patients who completed the trial. Over the 6‐month period, patients in the sham group (n=19) showed the expected decline, a 5.40‐point drop in ADCS‐ADL scores, whereas patients in the treatment group (n=33) receiving therapy exhibited only a 0.57‐point decline. Changes in ADCS‐ADL scores were statistically significant between the sham and treatment groups (P&lt;0.01). Nighttime active durations in the treatment group were significantly (p&lt;0.03) reduced in the second 3 months compared to the first 3 months but the opposite change was observed in the sham group. After normalizing the active durations by the corresponding nighttime period of each patient, the analysis confirmed opposite changes in nighttime active durations between the two groups (p&lt;0.001).ConclusionPatients in gamma sensory stimulation therapy maintained their activities of daily living and showed an improved sleep quality over a 6‐month treatment period; two outcome measures, functional ability and sleep quality known to be strongly linked in AD. Maintenance of functional ability represents an important treatment and management goal for AD patients, reducing formal and informal care, and delaying time to institutionalization.

Intepirdine as adjunctive therapy to donepezil for mild-to-moderate Alzheimer's disease: A randomized, placebo-controlled, phase 3 clinical trial (MINDSET).

IntroductionA previous phase 2b study supported the use of the 5‐HT6 receptor antagonist intepirdine as adjunctive therapy to donepezil for Alzheimer's disease (AD) dementia. A phase 3 study, MINDSET, was performed to test this hypothesis.MethodsMINDSET was a global, double‐blind, randomized, placebo‐controlled trial in 1315 mild‐to‐moderate AD dementia patients on stable donepezil. Patients received 35 mg/day intepirdine or placebo for 24 weeks. The co‐primary endpoints were change from baseline to week 24 on the Alzheimer's Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog) and Alzheimer's Disease Cooperative Study‐Activities of Daily Living (ADCS‐ADL).ResultsThere were no statistically significant differences between intepirdine and placebo groups (adjusted mean [95% confidence interval]) on the co‐primary endpoints ADAS‐Cog (−0.36 [−0.95, 0.22], P = 0.2249) and ADCS‐ADL (−0.09 [−0.90, 0.72], P = 0.8260). Intepirdine demonstrated a favorable safety profile similar to placebo.DiscussionIntepirdine as adjunctive therapy to donepezil did not produce statistical improvement over placebo on cognition or activities of daily living in mild‐to‐moderate AD dementia patients.

Factors associated with long-term impact on informal caregivers during Alzheimer's disease dementia progression: 36-month results from GERAS.

To identify, in caregivers of patients with Alzheimer's disease (AD) dementia, factors associated with subjective (personal, physical, emotional, and social) and objective (informal caregiver time and costs) caregiver burden. Prospective longitudinal European observational study: post-hoc analysis. Clinic. Community-dwelling patients in France and Germany aged ≥ 55 years (n = 969) with probable AD and their informal caregivers. Mini-Mental State Examination (MMSE), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), 12-item Neuropsychiatric Inventory (NPI-12), Zarit Burden Interview (ZBI), informal caregiver basic and instrumental ADL hours (Resource Utilization in Dementia instrument), and informal caregiver costs. Mixed-effect models of repeated measures (MMRM) were run, including baseline and time-dependent covariates (change from baseline [CFB] to 18 months in MMSE, ADCS-ADL, and NPI-12 scores) associated with CFB in ZBI score/informal caregiver time over 36 months (analyzed using linear regression models) and informal caregiver costs over 36 months (analyzed using generalized linear models). Greater decline in patient function (ADCS-ADL) over 18 months was associated with increased subjective caregiver burden (ZBI), hours, and costs over 36 months. Increased behavioral problems (NPI-12) over 18 months also negatively impacted ZBI. Cognitive decline (MMSE) over 18 months did not affect change in caregiver burden. Long-term informal caregiver burden was driven by worsening functional abilities and behavioral symptoms but not cognitive decline, over 18 months in community-dwelling patients with AD dementia. Identifying the drivers of caregiver burden could highlight areas in which interventions may benefit both caregivers and patients.

