Domain-specific cognitive effects of tramiprosate in patients with mild to moderate Alzheimer's disease: ADAS-cog subscale results from the Alphase Study.

OBJECTIVES: Tramiprosate (homotaurine, ALZHEMEDTM) was recently investigated for its efficacy, safety and disease-modification effects in a Phase III clinical study in mild to moderate Alzheimer's disease (AD) patients (the Alphase study). The primary cognitive endpoint measure of that study was the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog). To characterize potential cognitive benefits of tramiprosate, the present study describes exploratory analyses performed on scores obtained from the specific ADAS-cog subscales in order to determine whether specific domains of cognition may be differentially affected by tramiprosate, which would not have been evident from the measure's total score. DESIGN: Multi-center, double-blind, randomized, placebo-controlled study. SETTING: 67 investigative sites in the United States and Canada. PARTICIPANTS: A total of 1,052 patients were randomized. INTERVENTIONS: Patients were randomized to receive twice a day Placebo (n=353), tramiprosate 100 mg (n=352) and tramiprosate 150 mg (n=347). MEASUREMENTS: ADAS-cog assessments were conducted every three months over the 78-week study period. Exploratory analyses were performed by comparing ADAS-cog subscale scores between Placebo and each active treatment arm at each visit. RESULTS: The findings of this analysis revealed statistically significant differences or statistical trends in favour of tramiprosate on six ADAS-cog subscales, namely Following Commands, Language Comprehension, Ideational Praxis, Object Naming, Remembering Test Instructions, and Spoken Language Ability. Differences in favor of Placebo were only observed on the Constructional Praxis subscale. CONCLUSION: This exploratory analysis suggests that tramiprosate may have some benefit on memory, language and praxis skills in mild to moderate AD individuals. Future clinical studies of tramiprosate should include specialized neuropsychological tests to validate its effects within these cognitive domains.

Effect of tramiprosate in patients with mild-to-moderate Alzheimer's disease: exploratory analyses of the MRI sub-group of the Alphase study.

OBJECTIVES: The efficacy, safety and disease-modification of tramiprosate (homotaurine)were investigated in a recently completed large-scale Phase III clinical study in patients with mild to moderate Alzheimer's disease (AD), the Alphase study. Disease-modification was assessed using longitudinal volumetric MRI (vMRI) measurements of the hippocampus in a subgroup of patients. The present study describes the vMRI, cognitive and clinical results obtained in this subgroup. DESIGN: Multi-center, double-blind, randomized, placebo-controlled study in a subset of the 1052 patients of the Alphase study. SETTING: 51 vMRI investigative sites in the United States and Canada. PARTICIPANTS: A total of 508 patients underwent vMRI scanning. Of these, 312 provided scan pairs for assessing hippocampus volume changes and were included in the analyses. INTERVENTIONS: Patients were randomized to receive Placebo BID (n = 109), tramiprosate 100 mg BID (n = 103), or tramiprosate 150 mg BID (n = 100) for 78 weeks. MEASUREMENTS: Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Clinical Dementia Rating-Sum-of-boxes CDR-SB assessments were conducted at Baseline and at Weeks 13, 26, 39, 52, 65 and 78. Exploratory analyses were performed using similar First and Final mixed-effects repeated-measures models that were used for the analysis of the entire patient dataset. RESULTS: Psychometric score results showed numerical trends in favour of tramiprosate that did not reach statistical significance. While there were no statistically significant group differences in hippocampus volume using the First modeling approach, a significant dose-response reduction in hippocampus volume change was found in the Final models. Moreover, there was a marginally significant overall treatment main effect and a significant slope difference in favour of tramiprosate according to the Final model analysis of the ADAS-cog scores. ADAS-cog scores analyzed according to this model also revealed differences in favor of the tramiprosate 150 mg group at weeks 26 and 52, with marginally significant differences at Weeks 13 and 39. Slope analyses of ADAS-cog score changes showed significant differences in favor of the 150 mg BID group, and when both active groups were combined, in comparison to the placebo group. No between-group differences with respect to changes to each visit in the CDR-SB were observed with either modeling approach. Although there was a similar dose-response relationship observed in the hippocampus volume and ADAS-cog Final model analyses, the overall changes in psychometric scores and hippocampus volume were not significantly correlated. CONCLUSION: Exploratory analysis of the vMRI subgroup suggests that tramiprosate slows hippocampal atrophy, and reveals some evidence of a beneficial effect on cognition. The clinical validity of the vMRI biomarker is discussed.

