Rebecca L. Gould

Brain mechanisms of successful compensation during learning in Alzheimer disease

Objective: To determine whether patients with Alzheimer disease (AD) compensate for neuropathologic changes when performing a mnemonic task by recruiting 1) the same brain regions as age-matched, healthy controls, but to a greater extent; 2) additional brain regions not activated by controls; or 3) both. Methods: Twelve patients with mild probable AD and 12 healthy age- and education-matched controls participated in an fMRI study of successful encoding and retrieval of visuospatial paired associates. To ensure successful performance in both groups, participants were given multiple attempts to learn associations between two and three object locations. Results: The pattern of brain activity in patients with AD performing an easy version of the task was indistinguishable from that of controls performing a harder version of the task. Increased activation in left medial and right lateral prefrontal cortices was found in patients with AD compared to controls during encoding of two object locations, but not when this level of encoding in patients was compared with encoding of three object locations in controls. Conclusions: There was no evidence of neural plasticity in the form of recruitment of novel brain regions in patients with Alzheimer disease. Data supported greater recruitment of the same brain regions as age-matched controls as a means of compensating for neuropathology and associated cognitive impairment in Alzheimer disease.

Efficacy of cognitive behavioral therapy for anxiety disorders in older people: a meta-analysis and meta-regression of randomized controlled trials.

To review the magnitude and duration of and factors associated with effects of cognitive behavioral therapy (CBT) for anxiety disorders in older people.

Cognitive Behavioral Therapy for Depression in Older People: A Meta‐Analysis and Meta‐Regression of Randomized Controlled Trials

To review the effectiveness of cognitive behavioral therapy (CBT) for depression in older people, together with factors associated with its efficacy.

Interventions for reducing benzodiazepine use in older people: meta-analysis of randomised controlled trials

BACKGROUND The use of benzodiazepines has been advised against in older people, but prevalence rates remain high. AIMS To review the evidence for interventions aimed at reducing benzodiazepine use in older people. METHOD We conducted a systematic review, assessment of risk of bias and meta-analyses of randomised controlled trials of benzodiazepine withdrawal and prescribing interventions. RESULTS Ten withdrawal and eight prescribing studies met the inclusion criteria. At post-intervention, significantly higher odds of not using benzodiazepines were found with supervised withdrawal with psychotherapy (odds ratio (OR) = 5.06, 95% CI 2.68-9.57, P<0.00001) and withdrawal with prescribing interventions (OR = 1.43, 95% CI 1.02-2.02, P = 0.04) in comparison with the control interventions treatment as usual (TAU), education placebo, withdrawal with or without drug placebo, or psychotherapy alone. Significantly higher odds of not using benzodiazepines were also found for multifaceted prescribing interventions (OR = 1.37, 95% CI 1.10-1.72, P = 0.006) in comparison with control interventions (TAU and prescribing placebo). CONCLUSIONS Supervised benzodiazepine withdrawal augmented with psychotherapy should be considered in older people, although pragmatic reasons may necessitate consideration of other strategies such as medication review.

Task-induced deactivations during successful paired associates learning: An effect of age but not Alzheimer's disease

Task-induced fMRI deactivations during successful encoding and retrieval of visuospatial paired associates were examined at different levels of task difficulty in younger and older adults (Experiment 1), and older adults with and without mild probable Alzheimers disease (AD) (Experiment 2). Irrespective of the level of task difficulty, common deactivations (determined through the use of conjunction analyses) were observed in the lateral and medial prefrontal, anterior and posterior cingulate, and temporal brain regions and in the claustrum during both encoding and retrieval in younger and older adults (Experiment 1). In AD patients and healthy older adults, common deactivations were found in posterior cingulate, temporal, and lateral parietal regions and in the insula and claustrum during encoding and retrieval of paired associates (Experiment 2). As task difficulty increased, irrespective of the type of task, the magnitude of task-induced deactivations increased in the medial prefrontal/superior frontal gyrus and middle/posterior cingulate cortex in younger and older adults (Experiment 1), and in the middle cingulate cortex in older adults with and without AD (Experiment 2). In Experiment 1, greater deactivation was observed in the anterior cingulate gyrus in older compared to younger adults during retrieval of paired associates which was attributed to greater suppression of task-unrelated thoughts in the older group. No significant differences in task-induced deactivation, or in the type of relationship exhibited between deactivation and task difficulty, were observed between older adults with and without AD (Experiment 2). It was suggested that this was related to the matching of successful task performance and task difficulty across patient and control groups. Following previous proposals, task-induced deactivations were suggested to underlie a shifting of attentional focus from monitoring of the self and the environment (through attenuation of these activities) to external, goal-directed behaviour.

