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AbstractObjectivesMethodResultsConclusionNHS England publishes monthly national and regional estimated dementia diagnosis rates (DDR) to assess the healthcare system’s effectiveness in identifying dementia cases. Previous research indicates that sociodemographic factors, such as ethnic minority status, socioeconomic deprivation, and rurality, influence both healthcare quality and dementia risk. This study aimed to examine the association between these sociodemographic factors and DDR, and to estimate an ethnicity-adjusted DDR using available ethnic group data.We analysed NHS Digital Primary Care Dementia Data electronic health records for July 2023. We used a linear regression model to determine the association between DDR and ethnicity, deprivation, and rurality factors using local authority region level data. We also adjusted the DDR at the level of sub-integrated care boards based on previously published odds ratios of dementia diagnosis by ethnic group.Regression modelling revealed that areas with higher proportions of minority ethnic groups and greater rurality had lower DDRs. Conversely, higher levels of deprivation were linked to higher DDRs. After adjusting for different odds ratios for dementia in minority ethnic groups, the national DDR decreased by 1%, with regional diagnosis rates dropping by up to 5.4%.Higher regional proportional ethnic minority population and greater rurality were associated with a lower DDR which might reflect poorer access to diagnostic services. Higher deprivation levels were associated with a higher DDR which might reflect higher rates of dementia in more deprived populations. We discuss measures to improve the accuracy and utility of the DDR, with a specific focus on ethnicity. [ABSTRACT FROM AUTHOR]

Changes in diagnostic certainty can be evaluated by assessing the impact of a diagnostic test in driving decision making. Diagnostic tests can be appraised using validated measures of accuracy, i.e., sensitivity, specificity, and positive or negative predictive values against a known reference standard. However, other less well formalized factors affect diagnostic certainty. These inputs are under-researched and more difficult to quantify. Clinicians assess the significance of available data in the context of their expertise, pre-diagnostic confidence, and background knowledge of populations and disease. Inherent qualities of the diagnostic test and an individual clinician's interpretation of the meaning of test results will also affect the subsequent level of diagnostic certainty. These factors are only infrequently considered alongside the diagnostic accuracy of a test. In this paper, we present a model of the different processes which can affect diagnostic certainty in Alzheimer's disease (AD). This model builds upon existing understanding and provides further insights into the complexity of diagnostic certainty in AD and how we might improve this. [ABSTRACT FROM AUTHOR]

Background: The COVID‐19 pandemic impacted on the provision of care and routine activity of all National Health Service (NHS) services. While General Practitioner referrals to memory services in England have returned to pre‐pandemic levels, the estimated dementia diagnosis rate (DDR) fell by 5.4% between March 2020 and February 2023. Methods: In this paper we explore whether this reduction is accurate or is an artefact of the way the NHS collects data. Results: We explore the processes that may have affected national dementia diagnosis rates during and following the COVID‐19 pandemic. Conclusions: We discuss what action could be taken to improve the DDR in the future. Key points: Despite General Practitioner (GP) referrals to memory services in England returning to levels seen before the pandemic, there was a decline of 5.4% in the estimated dementia diagnosis rate (DDR) from March 2020 to February 2023.This paper explores the factors which may have affected the national DDR reduction. These include a backlog in dementia referrals, a reduction in coding of diagnoses, or a decrease in true dementia prevalence secondary to excess COVID‐19 deaths which has yet to be reflected in the DDR denominator.Further work is suggested to accurately capture dementia prevalence in the United Kingdom (UK). These include an up‐to‐date multicentre population‐based cohort study and adjusting the DDR denominator for factors known to affect dementia susceptibility such as deprivation, rurality, and ethnicity. [ABSTRACT FROM AUTHOR]

Objectives: In response to a commissioned research update on dementia during the COVID-19 pandemic, a UK-based working group, comprising dementia researchers from a range of fields and disciplines, aimed to describe the impact of the pandemic on dementia wellbeing and identify priorities for future research.Methods: We supplemented a rapid literature search (including unpublished, non-peer reviewed and ongoing studies/reports) on dementia wellbeing in the context of COVID-19 with expert group members' consensus about future research needs. From this we generated potential research questions the group judged to be relevant that were not covered by the existing literature.Results: Themes emerged from 141 studies within the six domains of the NHS England COVID-19 Dementia Wellbeing Pathway: Preventing Well, Diagnosing Well, Treating Well, Supporting Well, Living Well and Dying Well. We describe current research findings and knowledge gaps relating to the impact on people affected by dementia (individuals with a diagnosis, their carers and social contacts, health and social care practitioners and volunteers), services, research activities and organisations. Broad themes included the potential benefits and risks of new models of working including remote healthcare, the need for population-representative longitudinal studies to monitor longer-term impacts, and the importance of reporting dementia-related findings within broader health and care studies.Conclusions: The COVID-19 pandemic has had a disproportionately negative impact on people affected by dementia. Researchers and funding organisations have responded rapidly to try to understand the impacts. Future research should highlight and resolve outstanding questions to develop evidence-based measures to improve the quality of life of people affected by dementia. [ABSTRACT FROM AUTHOR]