A Phase II study targeting amyloid-beta with 3APS in mild-to-moderate Alzheimer disease.

BACKGROUND: As a potential disease-modifying treatment for Alzheimer disease (AD), 3-amino-1-propanesulfonic acid (3APS) is a compound that binds to amyloid beta (Abeta), a toxic protein known to aggregate, leading to amyloid plaque deposition in the brain. METHODS: We assessed the safety, tolerability, and pharmacokinetic/pharmacodynamic effect of 3APS in a randomized, double-blind, placebo-controlled Phase II study in which 58 subjects with mild-to-moderate AD were randomly assigned to receive placebo or 3APS 50, 100, or 150 mg BID for 3 months. At the end of the double-blind phase, 42 of these subjects entered an open-label phase in which they received 3APS 150 mg BID for 17 months. Assessments included plasma and CSF 3APS concentrations, CSF levels of Abeta (Abeta(40) and Abeta(42)), and total tau, as well as cognitive (Alzheimer's Disease Assessment Scale-cognitive subscale, Mini-Mental State Examination) and clinical (Clinical Dementia Rating scale-Sum of Boxes) measures. RESULTS: 3APS had no significant impact on vital signs or laboratory test values. The most frequent side effects were nausea, vomiting, and diarrhea, which were intermittent and mild to moderate in severity. Seven 3APS-treated subjects discontinued because of side effects (all causalities) over the course of the study, and there were no 3APS-related serious adverse events. 3APS crossed the blood-brain barrier, and dose-dependently reduced CSF Abeta(42) levels after 3 months of treatment. There were no psychometric score differences between groups over the 3-month double-blind period. CONCLUSION: Long-term administration of 3-amino-1-propanesulfonic acid is safe, tolerated and reduces CSF Abeta(42) levels in patients with mild-to-moderate Alzheimer disease.

Face perception in high-functioning autistic adults: evidence for superior processing of face parts, not for a configural face-processing deficit.

Configural processing in autism was studied in Experiment 1 by using the face inversion effect. A normal inversion effect was observed in the participants with autism, suggesting intact configural face processing. A priming paradigm using partial or complete faces served in Experiment 2 to assess both local and configural face processing. Overall, normal priming effects were found in participants with autism, irrespective of whether the partial face primes were intuitive face parts (i.e., eyes, nose, etc.) or arbitrary segments. An exception, however, was that participants with autism showed magnified priming with single face parts relative to typically developing control participants. The present findings argue for intact configural processing in autism along with an enhanced processing for individual face parts. The face-processing peculiarities known to characterize autism are discussed on the basis of these results and past congruent results with nonsocial stimuli.

Prosopagnosia: a case study involving problems in processing configural information.

An ongoing issue in face recognition research is whether holistic face processing relies on the segregation of local discrete facial parts. Evidence in favor of the holistic-plus-parts view stems from a recent study reported by Arguin and Saumier (1999), who show that the priming effects of individual facial parts (i.e., eyes, nose, mouth, orcontour) depends on the presence of configural information and that the magnitude of priming augments as the number of facial parts serving as primes increase. The present study demonstrates that these global processing effects are absent in a prosopagnosic patient (A.R.), who shows no priming from single face parts and a linear increase in the magnitude of priming as a function of the number of parts presented. These findings indicate that A.R. is incapable of integrating individual facial parts into a global facial configuration ant that this is likely at the root of her prosopagnosia.

Conjunction and linear non-separability effects in visual shape encoding.

Four visual search experiments are reported which used simple 2D shapes varying on the global dimensions of aspect ratio/curvature or aspect ratio/tapering. Results indicate serial self-terminating search in all conditions. Most importantly, search rates are markedly modulated by the particular forms of structural relations existing between the targets and their distractors. Thus, single-feature targets with shape properties that are linearly separable from those of their distractors yield markedly faster search rates than linearly separable targets made of a conjunction of distractor features. In addition, linearly separable single-feature targets are searched at a much faster rate than single-feature targets which are not linearly separable. Follow-up experiments demonstrate that these conjunction and linear non-separability effects cannot be attributed to pairwise target-distractor discriminability differences across conditions. The main conclusions are that the shapes used are parsed according to elementary features in visual encoding, and that a linear discrimination mechanism is available which permits fast visual search rates if a single-feature target is linearly separable from its distractors.