Relationships between Cognition and Activities of Daily Living in Alzheimer's Disease During a 5-Year Follow-Up: ALSOVA Study.

Impaired cognition and activities of daily living (ADL) are core symptoms of Alzheimer's disease (AD), but their relationship is unclear. To explore relationships between cognitive domains and functional ability during 5-year follow-up in persons with AD. We analyzed ALSOVA study data from 236 individuals with very mild or mild AD at baseline. The CERAD Neuropsychological Battery (CERAD-NB) was used as a cognitive measure and Alzheimer's Disease Cooperative Study ADL (ADCS-ADL) as a functional measure, analyzing the IADL and BADL sub-scores separately. Annual regression models and linear mixed-effect models (LMMs) covering a 5-year follow-up period were used. Annually, the CERAD-NB total and especially Verbal Fluency, Clock Drawing, and Constructional Praxis were associated with the total ADCS-ADL and IADL scores increasingly yet modestly, and to a lesser extent the BADL score. In the LMMs, the same measures and MMSE were associated with ADL. Measures of executive function and visuoconstructive skills appear to be associated with caregiver-interview based ADL measure during the progression of AD.

Alzheimer's Symptomatic Drug Set to Test as Donepezil Combo

BARCELONA — RVT-101, a novel small molecule that increases acetylcholine release, is poised for what its developers say could be its pivotal trial for U.S. approval. The MINDSET study will examine the effect of the 5-HT6 receptor antagonist RVT-101, which will be given in conjunction with donepezil. As an acetylcholine booster, RVT-101 would not be a disease-modifying therapy. And like other symptomatic drugs, it would not alter the trajectory of Alzheimer's disease. Launched last month, MINDSET will be conducted in North America, South America, Europe, and Asia. The study investigators want to enroll least 1,000 patients with mild to moderate Alzheimer's disease who are on stable doses of donepezil, Lawrence Friedhoff, MD, PhD, said at the Clinical Trials on Alzheimer's Disease conference. Axovant Sciences' RVT-101, formerly developed as SB742457 by GlaxoSmithKline, has been investigated in 13 studies of both monotherapy and adjunctive therapy in more than 2,000 patients with Alzheimer's, said Dr. Friedhoff, chief development officer at Axovant Sciences. As monotherapy, it was ineffective, conferring no significant benefits on either cognition or function. The earlier study upon which MINDSET is modeled was a modestly successful phase IIb dose-ranging trial that comprised 684 patients. At 48 weeks, the combination of 35 mg SB742457 (RVT-101) and donepezil conferred about a 2-point benefit on the Alzheimer's Disease Assessment Scale–Cognitive (ADAS-cog) and the Alzheimer's Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) over donepezil alone. Neither the 35-mg dose nor the 15-mg dose, which was also tested, conferred any benefit on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) test. “Regulators have told us that if our results are similar, then this study will be suitable for submission for approval,” Dr. Friedhoff said. “We have a reasonably high level of confidence that it will also be effective in this trial.” The 24-week MINDSET will randomize patients to their donepezil dosage plus either placebo or 35 mg RVT-101 daily. Coprimary endpoints are the ADAS-cog and the ADCS-ADL. The CDR-SB is not an endpoint in MINDSET, which Dr. Friedhoff noted was designed to maximize the chance of success. A 12-month open-label extension study focusing on long-term safety will follow the randomized trial. GSK ceased development of RVT-101 in 2010 without public explanation. However, a recent review of several of the GSK studies suggests that it simply didn't meet the studies' success criteria. Axovant was formed in 2014 to give RVT-101 a new shot as an add-on treatment. The combination makes sense, Dr. Friedhoff said. “It increases acetylcholine in the brain. We already know this is an effective way to treat Alzheimer's because our acetylcholinesterase inhibitors achieve this in a different way, by inhibiting the breakdown of acetylcholine,” Dr. Friedhoff explained. “It makes sense that they should work well together. It doesn't help much to increase the release if it's broken down quickly.” RVT-101 has an attractive safety profile, Dr. Friedhoff said. It had a low rate of gastrointestinal side effects (nausea, 2%; diarrhea, 5%) and was associated with very few falls in prior studies (about 3%). That relatively benign side effect profile is probably reflected in the study's large completer rate, Dr. Friedhoff said. The placebo and 35-mg dose had virtually identical completer rates of 88% and 89%, respectively. The dropout rates were low and similar in both groups. Axovant also aims to investigate RVT-101 in patients with Lewy body dementia, he added. The company expects to launch a phase IIb clinical study early next year. Dr. Friedhoff is an employee of Axovant Sciences. Michele G. Sullivan is with the Mid-Atlantic bureau of Frontline Medical News.

