; for the Minocycline in Alzheimer Disease Efficacy (MADE) Trialist Group IMPORTANCE There are no disease-modifying treatments for Alzheimer disease (AD), the most common cause of dementia. Minocycline is anti-inflammatory, protects against the toxic effects of β-amyloid in vitro and in animal models of AD, and is a credible repurposed treatment candidate. OBJECTIVE To determine whether 24 months of minocycline treatment can modify cognitive and functional decline in patients with mild AD. DESIGN, SETTING, AND PARTICIPANTS Participants were recruited into a double-blind randomized clinical trial from May 23, 2014, to April 14, 2016, with 24 months of treatment and follow-up. This multicenter study in England and Scotland involved 32 National Health Service memory clinics within secondary specialist services for people with dementia. From 886 screened patients, 554 patients with a diagnosis of mild AD (Standardised Mini-Mental State Examination [sMMSE] score Ն24) were randomized. INTERVENTIONS Participants were randomly allocated 1:1:1 in a semifactorial design to receive minocycline (400 mg/d or 200 mg/d) or placebo for 24 months. MAIN OUTCOMES AND MEASURES Primary outcome measures were decrease in sMMSE score and Bristol Activities of Daily Living Scale (BADLS), analyzed by intention-to-treat repeated-measures regression. RESULTS Of 544 eligible participants (241 women and 303 men), the mean (SD) age was 74.3 (8.2) years, and the mean (SD) sMMSE score was 26.4 (1.9). Fewer participants completed 400-mg minocycline hydrochloride treatment (28.8% [53 of 184]) than 200-mg minocycline treatment (61.9% [112 of 181]) or placebo (63.7% [114 of 179]; P < .001), mainly because of gastrointestinal symptoms (42 in the 400-mg group, 15 in the 200-mg group, and 10 in the placebo group; P < .001), dermatologic adverse effects (10 in the 400-mg group, 5 in the 200-mg group, and 1 in the placebo group; P = .02), and dizziness (14 in the 400-mg group, 3 in the 200-mg group, and 1 in the placebo group; P = .01). Assessment rates were lower in the 400-mg group: 68.4% (119 of 174 expected) for sMMSE at 24 months compared with 81.8% (144 of 176) for the 200-mg group and 83.8% (140 of 167) for the placebo group. Decrease in sMMSE scores over 24 months in the combined minocycline group was similar to that in the placebo group (4.1 vs 4.3 points). The combined minocycline group had mean sMMSE scores 0.1 points higher than the placebo group (95% CI, −1.1 to 1.2; P = .90). The decrease in mean sMMSE scores was less in the 400-mg group than in the 200-mg group (3.3 vs 4.7 points; treatment effect = 1.2; 95% CI, −0.1 to 2.5; P = .08). Worsening of BADLS scores over 24 months was similar in all groups: 5.7 in the 400-mg group, 6.6 in the 200-mg group, and 6.2 in the placebo groups (treatment effect for minocycline vs placebo =-0.53; 95% CI, −2.4 to 1.3; P = .57; treatment effect for 400 mg vs 200 mg of minocycline =-0.31; 95% CI, −0.2 to 1.8; P = .77). Results were similar in different patient subgroups and in sensitivity analyses adjusting...
Hemi-spatial neglect is an attentional disorder in which the sufferer fails to acknowledge or respond to stimuli appearing in contralesional space. In recent years, it has become clear that a measurable reduction in contralesional neglect can occur during galvanic vestibular stimulation, a technique by which transmastoid, small amplitude current induces lateral, attentional shifts via asymmetric modulation of the left and right vestibular nerves. However, it remains unclear whether this reduction persists after stimulation is stopped. To estimate longevity of effect, we therefore conducted a double-blind, randomized, dose-response trial involving a group of stroke patients suffering from left-sided neglect (n = 52, mean age = 66 years). To determine whether repeated sessions of galvanic vestibular stimulation more effectively induce lasting relief than a single session, participants received 1, 5, or 10 sessions, each lasting 25 min, of sub-sensory, left-anodal right-cathodal noisy direct current (mean amplitude = 1 mA). Ninety five percent confidence intervals indicated that all three treatment arms showed a statistically significant improvement between the pre-stimulation baseline and the final day of stimulation on the primary outcome measure, the conventional tests of the Behavioral Inattention Test. More remarkably, this change (mean change = 28%, SD = 18) was still evident 1 month later. Secondary analyses indicated an allied increase of 20% in median Barthel Index (BI) score, a measure of functional capacity, in the absence of any adverse events or instances of participant non-compliance. Together these data suggest that galvanic vestibular stimulation, a simple, cheap technique suitable for home-based administration, may produce lasting reductions in neglect that are clinically important. Further protocol optimization is now needed ahead of a larger effectiveness study.
We describe the effects of galvanic vestibular stimulation (GVS) on an individual who, following right hemisphere stroke, is unable to copy figures accurately. His copies contain most of the constituent elements, but are poorly integrated and drawn in a seemingly haphazard manner. To test whether GVS could help overcome these difficulties, we administered the Rey-Osterrieth complex figure copy task while manipulating both the presence and laterality of the galvanic signal. The signal was applied at a level that was too low to elicit sensation which ensured that the individual was unaware of either when or on what side he was being stimulated. Relative to a sham condition, two consecutive blocks of GVS increased both the accuracy with which the main configural elements of the figure were reconstructed, and there was some, albeit less consistent evidence, that these were drawn in a more wholistic as opposed to piecemeal manner. Improvement was not reliant on the polarity of the stimulating electrodes. These results suggest that GVS can help overcome difficulties in the perception and/or reconstruction of hierarchical visual form, and thereby uncover a new link between vestibular information processing and visual task performance.
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Results: Analyses of variance indicated that both participants missed significantly fewer targets in both tasks on the fifth day of stimulation compared to baseline. More so, this improvement was still evident at follow-up three days later. Conclusion:The results strengthen the need for a larger, sham-controlled trial to establish whether repeated GVS provides lasting relief from neglect.3
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