On 7 June 2021, aducanumab was granted accelerated approval for the treatment of Alzheimer disease (AD) by the FDA on the basis of amyloid-lowering effects considered reasonably likely to confer clinical benefit. This decision makes aducanumab the first new drug to be approved for the treatment of AD since 2003 and the first drug to ever be approved for modification of the course of AD. Many have questioned how scientific evidence, expert advice and the best interests of patients and families were considered in the approval decision. In this article, we argue that prior to approval, the FDA and Biogen's shared interpretation of clinical trial data - that high-dose aducanumab was substantially clinically effective - avoided conventional scientific scrutiny, was prominently advanced by patient representative groups who had been major recipients of Biogen funds, and raised concerns that safeguards were insufficient to mitigate regulatory capture within the FDA. Here, we reflect on events leading to the FDA's decision on 7 June 2021 and consider whether any lessons can be learned for the field. [ABSTRACT FROM AUTHOR]

Background: Agitation in Alzheimer's disease (AD) has been hypothesized to be an expression of anxiety, but whether anxiety early in the course of dementia could be a risk factor for developing later agitation is unknown.Objective: We used the Alzheimer's Disease Neuroimaging Initiative (ADNI) database to examine the longitudinal relationship between anxiety and incident agitation in individuals with a diagnosis of AD at baseline or during follow-up.Methods: Longitudinal neuropsychiatric symptom data from AD individuals who were agitation-free at study baseline (N = 272) were analyzed using mixed effects regression models to test the longitudinal relationship between baseline and incident anxiety with incident agitation.Results: Anxiety at baseline was not associated with subsequent agitation, but there was a positive linear relationship between incident anxiety and agitation over the study duration. Baseline apathy and delusions were consistently associated with subsequent agitation and greater disease severity and illness duration also appeared to be risk factors for agitation.Conclusion: Our findings support the concept that anxiety and agitation are likely to be distinct rather than equivalent constructs in mild-moderate AD. Future longitudinal cohort studies are needed to replicate these findings and further characterize potential risk factors for agitation, such as apathy and delusions. [ABSTRACT FROM AUTHOR]

There is clinical overlap between presentations of dementia due to limbic-predominant age-related TDP-43 encephalopathy (LATE) and Alzheimer's disease. It has been suggested that the combination of Alzheimer's disease neuropathological change (ADNC) and LATE neuropathological changes (LATE-NC) is associated with greater neuropsychiatric symptom burden, compared to either pathology alone. Longitudinal Neuropsychiatric Inventory and psychotropic medication prescription data from neuropathologically diagnosed pure ADNC (n = 78), pure LATE-NC (n = 14) and mixed ADNC/LATE-NC (n = 39) brain bank donors were analysed using analysis of variance and linear mixed effects regression models to examine the relationship between diagnostic group and neuropsychiatric symptom burden. Nearly all donors had dementia; three (two pure LATE-NC and one pure ADNC) donors had mild cognitive impairment and another two donors with LATE-NC did not have dementia. The mixed ADNC/LATE-NC group was older than the pure ADNC group, had a higher proportion of females compared to the pure ADNC and LATE-NC groups, and had more severe dementia versus the pure LATE-NC group. After adjustment for length of follow-up, cognitive and demographic factors, mixed ADNC/LATE-NC was associated with lower total Neuropsychiatric Inventory and agitation factor scores than pure ADNC, and lower frontal factor scores than pure LATE-NC. Our findings indicate that concomitant LATE pathology in Alzheimer's disease is not associated with greater neuropsychiatric symptom burden. Future longitudinal studies are needed to further investigate whether mixed ADNC/LATE-NC may be protective against agitation and frontal symptoms in dementia caused by Alzheimer's disease or LATE pathology. [ABSTRACT FROM AUTHOR]

Abstract The locus coeruleus (LC), the major origin of noradrenergic modulation of the central nervous system, may play an important role in neuropsychiatric disorders including Parkinson's disease and Alzheimer's disease. The pattern of age-related change of the LC across the life span is unclear. We obtained normalized, mean LC signal intensity values, that is, contrast ratios (CRs), from magnetization transfer–weighted images to investigate the relationship between LC CR and age in cognitively normal healthy adults (N = 605, age range 18–88 years). Study participants were part of the Cambridge Centre for Ageing and Neuroscience—an open-access, population-based data set. We found a quadratic relationship between LC CR and age, the peak occurring around 60 years, with no differences between males and females. Subregional analyses revealed that age-related decline in LC CR was confined to the rostral portion of the LC. Older adults showed greater variance in overall LC CR than younger adults, and the functional and clinical implications of these observed age-related differences require further investigation. Visualization of the LC in this study may inform how future scanning parameters can be optimized, and provides insight into how LC integrity changes across the life span. Highlights • A quadratic relationship between locus coeruleus signal intensity and age was found. • No differences between males and females were observed. • Older adults had higher variance than younger adults. • The functional and clinical implications of these changes require further research. [ABSTRACT FROM AUTHOR]