Acute Psychogeriatric Inpatient Treatment Improves Neuropsychiatric Symptoms but Impairs the Level of Functioning in Patients with Dementia

Aims: To explore the impact of hospitalization on neuropsychiatric symptoms (NPS) and the level of functioning in patients with dementia. Our aim was also to study the influence of psychotropic medications. Methods: Behavioral disturbances, cognition and functional status of 89 patients were assessed using the Neuropsychiatric Inventory (NPI), Mini-Mental State Examination, Barthel Index, and Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCSADL). Results: The total NPI score decreased from 34.6 to 19.5 (p < 0.001), and ADL decreased from 32.2 to 21.7 (p < 0.001) during the hospital stay (mean of 44 days). For a change in ADL, only the effect of anxiolytics was significant (p = 0.045). For a change in NPI with antipsychotic and anxiolytic doses and Mini-Mental State Examination as covariates, no significant relationship was found. Conclusion: NPS improved significantly during hospitalization, but neither antipsychotic nor anxiolytic medication use explained this improvement. In patients using anxiolytics, the functional decline was substantial. These results do not support anxiolytic use in demented patients with NPS.

Intravenous immunoglobulin for Alzheimer's disease.

The foundation for using intravenous immunoglobulin (IVIg) to treat Alzheimer's disease (AD) can be traced back to the discovery, in the early 1990s, of naturally occurring anti-amyloid antibodies in human blood. A decade later, a number of independent investigators reported reduced levels of naturally occurring anti-amyloid antibodies in the spinal fluid and blood of AD patients relative to age-matched controls 1–3. Dodel subsequently reported that IVIg contained elevated levels of antibodies against amyloid-β (Aβ) monomers and proposed its use as a potential treatment for AD 4.

Ideal combination of dementia screening tests.

Although many neuropsychological tests have been developed to evaluate higher brain dysfunction, conducting several tests in daily medical care is very difficult for both the patient and the examiner. We herein reviewed the correlation between the results of 11 neuropsychological tests in order to create a new compact and easily administered combination of screening tests to detect dementia. We performed 11 neuropsychological tests in 1,674 outpatients suspected of having cognitive dysfunction and 46 normal control subjects. The 11 tests included the following examinations: the mini mental state examination (MMSE) and Hasegawa dementia rating scale-revised (HDS-R) for the total intelligence function, the frontal assessment battery (FAB) and Montreal cognitive assessment (MoCA) for the frontal lobe function, the neuropsychiatric inventory (NPI) and Abe's behavioral and psychological symptoms of dementia score (ABS) for emotional changes, the geriatric depression scale (GDS) for depressive conditions, the vitality index (VI) and apathy score (AS) for reduced motivation and the clinical dementia rating (CDR) and Alzheimer's disease cooperative study-activities of daily living (ADCS-ADL) scale for ADL's. In order to determine the most compact test series, we compared all test features, correlations between the scores and the time required to complete each test. Correlations were found between tests of the cognitive function, tests of the cognitive function vs NPI, tests of the cognitive function vs ADL, NPI vs ABS, NPI vs GDS, GDS vs AS, VI vs AS and CDR vs ADCS-ADL. The duration of testing was shorter for the FAB than for the MoCA and for the ABS than for the NPI. A combination of six tests (MMSE or HDS-R, FAB, ABS, GDS, AS and ADCS-ADL) was found to be useful for screening dementia and reducing the test burden on the patient in daily medical practice.

