Daniel Saumier

Tramiprosate in mild-to-moderate Alzheimer's disease - a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study).

Introduction The aim of the study was to assess the clinical efficacy, safety, and disease-modification effects of tramiprosate (homotaurine, ALZHEMEDTM) in mild-to-moderate Alzheimer’s disease (AD). Material and methods Double-blind, placebo-controlled, randomized trial in 67 clinical centres across North America. Patients aged ≥ 50 years, with mild-to-moderate AD (Mini-Mental State Examination score between 16 and 26) and on stable doses of cholinesterase inhibitors, alone or with memantine. Intervention: 78-week treatment with placebo, tramiprosate 100 mg or tramiprosate 150 mg BID. Measurements: Alzheimer Disease Assessment Scale – cognitive subscale (ADAS-cog) and Clinical Dementia Rating – Sum of Boxes (CDR-SB) assessments were performed at baseline and every 13 weeks. Baseline and 78-week magnetic resonance imaging (MRI) hippocampus volume (HV) measurements were conducted in a subgroup of patients. Results A total of 1,052 patients were enrolled and 790 (75.1%) completed the 78-week trial. Patient discontinuation and reasons for withdrawal were similar across groups. Planned analyses did not reveal statistically significant between-group differences. Lack of adequate statistical validity of the planned analysis models led to the development of revised predictive models. These adjusted models showed a trend toward a treatment effect for ADAS-cog (P = 0.098) and indicated significantly less HV loss for tramiprosate 100 mg (P = 0.035) and 150 mg (P = 0.009) compared to placebo. The incidence of adverse events was similar across treatment groups. Conclusions The primary planned analyses did not show a significant treatment effect, but were confounded by unexplained variance. Post-hoc analyses showed a significant treatment-related reduction in HV loss. However, there was only a trend towards slowing of decline on the ADAS-cog and no slowing of decline on the CDR-SB. These results must be interpreted in consideration of the limitations of clinical and disease-modification outcome measures and their relationship, the heterogeneity of the disease and the impact of confounding demographic and clinical variables.

Alzhemed: A Potential Treatment for Alzheimers Disease

As a potential disease-modifying treatment for AD, Alzhemed (tramiprosate) is a compound that binds to soluble amyloid-beta peptide (Abeta) and inhibits the formation of neurotoxic aggregates that lead to amyloid plaque deposition in the brain. The safety, tolerability, and pharmacodynamic effects of Alzhemed were assessed in a double-blind study in which 58 individuals with mild-to-moderate AD (MMSE 13-25) were randomized to receive placebo or Alzhemed 50, 100 or 150 mg BID for 3 months. At the end of the double-blind phase, 42 of these subjects entered a 36-month open-label (OL) phase in which they received Alzhemed 150 mg BID. Assessments included plasma and cerebrospinal fluid (CSF) Alzhemed concentrations, CSF levels of Abeta, as well as cognitive (Alzheimers Disease Assessment Scale-cognitive subscale, Mini-Mental State Examination) and clinical performance (Clinical Dementia Rating scale, Sum-of-Boxes) measures. Alzhemed was safe and well tolerated, crossed the blood-brain barrier, and dose-dependently reduced CSF Abeta(42) levels after 3 months of treatment. Mild AD subjects (MMSE 19-25 at entry) displayed greater reduction of CSF Abeta(42) levels than moderate AD participants (MMSE 13-18 at entry). There was no effect of Alzhemed on the cognitive or clinical measures after 3 months of treatment. The OL follow-up suggested a stabilization of cognitive function especially in mild AD subjects over the 36-month study period. Alzhemed thus appears to be well tolerated with long-term exposure and reduces CSF Abeta(42) levels in mild-to-moderate AD subjects. These findings will be discussed in the context of two large-scale randomized, double-blind, placebo-controlled Phase III clinical trials that are currently being conducted to test the long-term safety and efficacy of Alzhemed.

Comprehension of Grammatical and Emotional Prosody Is Impaired in Alzheimer's Disease

Previous research has demonstrated impairment in comprehension of emotional prosody in individuals diagnosed with Alzheimers disease (AD). The present pilot study further explored the prosodic processing impairment in AD, aiming to extend our knowledge to encompass both grammatical and emotional prosody processing. As expected, impairments were seen in emotional prosody. AD individuals were also found to be impaired in detecting sentence modality, suggesting that impairments in affective prosody processing in AD may be ascribed to a more general prosodic processing impairment, specifically in comprehending prosodic information signaled across the sentence level. AD participants were at a very mild stage of the disease, suggesting that prosody impairments occur early in the disease course.

Scales as outcome measures for Alzheimer's disease.

