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Background Apolipoprotein E epsilon 4 ( APOE -ε4) carrier status is an established risk factor for Alzheimer’s disease (AD) dementia. It has also been linked with sleep disturbance in healthy older adults and increased insomnia risk. This association may be driven by the effect of APOE -ε4 on AD pathological change, itself associated with sleep abnormalities. To assess this relationship, we have evaluated post-mortem neuropathological findings in patients with and without cognitive impairment and AD pathology, who had extensive clinical assessment within 12 months of death. Methods This retrospective cohort study used UK Brain Banks Network data. Eligible subjects were aged over 50, with pre-mortem neuropsychiatry inventory scores of sleep disturbance (NPI-K), neurocognitive testing and functional cognitive status assessment (Clinical Dementia Rating scale). Neuropathological data included Thal phase, Braak stage and CERAD scores (measures of Aβ plaque distribution, tangle distribution and neuritic plaque density, respectively) combined to form the National Institute on Aging Alzheimer’s Association (NIA-AA) ABC score reflecting AD neuropathology. Participants with other significant intracerebral pathology or pathological features of non-AD dementia were excluded. Multivariate linear regression was performed with NPIK Global Score (NPIK frequency score multiplied by severity score) as the dependent variable and APOE -ε4 heterozygosity or homozygosity as independent variables. Covariates included age, gender, APOE -ε2 status and ABC NPI measures reflecting depression and anxiety. Further models stratified by ABC score and functional cognitive status were also produced. Results Seven hundred twenty-eight records were identified. Two hundred two participants were included in the final analysis: mean (SD) age 84.0 (9.2) and MMSE 14.0 (11.8). Mean sleep disturbance scores were highest in ε4 homozygosity ( n =11), 4.55 (5.4); intermediate in ε4 heterozygosity ( n =95), 2.03 (4.0); and lowest in non-ε4 carriers ( n =96), 1.36 (3.3). Within the full sample, controlling for pathological status, age, gender, depression, anxiety and CDR-SOB status, APOE -ε4 homozygosity was associated with sleep disturbance ( β 2.53, p =0.034). APOE- ε4 heterozygosity was similarly associated in individuals without dementia ( β 1.21, p =0.048). Conclusion These findings lend weight to the hypothesis that APOE -ε4 affects sleep by mechanisms independent of AD pathological change. Evaluation of those mechanisms would enhance understanding of sleep disturbance pathways and potentially provide treatment targets.

A better understanding of early brain changes that precede loss of independence in diseases like Alzheimer's disease (AD) is critical for development of disease-modifying therapies. Quantitative MRI, such as T2 relaxometry, can identify microstructural changes relevant to early stages of pathology. Recent evidence suggests heterogeneity of T2 may be a more informative MRI measure of early pathology than absolute T2. Here we test whether T2 markers of brain integrity precede the volume changes we know are present in established AD and whether such changes are most marked in medial temporal lobe (MTL) subfields known to be most affected early in AD. We show that T2 heterogeneity was greater in people with mild cognitive impairment (MCI; n = 49) compared to healthy older controls (n = 99) in all MTL subfields, but this increase was greatest in MTL cortices, and smallest in dentate gyrus. This reflects the spatio-temporal progression of neurodegeneration in AD. T2 heterogeneity in CA1-3 and entorhinal cortex and volume of entorhinal cortex showed some ability to predict cognitive decline, where absolute T2 could not, however further studies are required to verify this result. Increases in T2 heterogeneity in MTL cortices may reflect localised pathological change and may present as one of the earliest detectible brain changes prior to atrophy. Finally, we describe a mechanism by which memory, as measured by accuracy and reaction time on a paired associate learning task, deteriorates with age. Age-related memory deficits were explained in part by lower subfield volumes, which in turn were directly associated with greater T2 heterogeneity. We propose that tissue with high T2 heterogeneity represents extant tissue at risk of permanent damage but with the potential for therapeutic rescue. This has implications for early detection of neurodegenerative diseases and the study of brain-behaviour relationships.