Long-term Safety of Rivastigmine in Parkinson Disease Dementia

This study investigated the long-term safety of rivastigmine (12 mg/d capsules, 9.5 mg/24 h patch) and effects on motor symptoms in patients with mild-to-moderately severe Parkinson disease dementia. This was a 76-week, prospective, open-label, randomized study in patients aged 50 to 85 years. Primary outcomes included incidence of, and discontinuation due to, predefined adverse events (AEs) potentially arising from worsening of Parkinson disease motor symptoms with capsules. Secondary outcomes included frequency of AEs/serious AEs. Efficacy outcomes included Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), Neuropsychiatric Inventory (NPI-10), and Mattis Dementia Rating Scale (MDRS). Five hundred eighty-three patients were randomized to rivastigmine capsules (n = 295) or patch (n = 288). Incidence of predefined AEs was 36.1% for capsules, 31.9% for patch; discontinuation due to worsening of motor symptoms was 4.4% and 2.4%, respectively. Most common AEs were nausea (capsules, 40.5%; patch, 8.3%), tremor (24.5%; 9.7%), fall (17.0%; 20.1%), vomiting (15.3%; 2.8%), and application site erythema (0%; 13.9%). Significant efficacy in favor of capsules was observed at weeks 24 to 76 on MDRS; 24 and 76 on NPI-10; weeks 52 and 76 on ADCS-ADL. In patients with Mini-Mental State Examination (MMSE) greater than 21, no differences in efficacy on MDRS and ADCS-ADL were observed at any time point; significant differences in favor of capsules were maintained in patients with MMSE less than or equal to 21. This study supports the long-term safety of rivastigmine in Parkinson disease dementia. The rate of worsening of motor symptoms was in the range expected due to the natural progression of Parkinson disease, no new or unexpected safety issues emerged in the long-term.

Effect of Vitamin E and Memantine on Functional Decline in Alzheimer Disease

Although vitamin E and memantine have been shown to have beneficial effects in moderately severe Alzheimer disease (AD), evidence is limited in mild to moderate AD. To determine if vitamin E (alpha tocopherol), memantine, or both slow progression of mild to moderate AD in patients taking an acetylcholinesterase inhibitor. Double-blind, placebo-controlled, parallel-group, randomized clinical trial involving 613 patients with mild to moderate AD initiated in August 2007 and concluded in September 2012 at 14 Veterans Affairs medical centers. Participants received either 2000 IU/d of alpha tocopherol (n = 152), 20 mg/d of memantine (n = 155), the combination (n = 154), or placebo (n = 152). Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Inventory score (range, 0-78). Secondary outcomes included cognitive, neuropsychiatric, functional, and caregiver measures. Data from 561 participants were analyzed (alpha tocopherol = 140, memantine = 142, combination = 139, placebo = 140), with 52 excluded because of a lack of any follow-up data. Over the mean (SD) follow-up of 2.27 (1.22) years, ADCS-ADL Inventory scores declined by 3.15 units (95% CI, 0.92 to 5.39; adjusted P = .03) less in the alpha tocopherol group compared with the placebo group. In the memantine group, these scores declined 1.98 units less (95% CI, -0.24 to 4.20; adjusted P = .40) than the placebo group's decline. This change in the alpha tocopherol group translates into a delay in clinical progression of 19% per year compared with placebo or a delay of approximately 6.2 months over the follow-up period. Caregiver time increased least in the alpha tocopherol group. All-cause mortality and safety analyses showed a difference only on the serious adverse event of "infections or infestations," with greater frequencies in the memantine (31 events in 23 participants) and combination groups (44 events in 31 participants) compared with placebo (13 events in 11 participants). Among patients with mild to moderate AD, 2000 IU/d of alpha tocopherol compared with placebo resulted in slower functional decline. There were no significant differences in the groups receiving memantine alone or memantine plus alpha tocopherol. These findings suggest benefit of alpha tocopherol in mild to moderate AD by slowing functional decline and decreasing caregiver burden. clinicaltrials.gov Identifier: NCT00235716.

