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Mild Cognitive Impairment (MCI) is a clinical condition with a high risk of progression to dementia. One of its most common consequences is a difficulty in people's ability to remember past information and events, caused by an impairment of their long-term episodic memory system (Winblad et al. 2004; Dubois et al. 2007; Petersen et al. 2014). MCI may also damage people’s ability to follow and understand a situation as it unfolds and to recall it soon after it happens. While many studies have demonstrated the long-term memory episodic difficulties that adults with MCI experience (Della Sala et al. 2005; Irish et al. 2011; Walsh et al. 2014), there is a paucity of research investigating if this impairment also extends to their comprehension and immediate memory. Therefore, the aim of the present study is to test if individuals with MCI, who experience memory difficulties, also show problems in comprehending ongoing information and in recalling it immediately afterwards. The present study is based on a prominent theory of event comprehension, called “Event segmentation theory” (EST; Zacks & Tversky, 2001; Zacks et al. 2007). According to this theory, when people experience an event (e.g., listening to the TV news), they create and maintain a description of the current situation in their immediate memory for a short period of time, and then they transfer this information in their long-term memory when they detect a change (called “event boundary”) in the ongoing situation (e.g., the news switches to a different story). Detecting event changes helps people to ascribe those happenings to distinct situations and facilitates their storage in memory and their subsequent retrieval. Our study will test this theory by using a task that probes the detection and memory of event changes. The task will require participants to listen to short stories containing two separate activities (e.g., looking for car keys then making a sandwich; change of events, multiple situations) and equally long stories containing just one activity (e.g., looking for car keys; no change of events, single situation), and to recall them immediately and after an hour delay. In line with the existing literature (e.g., Della Sala et al. 2005; Irish et al. 2011; Walsh et al. 2014), adults with MCI who typically experience memory problems, should find it difficult to recall an event after a long delay, regardless of whether the event describes a single situation or multiple situations. However, MCI individuals may also show difficulties in comprehending and recalling an event immediately after it happens, if that event describes multiple situations. This is because the switch between different situations requires the ability to detect the change of situation and safely store the previous situation in long-term memory, in order to build a new description of the current situation. MCI individuals might find it difficult to detect changes between situations, as even healthy older adults typically show less agreement than younger adults in establishing when event changes occur, while watching movies or reading narratives (Zacks et al. 2006; Kurby and Zacks, 2011; Magliano et al. 2012). Difficulties in detecting event changes should impair their ability to store an event in memory and retrieve it, even immediately after its presentation. By contrast, MCI individuals should be able to comprehend and recall immediately more simple events describing a single situation that does not involve changes.

Background: Agitation is common in people with dementia and negatively affects the quality of life of both people with dementia and carers. Non-drug patient-centred care is the first-line treatment, but there is a need for other treatment when this care is not effective. Current evidence is sparse on safer and effective alternatives to antipsychotics. We assessed the efficacy and safety of mirtazapine, an antidepressant prescribed for agitation in dementia. Methods: This parallel-group, double-blind, placebo-controlled trial—the Study of Mirtazapine for Agitated Behaviours in Dementia trial (SYMBAD)—was done in 26 UK centres. Participants had probable or possible Alzheimer's disease, agitation unresponsive to non-drug treatment, and a Cohen-Mansfield Agitation Inventory (CMAI) score of 45 or more. They were randomly assigned (1:1) to receive either mirtazapine (titrated to 45 mg) or placebo. The primary outcome was reduction in CMAI score at 12 weeks. This trial is registered with ClinicalTrials.gov, NCT03031184, and ISRCTN17411897. Findings: Between Jan 26, 2017, and March 6, 2020, 204 participants were recruited and randomised. Mean CMAI scores at 12 weeks were not significantly different between participants receiving mirtazapine and participants receiving placebo (adjusted mean difference –1·74, 95% CI –7·17 to 3·69; p=0·53). The number of controls with adverse events (65 [64%] of 102 controls) was similar to that in the mirtazapine group (67 [66%] of 102 participants receiving mirtazapine). However, there were more deaths in the mirtazapine group (n=7) by week 16 than in the control group (n=1), with post-hoc analysis suggesting this difference was of marginal statistical significance (p=0·065). Interpretation: This trial found no benefit of mirtazapine compared with placebo, and we observed a potentially higher mortality with use of mirtazapine. The data from this study do not support using mirtazapine as a treatment for agitation in dementia. Funding: UK National Institute for Health Research Health Technology Assessment Programme.

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.\ud Objective - To determine whether 24 months of minocycline treatment can modify cognitive and functional decline in patients with mild AD.\ud 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 ≥24) were randomized.\ud 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.\ud 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.\ud 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

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 ≥24) 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 P 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 for missing data.Conclusions and Relevance Minocycline did not delay the progress of cognitive or functional impairment in people with mild AD during a 2-year period. This study also found that 400 mg of minocycline is poorly tolerated in this population.