In order to make spatial inferences about the brain across a group of patients, it is usually necessary to employ some means of bringing each brain image into register with either a group mean image or a standard template. In the presence of focal brain lesions, automated methods for performing such so-called normalization are liable to distortion from the abnormal signal within the lesion, especially when the non-linear warping necessary for maximum registration fidelity is used. The most frequently used method for minimizing this distortion – cost function masking – simply eliminates the lesioned area when deriving the normalization parameters. As lesion size increases, however, the normalization error may be expected to rise steeply since the volume of brain from which the parameters are derived falls with it. Here we propose an alternative non-linear registration method that exploits a natural redundancy in the brain – the enantiomorphic relation between the two hemispheres – to correct the signal within the lesion using information from the undamaged homologous region within the contralesional hemisphere. As lesion size increases, the normalization error should theoretically asymptote to inter-hemispheric differences, which are both quantifiable and much lower than the inter-subject difference. Using SPM’s non-linear normalization routines, we evaluate this technique with images of normal brains to which lesions selected from a large dataset have been artificially applied. Our results show the enantiomorphic method to be vastly superior to cost function masking across subjects, lesion characteristics, and brain voxels. We therefore propose that it should be the method of choice for normalizing images of focally lesioned brains.

Emerging evidence suggests that dopamine may modulate learning and memory with important implications for understanding the neurobiology of memory and future therapeutic targeting. An influential hypothesis posits that dopamine biases reinforcement learning. More recent data also suggest an influence during both consolidation and retrieval. Eighteen Parkinson’s disease patients learned through feedback ON or OFF medication, with memory tested 24 hr later ON or OFF medication (4 conditions, within-subjects design with matched healthy control group). Patients OFF medication during learning decreased in memory accuracy over the following 24 hr. In contrast to previous studies, however, dopaminergic medication during learning and testing did not affect expression of positive or negative reinforcement. Two further experiments were run without the 24 hr delay, but they too failed to reproduce effects of dopaminergic medication on reinforcement learning. While supportive of a dopaminergic role in consolidation, this study failed to replicate previous findings on reinforcement learning. Brain cells release a naturally occurring chemical called dopamine. The release of this chemical affects how people respond to their ever-changing environment, including how they learn from rewards and punishments. Parkinson’s disease is a condition where the brain cells that make dopamine start to die, and so the levels of dopamine in the brain begin to drop. Parkinson’s disease patients are routinely given drugs to bring their dopamine levels back up to near-normal levels. About 13 years ago, researchers found that when patients with Parkinson’s disease were given dopamine-medication they were better at learning from rewards and worse at learning from punishments. If the patients were withdrawn from their dopamine-medications they were worse at learning from rewards but better at learning from punishments. However, it was not clear if this was because the dopamine affects the learning process, or if it affects how people remember what they learned and how they make choices later on. To better understand how dopamine is involved in learning in people with Parkinson’s disease, Grogan et al. looked at the effects of dopamine on memory over a timescale of 24 hours. People with Parkinson’s disease and healthy volunteers were shown a choice of symbols and given the chance to learn which gave a reward – a picture of a smiling face – and which gave a punishment – a frowning face. If the Parkinson’s disease patients had taken their dopamine-medication before learning the task, their memory did not worsen over the next 24 hours. This suggests that having dopamine in the brain around the time of learning helped the patients to store the memory. The patients, however, were not any better at learning from rewards when taking their medication, which contradicts some earlier studies. To explore this further, Grogan et al. copied the exact same task from the 13-year-old study, and still did not find that patients were better at learning from reward when taking dopamine. These findings could help scientists to better understand what dopamine does during learning and memory, and how the brain normally works. Finally, Parkinson’s disease causes problems with memory. A clearer picture of the types of memory problems patients have, and of how their dopamine-medication can help, might make it easier for clinicians to treat patients with Parkinson’s disease.

Background Here, we address a pivotal factor in Alzheimer’s prevention—identifying those at risk early, when dementia can still be avoided. Recent research highlights an accelerated forgetting phenotype as a risk factor for Alzheimer’s disease. We hypothesized that delayed recall over 4 weeks would predict cognitive decline over 1 year better than 30-min delayed recall, the current gold standard for detecting episodic memory problems which could be an early clinical manifestation of incipient Alzheimer’s disease. We also expected hippocampal subfield volumes to improve predictive accuracy. Methods Forty-six cognitively healthy older people (mean age 70.7 ± 7.97, 21/46 female), recruited from databases such as Join Dementia Research, or a local database of volunteers, performed 3 memory tasks on which delayed recall was tested after 30 min and 4 weeks, as well as Addenbrooke’s Cognitive Examination III (ACE-III) and CANTAB Paired Associates Learning. Medial temporal lobe subregion volumes were automatically measured using high-resolution 3T MRI. The ACE-III was repeated after 12 months to assess the change in cognitive ability. We used univariate linear regressions and ROC curves to assess the ability of tests of delayed recall to predict cognitive decline on ACE-III over the 12 months. Results Fifteen of the 46 participants declined over the year (≥ 3 points lost on ACE-III). Four-week verbal memory predicted cognitive decline in healthy older people better than clinical gold standard memory tests and hippocampal MRI. The best single-test predictor of cognitive decline was the 4-week delayed recall on the world list ( R 2  = .123, p  = .018, β  = .418). Combined with hippocampal subfield volumetry, 4-week verbal recall identifies those at risk of cognitive decline with 93% sensitivity and 86% specificity (AUC = .918, p  < .0001). Conclusions We show that a test of accelerated long-term forgetting over 4 weeks can predict cognitive decline in healthy older people where traditional tests of delayed recall cannot. Accelerated long-term forgetting is a sensitive, easy-to-test predictor of cognitive decline in healthy older people. Used alone or with hippocampal MRI, accelerated forgetting probes functionally relevant Alzheimer’s-related change. Accelerated forgetting will identify early-stage impairment, helping to target more invasive and expensive molecular biomarker testing.