The assessment of patient outcomes in clinical trials of new therapeutics for Alzheimers disease (AD) continues to evolve. In addition to assessing drugs for symptomatic relief, an increasing number of trials are focusing on potential disease‐modifying agents. Moreover, participants with AD are being studied earlier in their course of disease. As a result, the limitations of current outcome measures have become more apparent, as has the need for better instruments. In recognition of the need to review and possibly revise current assessment measures, the Alzheimers Association, in cooperation with industry leaders and academic investigators, convened a Research Roundtable meeting devoted to scales as outcome measures for AD clinical trials. The meeting included a discussion of methodological issues in the use of scales in AD clinical trials, including cross‐cultural issues. Specific topics related to the use of cognitive, functional, global, and neuropsychiatric scales were also presented. Speakers also addressed academic and industry initiatives for pooling data from untreated and placebo‐treated patients in clinical trials. A number of regulatory topics were also discussed with agency representatives. Panel discussions highlighted areas of controversy, in an effort to gain consensus on various topics.

Trauma reactivation plus propranolol is associated with durably low physiological responding during subsequent script-driven traumatic imagery.

Objective: In a previous, double-blind, placebo-controlled study, patients with posttraumatic stress disorder (PTSD) showed lower physiological response during script-driven traumatic imagery 1 week after receiving a single dose of propranolol given after the retrieval of a traumatic memory. We hypothesized that this effect would extend beyond 1 week using a modified treatment approach. Method: Twenty-eight participants with PTSD read an account of their traumatic event once weekly for 6 consecutive weeks under the influence of open-label propranolol. One week and 4-months later, skin conductance, heart rate, and left corrugator electromyogram responses were measured while participants engaged in script-driven mental imagery of their traumatic event. Results from the 22 study participants were compared with results from treated and untreated participants in a previously published trial. Results: Most participants in our study were classified as non-PTSD cases at posttreatment and follow-up according to a psychophysiological discriminant function analysis. Posttreatment skin conductance and heart rate responses of the current (propranolol-treated) participants were lower than those of placebo participants from the previous study. No difference was observed between physiological responding measured posttreatment and at follow-up. Conclusions: Low physiological responding during script-driven traumatic imagery after treatment extends up to 4 months, demonstrating the durability of the treatment effects. Limitations include the absence of a placebo-controlled group and lack of physiological baseline measures. Despite these limitations, results point to the need for future trials examining the clinical efficacy of trauma reactivation plus propranolol, as it has the potential to become a novel, cost- and time-effective treatment for PTSD.

Peritraumatic Distress and the Course of Posttraumatic Stress Disorder Symptoms: A Meta-Analysis:

Objective: To examine how peritraumatic distress modulates the severity of posttraumatic stress disorder (PTSD) according to the timing of the PTSD symptom assessments. Method: A systematic literature review of English- and French-language studies having administered the Peritraumatic Distress Inventory (PDI) was conducted. Meta-analyses were performed on correlations relating PDI and PTSD symptom scores obtained from the sampled studies. The meta-analyses, which included calculations of regression slopes, took into consideration the time at which PTSD symptoms were assessed following the traumatic event and the timing of the PDI assessment. Results: The literature review yielded a total of 22 studies. The meta-analysis performed over all studies resulted in a pooled correlation coefficient of 0.55 between the PDI and PTSD symptom scores. Meta-regression analyses conducted over all data revealed no apparent decrease in the correlations according to the timing of the PTSD symptom assessments. However, there were numerical or statistically significant declines in regression slopes when the meta-regressions were separately conducted on studies having administered the PDI either within, or following, a 1-month period after a traumatic event. Conclusions: While PDI or PTSD symptom score correlations remain generally significant, they tend to decline as time elapses between the traumatic event and the PTSD assessment. This suggests there may be factors other than peritraumatic distress that increasingly account for the long-term trajectory PTSD symptoms.

Reactivating addiction-related memories under propranolol to reduce craving: A pilot randomized controlled trial

BACKGROUND The reconsolidation blocker propranolol abolishes alcohol and drug-seeking behavior in rodents and attenuates conditioned emotional responses to drug-cues in humans in experimental settings. This suggests a role for its use in the treatment of substance dependence. In this translational pilot study, we explored the feasibility and efficacy of this procedure as an adjunct treatment for addiction. We hypothesized that guided addiction-related memory reactivation under propranolol would significantly attenuate tonic craving, a central element in relapse following addiction treatment. METHODS Seventeen treatment-seeking adults diagnosed with substance dependence were randomized to receive double-blind propranolol (n = 9) or placebo (n = 8) on six occasions prior to reading a personalized script detailing a drug-using experience. The primary outcome measure was self-reported craving intensity. RESULTS After controlling for baseline craving scores, intent-to-treat analysis revealed a time by group interaction, F(1, 14) = 5.68, p = .03, η(2) = 0.29; craving was reduced in the propranolol-treated group (Cohens d = 1.40, p < .05) but not in the placebo group (d = 0.06, n.s.). LIMITATIONS The usual limitations related to small sample size and the lack of a follow-up apply here. CONCLUSION Drug-related memory reactivation under propranolol can subsequently reduce craving among substance-dependent individuals. Considering the relapse rate among individuals treated for substance dependence, our study highlights the feasibility of, and need for, more comprehensive trials of this treatment approach.

