Memory markers in the continuum of the Alzheimer's clinical syndrome.

BACKGROUND: The individual and complementary value of the Visual Short-Term Memory Binding Test (VSTMBT) and the Free and Cued Selective Reminding Test (FCSRT) as markers to trace the AD continuum was investigated. It was hypothesised that the VSTMBT would be an early indicator while the FCSRT would inform on imminent progression. METHODS: Healthy older adults (n=70) and patients with mild cognitive impairment (MCI) (n=80) were recruited and followed up between 2012 and 2017. Participants with at least two assessment points entered the study. Using baseline and follow-up assessments four groups were defined: Older adults who were healthy (HOA), with very mild cognitive but not functional impairment (eMCI), and with MCI who did and did not convert to dementia (MCI converters and non-converters). RESULTS: Only the VSTMBT predicted group membership in the very early stages (HOA vs eMCI). As the disease progressed, the FCSRT became a strong predictor excluding the VSTMB from the models. Their complementary value was high during the mid-prodromal stages and decreased in stages closer to dementia. DISCUSSION: The study supports the notion that neuropsychological assessment for AD needs to abandon the notion of one-size-fits-all. A memory toolkit for AD needs to consider tools that are early indicators and tools that suggest imminent progression. The VSTMBT and the FSCRT are such tools.

The striatum, the hippocampus, and short-term memory binding: Volumetric analysis of the subcortical grey matter's role in mild cognitive impairment.

BACKGROUND: Deficits in short-term memory (STM) binding are a distinguishing feature of preclinical stages leading to Alzheimer's disease (AD). However, the neuroanatomical correlates of conjunctive STM binding are largely unexplored. Here we examine the possible association between the volumes of hippocampi, parahippocampal gyri, and grey matter within the subcortical structures - all found to have foci that seemingly correlate with basic daily living activities in AD patients - with cognitive tests related to conjunctive STM binding. MATERIALS AND METHODS: Hippocampal, thalamic, parahippocampal and corpus striatum volumes were semi-automatically quantified in brain magnetic resonance images from 25 cognitively normal people and 21 patients with Mild Cognitive Impairment (MCI) at high risk of AD progression, who undertook a battery of cognitive tests and the short-term memory binding test. Associations were assessed using linear regression models and group differences were assessed using the Mann-Whitney U test. RESULTS: Hippocampal and parahippocampal gyrus volumes differed between MCI and control groups. Although the grey matter volume in the globus pallidus (r = -0.71, p < 0.001) and parahippocampal gyry (r = -0.63, p < 0.05) correlated with a STM binding task in the MCI group, only the former remained associated with STM binding deficits in MCI patients, after correcting for age, gender and years of education (ß = -0.56,P = 0.042) although with borderline significance. CONCLUSIONS: Loss of hippocampal volume plays no role in the processing of STM binding. Structures within the basal ganglia, namely the globus pallidus, could be part of the extrahippocampal network supporting binding. Replication of this study in large samples is now needed.

Amisulpride for very late-onset schizophrenia-like psychosis: the ATLAS three-arm RCT.