Comparing Clinical Profiles in Alzheimer's Disease and Parkinson's Disease Dementia

Background: Greater understanding of differences in baseline impairment and disease progression in patients with Alzheimer's disease (AD) and Parkinson's disease dementia (PDD) may improve the interpretation of drug effects and the design of future studies. Methods: This was a retrospective analysis of three randomized, double-blind rivastigmine databases (one in PDD, two in AD). Impairment on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, 10-item Neuropsychiatric Inventory (NPI-10) and the ADCS-Clinical Global Impression of Change (CGIC) was compared [standardized difference (Cohen's d), similar if <0.1]. Results: Patients with AD or PDD had similar levels of impairment on the ADAS-cog and NPI-10. Scores on the ADCS-ADL scale (standardized difference = 0.47) and the ADAS-cog memory domain (total, 0.33; items, 0.10-0.58) were higher in AD; PDD patients were more impaired in the language (0.23) and praxis (0.34) domains. AD patients receiving placebo showed greater deterioration on the ADAS-cog (0.14) and improvement on the NPI-10 (0.11) compared with patients with PDD. Conclusion: Differing patterns of impairment occur in AD and PDD.

A Phase 3 Trial of Semagacestat for Treatment of Alzheimer's Disease

BackgroundAlzheimer's disease is characterized by the presence of cortical amyloid-beta (Aβ) protein plaques, which result from the sequential action of β-secretase and γ-secretase on amyloid precursor protein. Semagacestat is a small-molecule γ-secretase inhibitor that was developed as a potential treatment for Alzheimer's disease.MethodsWe conducted a double-blind, placebo-controlled trial in which 1537 patients with probable Alzheimer's disease underwent randomization to receive 100 mg of semagacestat, 140 mg of semagacestat, or placebo daily. Changes in cognition from baseline to week 76 were assessed with the use of the cognitive subscale of the Alzheimer's Disease Assessment Scale for cognition (ADAS-cog), on which scores range from 0 to 70 and higher scores indicate greater cognitive impairment, and changes in functioning were assessed with the Alzheimer's Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) scale, on which scores range from 0 to 78 and higher scores indicate better functioning. A mixed-model repeated-measures analysis was used.ResultsThe trial was terminated before completion on the basis of a recommendation by the data and safety monitoring board. At termination, there were 189 patients in the group receiving placebo, 153 patients in the group receiving 100 mg of semagacestat, and 121 patients in the group receiving 140 mg of semagacestat. The ADAS-cog scores worsened in all three groups (mean change, 6.4 points in the placebo group, 7.5 points in the group receiving 100 mg of the study drug, and 7.8 points in the group receiving 140 mg; P=0.15 and P=0.07, respectively, for the comparison with placebo). The ADCS-ADL scores also worsened in all groups (mean change at week 76, −9.0 points in the placebo group, −10.5 points in the 100-mg group, and −12.6 points in the 140-mg group; P=0.14 and P<0.001, respectively, for the comparison with placebo). Patients treated with semagacestat lost more weight and had more skin cancers and infections, treatment discontinuations due to adverse events, and serious adverse events (P<0.001 for all comparisons with placebo). Laboratory abnormalities included reduced levels of lymphocytes, T cells, immunoglobulins, albumin, total protein, and uric acid and elevated levels of eosinophils, monocytes, and cholesterol; the urine pH was also elevated.ConclusionsAs compared with placebo, semagacestat did not improve cognitive status, and patients receiving the higher dose had significant worsening of functional ability. Semagacestat was associated with more adverse events, including skin cancers and infections. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT00594568.)