Does reconsolidation occur in humans: a reply

Schiller and Phelps (2011) have provided a thoughtful and comprehensive review in the May issue of Frontiers in Behavioral Neurosciences entitled, “Does reconsolidation occur in humans?” This scholarly paper captures many of the challenges in translating the animal research on reconsolidation to humans. We agree with their main argument that there is little published evidence in humans that meets one important reconsolidation criterion, namely, that the memory-weakening treatment should be administered after the memory reactivation, so as not to influence the preceding memory retrieval process. However, it is unclear whether pre-reactivation propranolol significantly hampers memory retrieval. On the basis of this uncertainty, Schiller and Phelps go on to suggest that the memory impairing effects of pre-reactivation propranolol (e.g., Kindt et al., 2009; Brunet et al., 2011) must be explained by some process other than reconsolidation. Such a conclusion appears illogical, because if propranolol does not impair retrieval sufficiently to preclude reconsolidation, then blockade of memory reconsolidation remains a viable explanation for pre-reactivation propranolols memory-weakening action. Indeed, the ultimate evidence for successful memory retrieval is measured during reactivation (e.g., freezing behavior in rodent fear conditioning, GSR in human fear conditioning, etc.). Therefore, any impairment of retrieval should be detected. Moreover, as shown recently by Debiec et al. (2011) immediate post-retrieval beta-adrenergic receptor stimulation enhances reconsolidation of fear conditioning in the amygdala. In this scenario, administration of propranolol following memory retrieval (which results in arousal and noradrenergic stimulation) may be too late to be effective. So, a parsimonious explanation is that pre-reactivation propranolol did block reconsolidation to some extent in the above-mentioned studies. Pre-reactivation propranolol studies (and other studies with a similar design) ought to be pursued vigorously because, irrespective of how the memory impairing effect is obtained, they offer the prospect of a novel approach to treating mental disorders that have at their core an emotional, usually traumatic, memory. Although Schiller and Phelps acknowledge some of the challenges of blocking reconsolidation using pharmacological means in humans, it is important to note the reasons for this difficulty. In animals, reconsolidation (i.e., protein synthesis) is believed to begin 3–10 min after memory reactivation (Monfils et al., 2009). Most of it appears to take place within the first 2 h (Przybyslawski et al., 1999) and to be over by the sixth hour (Duvarci and Nader, 2004). Considering that oral propranolol takes about 90 min to reach its peak bioavailability in human blood (Marino, 1987); and considering that only a fraction of this drug will eventually cross the blood–brain barrier to be available to exert the necessary effect, protocols that use post-reactivation propranolol are vulnerable to yielding negative results because not enough protein synthesis will have been blocked by the time the drug reaches its full effect in the human brain. Since conducting our proof-of-concept study in posttraumatic stress disorder (PTSD; Brunet et al., 2008), which used post-reactivation propranolol, we have opted to use pre-reactivation propranolol in an attempt to develop what we hope will be a more potent therapeutic protocol (see Brunet et al., 2011). It is unfortunate that this type of protocol does not meet an important scientific criterion for studies that use it to be labeled as genuine “reconsolidation” studies, but this is the price to pay for conducting sound translational research in patients. Schiller et al. (2010) are to be commended for their efforts to devise a human protocol that circumvents the problems associated with pharmacological blockade of reconsolidation by incorporating new material into a destabilized old memory, rather than simply blocking its reconsolidation. However, they have yet to show that such an approach is sufficiently potent to help patients overcome their psychological symptoms stemming from a traumatic emotional memory.

Independent Processing of Parts and of Their Spatial Organization in Complex Visual Objects

A visual search experiment using synthetic three-dimensional objects is reported. The target shared its constituent parts, the spatial organization of its parts, or both with the distractors displayed with it. Sharing of parts and sharing of spatial organization both negatively affected visual search performance, and these effects were strictly additive. These findings support theories of complex visual object perception that assume a parsing of the stimulus into its higher-order constituents (volumetric parts or visible surfaces). The additivity of the effects demonstrates that information on parts and information on spatial organization are processed independently in visual search.

Cognitive Predictors of Donepezil Therapy Response in Alzheimer Disease

Objectives: To examine whether the presence of domain-specific cognitive impairments would predict a response to donepezil medication in patients with mild-to-moderate Alzheimer disease (AD). Methods: The protocol was an open-label study of 30 AD subjects (mean age 74 years; education 11 years; Mini-Mental State Exam (MMSE) 23 of 30) beginning a 6-month course of treatment with donepezil. Global response to treatment was determined using a combination algorithm based on changes over 6 months in the ADAS-cog, MMSE and CIBIC. In addition, a set of neuropsychological and experimental cognitive tests designed to test five domains of cognition were administered before beginning therapy in order to determine which domain of testing would be predictive to response to treatment. The tests examined attention, short-term and working memory, learning and memory, visuo-spatial motor skills, and lexical-semantic knowledge. Results: Eighteen of the thirty subjects were rated as having responded (stable or improved scores on the combination algorithm) to the therapy. Responders were significantly less impaired prior to treatment on the following tests: the Clock Drawing Test, a Visual-Spatial Motor Tracking Test, and the Boston Picture Naming Test. No significant initial group differences were noted on the other neuropsychological or experimental cognitive measures. Conclusion: The tests that most reliably predicted response to donepezil in AD subjects were in the domains of visual-spatial motor abilities and lexical-semantic functioning.