BACKGROUND: Very late-onset (aged ≥ 60 years) schizophrenia-like psychosis (VLOSLP) occurs frequently but no placebo-controlled, randomised trials have assessed the efficacy or risks of antipsychotic treatment. Most patients are not prescribed treatment. OBJECTIVES: The study investigated whether or not low-dose amisulpride is superior to placebo in reducing psychosis symptoms over 12 weeks and if any benefit is maintained by continuing treatment thereafter. Treatment safety and cost-effectiveness were also investigated. DESIGN: Three-arm, parallel-group, placebo-controlled, double-blind, randomised controlled trial. Participants who received at least one dose of study treatment were included in the intention-to-treat analyses. SETTING: Secondary care specialist old age psychiatry services in 25 NHS mental health trusts in England and Scotland. PARTICIPANTS: Patients meeting diagnostic criteria for VLOSLP and scoring > 30 points on the Brief Psychiatric Rating Scale (BPRS). INTERVENTION: Participants were randomly assigned to three arms in a two-stage trial: (1) 100 mg of amisulpride in both stages, (2) amisulpride then placebo and (3) placebo then amisulpride. Treatment duration was 12 weeks in stage 1 and 24 weeks (later reduced to 12) in stage 2. Participants, investigators and outcome assessors were blind to treatment allocation. MAIN OUTCOME MEASURES: Primary outcomes were psychosis symptoms assessed by the BPRS and trial treatment discontinuation for non-efficacy. Secondary outcomes were extrapyramidal symptoms measured with the Simpson-Angus Scale, quality of life measured with the World Health Organization's quality-of-life scale, and cost-effectiveness measured with NHS, social care and carer work loss costs and EuroQol-5 Dimensions. RESULTS: A total of 101 participants were randomised. Ninety-two (91%) participants took the trial medication, 59 (64%) completed stage 1 and 33 (56%) completed stage 2 treatment. Despite suboptimal compliance, improvements in BPRS scores at 12 weeks were 7.7 points (95% CI 3.8 to 11.5 points) greater with amisulpride than with placebo (11.9 vs. 4.2 points; p = 0.0002). In stage 2, BPRS scores improved by 1.1 point in those who continued with amisulpride but deteriorated by 5.2 points in those who switched from amisulpride to placebo, a difference of 6.3 points (95% CI 0.9 to 11.7 points; p = 0.024). Fewer participants allocated to the amisulpride group stopped treatment because of non-efficacy in stages 1 (p = 0.01) and 2 (p = 0.031). The number of patients stopping because of extrapyramidal symptoms and other side effects did not differ significantly between groups. Amisulpride treatment in the base-case analyses was associated with non-significant reductions in combined NHS, social care and unpaid carer costs and non-significant reductions in quality-adjusted life-years (QALYs) in both stages. Including patients who were intensive users of inpatient services in sensitivity analyses did not change the QALY result but resulted in placebo dominance in stage 1 and significant reductions in NHS/social care (95% CI -£8923 to -£122) and societal costs (95% CI -£8985 to -£153) for those continuing with amisulpride. LIMITATIONS: The original recruitment target of 300 participants was not achieved and compliance with trial medication was highly variable. CONCLUSIONS: Low-dose amisulpride is effective and well tolerated as a treatment for VLOSLP, with benefits maintained by prolonging treatment. Potential adverse events include clinically significant extrapyramidal symptoms and falls. FUTURE WORK: Trials should examine the longer-term effectiveness and safety of antipsychotic treatment in this patient group, and assess interventions to improve their appreciation of potential benefits of antipsychotic treatment and compliance with prescribed medication. TRIAL REGISTRATION: Current Controlled Trials ISRCTN45593573 and EudraCT2010-022184-35. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 67. See the NIHR Journals Library website for further project information.

Antipsychotic treatment of very late-onset schizophrenia-like psychosis (ATLAS): a randomised, controlled, double-blind trial.

BACKGROUND: Very late (aged ≥60 years) onset schizophrenia-like psychosis occurs frequently but no placebo-controlled, randomised trials have assessed the efficacy and risks of antipsychotic treatment. We investigated whether low-dose amisulpride (100 mg daily) is superior to placebo in reducing psychosis symptoms over 12 weeks and whether any benefit is maintained by continuing treatment after 12 weeks. METHODS: The ATLAS double-blind controlled trial enrolled participants from 25 old age psychiatry services in the UK. Eligible participants (ie, those with a diagnosis of very late-onset schizophrenia-like psychosis and a Brief Psychiatric Rating Scale [BPRS] score of ≥30, without cognitive impairment) were randomly assigned (1:1:1) to one of three groups in a two-stage trial: amisulpride in stage 1 and 2 (group A), amisulpride then placebo (group B), or placebo then amisulpride (group C). Treatment (100 mg oral amisulpride daily vs placebo) was given for 12 weeks in stage 1 and, initially, 24 weeks then reduced to 12 weeks in stage 2. Participants, investigators, and outcome assessors were masked to treatment allocation. Primary outcomes were psychosis symptoms assessed by the BPRS at 4, 12, and 24, or 36 weeks, and trial treatment discontinuation for non-efficacy. The primary, secondary, and safety endpoints were all analysed in participants given at least one dose of study treatment in modified intention-to-treat analyses. This study is registered with EudraCT, number 2010-022184-35, and ISRCTN, number ISRCTN45593573. FINDINGS: Between Sept 27, 2012, and June 28, 2016, we recruited 101 participants. 92 (91%) of 101 participants took trial medication, of whom 59 (64%) completed stage 1 and 34 (58%) of these 59 participants completed stage 2 treatment. Despite suboptimal compliance, improvements in BPRS scores at 12 weeks were 7·7 points (95% CI 3·8-11·5, p=0·0002) greater with amisulpride (mean 11·9 points [SE 1·3]) than with placebo (4·2 points [1·0]). In stage 2, BPRS scores improved by a mean of 1·1 points (1·6) from 12 weeks to the final assessment in those who continued amisulpride but deteriorated by 5·2 points (2·0) in those who switched from amisulpride to placebo (difference 6·3 points [95% CI 0·9-11·7], p=0·024). Fewer participants who were allocated amisulpride than placebo stopped treatment because of non-efficacy in stage 1 (p=0·010) and stage 2 (p=0·031). Serious adverse events were reported more frequently in the amisulpride group than in the placebo group in stage 1 (p=0·057) and stage 2 (p=0·19). The most common serious adverse events were infection (five patients in the amisulpride group, three in the placebo group) and extrapyramidal side-effects (three patients in the amisulpride group, none in the placebo group). Five patients died during the study, one from a gastric ulcer bleed before treatment started (group B), two while taking stage 2 treatment (one in group A and one in group C), and two who stopped trial treatment in stage 1 and died many weeks later (one in group B and one in group C). No deaths were related to treatment. INTERPRETATION: Low-dose amisulpride is effective and well tolerated as a treatment for very late-onset schizophrenia-like psychosis, with benefits maintained by prolonging treatment. FUNDING: UK National Institute for Health Research.

