A phase 1, randomized double-blind, placebo controlled trial to evaluate safety and efficacy of epigallocatechin-3-gallate and cognitive training in adults with Fragile X syndrome.

BACKGROUND & AIMS: Despite the wide spectrum of experimental compounds tested in clinical trials, there is still no proven pharmacological treatment available for Fragile-X syndrome (FXS), since several targeted clinical trials with high expectations of success have failed to demonstrate significant improvements. Here we tested epigallocatechin-3-gallate (EGCG) as a treatment option for ameliorating core cognitive and behavioral features in FXS. METHODS: We conducted preclinical studies in Fmr1 knockout mice (Fmr1-/y) using novel object-recognition memory paradigm upon acute EGCG (10 mg/kg) administration. Furthermore we conducted a double-blind placebo-controlled phase I clinical trial (TESXF; NCT01855971). Twenty-seven subjects with FXS (18-55 years) were administered of EGCG (5-7 mg/kg/day) combined with cognitive training (CT) during 3 months with 3 months of follow-up after treatment discontinuation. RESULTS: Preclinical studies showed an improvement in memory using the Novel Object Recognition paradigm. We found that FXS patients receiving EGCG + CT significantly improved cognition (visual episodic memory) and functional competence (ABAS II-Home Living skills) in everyday life compared to subjects receiving Placebo + CT. CONCLUSIONS: Phase 2 clinical trials in larger groups of subjects are necessary to establish the therapeutic potential of EGCG for the improvement of cognition and daily life competences in FXS.

Safety and efficacy of cognitive training plus epigallocatechin-3-gallate in young adults with Down's syndrome (TESDAD): a double-blind, randomised, placebo-controlled, phase 2 trial.

BACKGROUND: Early cognitive intervention is the only routine therapeutic approach used for amelioration of intellectual deficits in individuals with Down's syndrome, but its effects are limited. We hypothesised that administration of a green tea extract containing epigallocatechin-3-gallate (EGCG) would improve the effects of non-pharmacological cognitive rehabilitation in young adults with Down's syndrome. METHODS: We enrolled adults (aged 16-34 years) with Down's syndrome from outpatient settings in Catalonia, Spain, with any of the Down's syndrome genetic variations (trisomy 21, partial trisomy, mosaic, or translocation) in a double-blind, placebo-controlled, phase 2, single centre trial (TESDAD). Participants were randomly assigned at the IMIM-Hospital del Mar Medical Research Institute to receive EGCG (9 mg/kg per day) or placebo and cognitive training for 12 months. We followed up participants for 6 months after treatment discontinuation. We randomly assigned participants using random-number tables and balanced allocation by sex and intellectual quotient. Participants, families, and researchers assessing the participants were masked to treatment allocation. The primary endpoint was cognitive improvement assessed by neuropsychologists with a battery of cognitive tests for episodic memory, executive function, and functional measurements. Analysis was on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01699711. FINDINGS: The study was done between June 5, 2012, and June 6, 2014. 84 of 87 participants with Down's syndrome were included in the intention-to-treat analysis at 12 months (43 in the EGCG and cognitive training group and 41 in the placebo and cognitive training group). Differences between the groups were not significant on 13 of 15 tests in the TESDAD battery and eight of nine adaptive skills in the Adaptive Behavior Assessment System II (ABAS-II). At 12 months, participants treated with EGCG and cognitive training had significantly higher scores in visual recognition memory (Pattern Recognition Memory test immediate recall, adjusted mean difference: 6·23 percentage points [95% CI 0·31 to 12·14], p=0·039; d 0·4 [0·05 to 0·84]), inhibitory control (Cats and Dogs total score, adjusted mean difference: 0·48 [0·02 to 0·93], p=0·041; d 0·28 [0·19 to 0·74]; Cats and Dogs total response time, adjusted mean difference: -4·58 s [-8·54 to -0·62], p=0·024; d -0·27 [-0·72 to -0·20]), and adaptive behaviour (ABAS-II functional academics score, adjusted mean difference: 5·49 [2·13 to 8·86], p=0·002; d 0·39 [-0·06 to 0·84]). No differences were noted in adverse effects between the two treatment groups. INTERPRETATION: EGCG and cognitive training for 12 months was significantly more effective than placebo and cognitive training at improving visual recognition memory, inhibitory control, and adaptive behaviour. Phase 3 trials with a larger population of individuals with Down's syndrome will be needed to assess and confirm the long-term efficacy of EGCG and cognitive training. FUNDING: Jérôme Lejeune Foundation, Instituto de Salud Carlos III FEDER, MINECO, Generalitat de Catalunya.

Horner syndrome associated with ipsilateral facial and extremity anhydrosis.

We report a patient with Horner syndrome together with anhidrosis affecting the ipsilateral face and extremities confirmed with starch-iodine and sympathetic skin response testing. No anatomic lesion was apparent. This is the first reported case in which Horner syndrome has been associated with such extensive hemibody sympathetic dysfunction in the absence of other neurologic findings. We propose a developmental disorder of neural crest migration as the cause.

Auditory event-related potentials (P3) and cognitive performance in recreational ecstasy polydrug users: evidence from a 12-month longitudinal study.

RATIONALE: There is important preclinical evidence of the long-lasting neurotoxic and selective effects of ecstasy (MDMA) on serotonin systems in nonhuman primates. In humans, long-term recreational use of ecstasy has been mainly associated with memory impairment. OBJECTIVE: The first aim of our study was to evaluate the cognitive and electrophysiological long-term alterations associated with lifetime ecstasy use within a sample of ecstasy polydrug users along a 1-year follow-up. Our second aim was to explore the relationship between specific cognitive functions and P300 (P3) event-related potentials (ERPs) in ecstasy users. MATERIALS AND METHODS: We conducted auditory P3 latency and amplitude and administered a battery of cognitive tests to three groups of subjects: 14 current ecstasy polydrug users, 13 current cannabis users, and 22 controls free of illicit drugs in two evaluations during 1 year. RESULTS: We found significant differences between ecstasy users and controls on cognitive measures of word fluency, processing speed, and memory recognition after 1-year follow-up. We found no significant differences between ecstasy and cannabis users or cannabis users and controls on cognitive tests. Lifetime ecstasy use was associated with poorer memory recognition. No group differences were shown on P3 latency or amplitude. Significant correlations emerged between P3 latency and cannabis lifetime use (higher cannabis use was related to faster latency, showing a paradoxical effect) but not with ecstasy exposure. CONCLUSIONS: Our findings provide evidence of mild long-term cognitive deficits among ecstasy polydrug users. Both ecstasy use and the dynamic interaction between ecstasy and cannabis effects may account for these deficits. No significant P3 alterations were found in ecstasy users.