Do cognitive interventions improve general cognition in dementia?: A meta-analysis and meta-regression

Objectives To review the efficacy of cognitive interventions on improving general cognition in dementia. Method Online literature databases and trial registers, previous systematic reviews and leading journals were searched for relevant randomised controlled trials. A systematic review, random-effects meta-analyses and meta-regression were conducted. Cognitive interventions were categorised as: cognitive stimulation (CS), involving a range of social and cognitive activities to stimulate multiple cognitive domains; cognitive training (CT), involving repeated practice of standardised tasks targeting a specific cognitive function; cognitive rehabilitation (CR), which takes a person-centred approach to target impaired function; or mixed CT and stimulation (MCTS). Separate analyses were conducted for general cognitive outcome measures and for studies using ‘active’ (designed to control for non-specific therapeutic effects) and non-active (minimal or no intervention) control groups. Results 33 studies were included. Significant positive effect sizes (Hedges’ g) were found for CS with the mini-mental state examination (MMSE) (g=0.51, 95% CI 0.29 to 0.69; p<0.001) compared to non-active controls and (g=0.35, 95% CI 0.06 to 0.65; p=0.019) compared to active controls. Significant benefit was also seen with the Alzheimers disease Assessment Scale-Cognition (ADAS-Cog) (g=−0.26, 95% CI −0.445 to −0.08; p=0.005). There was no evidence that CT or MCTS produced significant improvements on general cognition outcomes and not enough CR studies for meta-analysis. The lowest accepted minimum clinically important difference was reached in 11/17 CS studies for the MMSE, but only 2/9 studies for the ADAS-Cog. Additionally, 95% prediction intervals suggested that although statistically significant, CS may not lead to benefits on the ADAS-Cog in all clinical settings. Conclusions CS improves scores on MMSE and ADAS-Cog in dementia, but benefits on the ADAS-Cog are generally not clinically significant and difficulties with blinding of patients and use of adequate placebo controls make comparison with the results of dementia drug treatments problematic.

Origins of delusions in Alzheimer's disease.

Research over the past two decades supports a shared aetiology for delusions in Alzheimers disease (AD) and schizophrenia. Functional networks involved in salience attribution and belief evaluation have been implicated in the two conditions, and striatal D2/3 receptors are increased to a comparable extent. Executive/frontal deficits are common to both disorders and predict emergent symptoms. Putative risk genes for schizophrenia, which may modify the AD process, have been more strongly implicated in delusions than those directly linked with late-onset AD. Phenotypic correlates of delusions in AD may be dependent upon delusional subtype. Persecutory delusions occur early in the disease and are associated with neurochemical and neuropathological changes in frontostriatal circuits. In contrast, misidentification delusions are associated with greater global cognitive deficits and advanced limbic pathology. It is unclear whether the two subtypes are phenomenologically and biologically distinct or are part of a continuum, in which misidentification delusions manifest increasingly as the pathological process extends. This has treatment implications, particularly if they are found to have discrete chemical and/or pathological markers.

Tests of pattern separation and pattern completion in humans—A systematic review

To systematically review the characteristics, validity and outcome measures of tasks that have been described in the literature as assessing pattern separation and pattern completion in humans. Electronic databases were searched for articles. Parameters for task validity were obtained from two reviews that described optimal task design factors to evaluate pattern separation and pattern completion processes. These were that pattern separation should be tested during an encoding task using abstract, never‐before‐seen visual stimuli, and pattern completion during a retrieval task using partial cues; parametric alteration of the degree of interference of stimuli or degradation of cues should be used to generate a corresponding gradient in behavioral output; studies should explicitly identify the specific memory domain under investigation (sensory/perceptual, temporal, spatial, affect, response, or language) and account for the contribution of other potential attributes involved in performance of the task. A systematic, qualitative assessment of validity in relation to these parameters was performed, along with a review of general validity and task outcome measures. Sixty‐two studies were included. The majority of studies investigated pattern separation and most tasks were performed on young, healthy adults. Pattern separation and pattern completion were most frequently tested during a retrieval task using familiar or recognizable visual stimuli and cues. Not all studies parametrically altered the degree of stimulus interference or cue degradation, or controlled for potential confounding factors. This review found evidence that some of the parameters for task validity have been followed in some human studies of pattern separation and pattern completion, but no study was judged to have adequately met all the parameters for task validity. The contribution of these parameters and other task design factors towards an optimal behavioral paradigm is discussed and recommendations for future research are made.

Psychotherapy and pharmacotherapy interventions to reduce distress or improve well-being in people with amyotrophic lateral sclerosis: A systematic review

Our objective was to systematically review and critically evaluate the evidence for psychotherapy and pharmacotherapy interventions for reducing distress or improving well-being in people with amyotrophic lateral sclerosis (pwALS). Online bibliographic databases and clinical trial registers were searched and an assessment of study quality was conducted. Seven thousand two hundred and twenty-three studies were identified, of which five met inclusion criteria (four completed and one in progress). All studies examined psychotherapeutic interventions, and no studies investigated pharmacotherapy. Two studies adopted a randomized controlled trial design, one a controlled trial design and two a cohort design. Sample sizes were small in all studies (overall n = 145). The quality of completed studies was generally poor, with evidence that all were at potential risk of bias in numerous areas. Improvements in well-being were found with expressive disclosure (compared to no disclosure), cognitive behavioural therapy/counselling (compared to non-randomized pharmacotherapy) and hypnosis in the short term only, while no improvements were seen with a life review intervention. In conclusion, there is currently insufficient evidence to recommend the use of specific psychotherapy interventions for reducing distress or improving well-being in pwALS, and no evidence to support pharmacotherapy interventions. Research is urgently needed to address these significant gaps in the literature.

Cognitive phenotype of psychotic symptoms in Alzheimer’s disease: Evidence for impaired visuoperceptual function in the misidentification subtype

Establishing the cognitive phenotype of psychotic symptoms in Alzheimers disease (AD) could localise discrete pathology and target symptomatic treatment. This study aimed to establish whether psychotic symptoms would be associated with poorer performance on neuropsychological tests known to correlate with striatal dopaminergic function and to investigate whether these differences would be attributed to the paranoid (persecutory delusions) or misidentification (misidentification phenomena +/− hallucinations) subtype.