Medial temporal lobe function during emotional memory in early Alzheimer's disease, mild cognitive impairment and healthy ageing: an fMRI study.

BACKGROUND: Relative to intentional memory encoding, which quickly declines in Mild Cognitive Impairment (MCI) and Alzheimer's disease (AD), incidental memory for emotional stimuli appears to deteriorate more slowly. We hypothesised that tests of incidental emotional memory may inform on different aspects of cognitive decline in MCI and AD. METHODS: Patients with MCI, AD and Healthy Controls (HC) were asked to attend to emotional pictures (i.e., positive and neutral) sequentially presented during an fMRI session. Attention was monitored behaviourally. A surprise post-scan recognition test was then administered. RESULTS: The groups remained attentive within the scanner. The post-scan recognition pattern was in the form of (HC = MCI) > AD, with only the former group showing a clear benefit from emotional pictures. fMRI analysis of incidental encoding demonstrated clusters of activation in para-hippocampal regions and in the hippocampus in HC and MCI patients but not in AD patients. The pattern of activation observed in MCI patients tended to be greater than that found in HC. CONCLUSIONS: The results suggest that incidental emotional memory might offer a suitable platform to investigate, using behavioural and fMRI measures, subtle changes in the process of developing AD. These changes seem to differ from those found using standard episodic memory tests. The underpinnings of such differences and the potential clinical use of this methodology are discussed in depth.

Comparison of electroconvulsive therapy practice between London and Bengaluru.

OBJECTIVE: To compare electroconvulsive therapy (ECT) practice between London in the United Kingdom and Bengaluru in India. METHODS: A retrospective case note study was conducted to compare patterns of referrals for ECT in university teaching hospitals in London (n = 46) and Bengaluru (n = 345) during a 1-year period. Further comparison of ECT practice was made for a consecutive series of depressed patients between London (n = 104) and Bengaluru (n = 125). RESULTS: The rates of ECT referral were 0.9% of total annual admissions at the London site and 8.2% at the Bengaluru site. At the Bengaluru site, a higher proportion of patients were referred for ECT with a diagnosis of schizophrenia (P < 0.0001). Compared to the Bengaluru sample, depressed patients treated with ECT in London (n = 104) were older with more treatment resistance (P < 0.0001), had longer inpatient stays, and were less responsive to ECT. CONCLUSIONS: The practice of ECT differed substantially between the London and Bengaluru sites. The relatively limited use of ECT in London reflects local treatment guidelines and may reflect the stigma associated with ECT. Electroconvulsive therapy is more widely used in Bengaluru with good outcomes. Further cross-cultural research is required to study the reasons for such contrasting practices and what constitutes the optimal practice of ECT for health systems in different countries.