Millions of people worldwide take medications such as L-DOPA that increase dopamine to treat Parkinson's disease. Yet, we do not fully understand how L-DOPA affects sleep and memory. Our earlier research in Parkinson's disease revealed that the timing of L-DOPA relative to sleep affects dopamine's impact on long-term memory. Dopamine projections between the midbrain and hippocampus potentially support memory processes during slow wave sleep. In this study, we aimed to test the hypothesis that L-DOPA enhances memory consolidation by modulating NREM sleep. We conducted a double-blind, randomised, placebo-controlled crossover trial with healthy older adults (65-79 years, = 35). Participants first learned a word list and were then administered long-acting L-DOPA (or placebo) before a full night of sleep. Before sleeping, a proportion of the words were re-exposed using a recognition test to strengthen memory. L-DOPA was active during sleep and the practice-recognition test, but not during initial learning. The single dose of L-DOPA increased total slow-wave sleep duration by approximately 11% compared to placebo, while also increasing spindle amplitudes around slow oscillation peaks and around 1-4 Hz NREM spectral power. However, behaviourally, L-DOPA worsened memory of words presented only once compared to re-exposed words. The coupling of spindles to slow oscillation peaks correlated with these differential effects on weaker and stronger memories. To gauge whether L-DOPA affects encoding or retrieval of information in addition to consolidation, we conducted a second experiment targeting L-DOPA only to initial encoding or retrieval and found no behavioural effects. Our results demonstrate that L-DOPA augments slow wave sleep in elderly, perhaps tuning coordinated network activity and impacting the selection of information for long-term storage. The pharmaceutical modification of slow-wave sleep and long-term memory may have clinical implications. Eudract number: 2015-002027-26; https://doi.org/10.1186/ISRCTN90897064, ISRCTN90897064.

Both recognition of familiar objects and pattern separation, a process that orthogonalises overlapping events, are critical for effective memory. Evidence is emerging that human pattern separation requires dentate gyrus. Dentate gyrus is intimately connected to CA3 where, in animals, an autoassociative network enables recall of complete memories to underpin object/event recognition. Despite huge motivation to treat age-related human memory disorders, interaction between human CA3 and dentate subfields is difficult to investigate due to small size and proximity. We tested the hypothesis that human dentate gyrus is critical for pattern separation, whereas, CA3 underpins identical object recognition. Using 3 T MR hippocampal subfield volumetry combined with a behavioural pattern separation task, we demonstrate that dentate gyrus volume predicts accuracy and response time during behavioural pattern separation whereas CA3 predicts performance in object recognition memory. Critically, human dentate gyrus volume decreases with age whereas CA3 volume is age-independent. Further, decreased dentate gyrus volume, and no other subfield volume, mediates adverse effects of aging on memory. Thus, we demonstrate distinct roles for CA3 and dentate gyrus in human memory and uncover the variegated effects of human ageing across hippocampal regions. Accurate pinpointing of focal memory-related deficits will allow future targeted treatment for memory loss.

Soft robotics is used in real-world clinical situations, including surgery, rehabilitation, and diagnosis. However, several challenges remain to make soft robots more viable, especially for clinical interventions such as improving sleep quality, which impacts physiological and mental health. This paper presents an autoethnographic account of the experience of sleeping with a companion robot (Somnox), which mimics breathing to promote better sleep. The study is motivated by the key author’s experience with insomnia and a desire to better understand how Somnox is used in different social contexts. Data were collected through diary entries for 16 weeks (8 weeks without, 8 weeks with) and analysed thematically. The findings indicate improved sleep and observations about the relationship developed with the companion robot, including emotional connection and empathy for the technology. Furthermore, Somnox is a multidimensional family companion robot that can ease stomach discomfort and stress, reduce anxiety, and provide holistic care.

[This corrects the article DOI: 10.3389/fnbeh.2023.1096720.].