Objective To provide an up-to-date systematic review of the characteristics, methodology and findings of studies that have investigated the neurochemistry of agitation in Alzheimer’s disease (AD). Methods Electronic databases were searched for published peer-reviewed articles which provided data on any neurotransmitter system in relation to agitation in AD. Screening of titles and abstracts and data extraction from full texts were conducted in duplicate. Results Forty-five studies were included. Monoamines (serotonin, dopamine and noradrenaline) were most commonly investigated. A variety of methods were used to investigate the neurochemistry underlying agitation in AD and, although there were several conflicting findings, there was evidence of serotonergic deficit, relatively preserved dopaminergic function and compensatory overactivity of postsynaptic noradrenergic neurons in agitation in AD. Conclusions Disruption of the dynamic balance between multiple neurotransmitter systems could impair functional neural networks involved in affective regulation and executive function. Differences in study design and methodology may have contributed to conflicting findings. Future studies that overcome these limitations (e.g. using standardized criteria to define agitation) and employ neuroimaging methods such as MRI/PET to investigate specific neural networks are needed to clarify the role of neurotransmitter alterations in these patients. [ABSTRACT FROM AUTHOR]

The locus coeruleus (LC), the major origin of noradrenergic modulation of the central nervous system, innervates extensive areas throughout the brain and is implicated in a variety of autonomic and cognitive functions. Alterations in the LC-noradrenergic system have been associated with healthy ageing and neuropsychiatric disorders including Parkinson’s disease, Alzheimer’s disease and depression. The last decade has seen advances in imaging the structure and function of the LC, and this paper systematically reviews the methodology and outcomes of sixty-nine structural and functional MRI studies of the LC in humans. Structural MRI studies consistently showed lower LC signal intensity and volume in clinical groups compared to healthy controls. Within functional studies, the LC was activated by a variety of tasks/stimuli and had functional connectivity to a range of brain regions. However, reported functional LC location coordinates were widely distributed compared to previously published neuroanatomical locations. Methodological and demographic factors potentially contributing to these differences are discussed, together with recommendations to optimize the reliability and validity of future LC imaging studies. [ABSTRACT FROM AUTHOR]

ABSTRACT 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. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases, which frequently present with neuropsychiatric symptoms related to prefrontal cortical dysfunction, can alter the integrity of the neural networks involved in central autonomic nervous system regulation, which is proposed to be indexed by heart rate variability (HRV). We systematically reviewed the characteristics, methodology and outcomes of 27 studies of HRV in relation to measures of cognition and behavior in neurodegenerative conditions, and assessed the strength of this relationship, cross-sectionally, across 18 studies. A significant, moderate effect was observed (r = 0.25), such that higher HRV was related to better cognitive and behavioral scores, which was not influenced by mean age or cognitive status. There was no evidence of small-study effects but we could not rule out publication bias, and other factors may have contributed to heterogeneity between studies. Our findings support the proposal that HRV may be a marker of self-regulatory processes in neurodegenerative conditions, and further research on this association is needed in relation to neuropsychiatric symptoms and alongside neuroimaging methods. • Heart rate variability is proposed to be influenced by a neural network involved in autonomic regulation. • Neurodegenerative processes alter the integrity of the central autonomic network. • We reviewed studies of HRV and cognition/behavior in neurodegenerative diseases. • We found a moderate correlation between HRV and measures of cognition/behavior. [ABSTRACT FROM AUTHOR]

Trials of aducanumab in Alzheimer disease were previously discontinued following a phase III futility analysis, but Biogen now says that additional data indicate that longer exposure to the higher dose might be effective. The company is seeking FDA approval for the treatment; however, the limited data released do not establish efficacy. [ABSTRACT FROM AUTHOR]

Pathological alterations to the locus coeruleus, the major source of noradrenaline in the brain, are histologically evident in early stages of neurodegenerative diseases. Novel MRI approaches now provide an opportunity to quantify structural features of the locus coeruleus in vivo during disease progression. In combination with neuropathological biomarkers, in vivo locus coeruleus imaging could help to understand the contribution of locus coeruleus neurodegeneration to clinical and pathological manifestations in Alzheimer's disease, atypical neurodegenerative dementias and Parkinson's disease. Moreover, as the functional sensitivity of the noradrenergic system is likely to change with disease progression, in vivo measures of locus coeruleus integrity could provide new pathophysiological insights into cognitive and behavioural symptoms. Locus coeruleus imaging also holds the promise to stratify patients into clinical trials according to noradrenergic dysfunction. In this article, we present a consensus on how non-invasive in vivo assessment of locus coeruleus integrity can be used for clinical research in neurodegenerative diseases. We outline the next steps for in vivo, post-mortem and clinical studies that can lay the groundwork to evaluate the potential of locus coeruleus imaging as a biomarker for neurodegenerative diseases. [ABSTRACT FROM AUTHOR]