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The neuromodulatory subcortical system (NSS) nuclei are critical hubs for survival, hedonic tone, and homeostasis. Tau-associated NSS degeneration occurs early in Alzheimer's disease (AD) pathogenesis, long before the emergence of pathognomonic memory dysfunction and cortical lesions. Accumulating evidence supports the role of NSS dysfunction and degeneration in the behavioral and neuropsychiatric manifestations featured early in AD. Experimental studies even suggest that AD-associated NSS degeneration drives brain neuroinflammatory status and contributes to disease progression, including the exacerbation of cortical lesions. Given the important pathophysiologic and etiologic roles that involve the NSS in early AD stages, there is an urgent need to expand our understanding of the mechanisms underlying NSS vulnerability and more precisely detail the clinical progression of NSS changes in AD. Here, the NSS Professional Interest Area of the International Society to Advance Alzheimer's Research and Treatment highlights knowledge gaps about NSS within AD and provides recommendations for priorities specific to clinical research, biomarker development, modeling, and intervention. HIGHLIGHTS: Neuromodulatory nuclei degenerate in early Alzheimer's disease pathological stages. Alzheimer's pathophysiology is exacerbated by neuromodulatory nuclei degeneration. Neuromodulatory nuclei degeneration drives neuropsychiatric symptoms in dementia. Biomarkers of neuromodulatory integrity would be value-creating for dementia care. Neuromodulatory nuclei present strategic prospects for disease-modifying therapies.

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.

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]

After clinical trial failures in symptomatic Alzheimer's disease (AD), our field has moved to earlier intervention in cognitively normal individuals with biomarker evidence of AD. This offers potential for dementia prevention, but mainly low and variable rates of progression to AD dementia reduce the usefulness of trials' data in decision making by potential prescribers. With results from several Phase 3 secondary prevention studies anticipated within the next few years and the Food and Drug Administration's recent endorsement of amyloid beta as a surrogate outcome biomarker for AD clinical trials, it is time to question the clinical significance of changes in biomarkers, adequacy of current trial durations, and criteria for treatment success if cognitively unimpaired patients and their doctors are to meaningfully evaluate the potential value of new agents. We argue for a change of direction toward trial designs that can unambiguously inform clinical decision making about dementia risk and progression. [ABSTRACT FROM AUTHOR]

Background: In the treatment of psychosis, agitation and aggression in Alzheimer's disease, guidelines emphasise the need to 'use the lowest possible dose' of antipsychotic drugs, but provide no information on optimal dosing.Aims: This analysis investigated the pharmacokinetic profiles of risperidone and 9-hydroxy (OH)-risperidone, and how these related to treatment-emergent extrapyramidal side-effects (EPS), using data from The Clinical Antipsychotic Trials of Intervention Effectiveness in Alzheimer's Disease study (Clinicaltrials.gov identifier: NCT00015548).Method: A statistical model, which described the concentration-time course of risperidone and 9-OH-risperidone, was used to predict peak, trough and average concentrations of risperidone, 9-OH-risperidone and 'active moiety' (combined concentrations) (n = 108 participants). Logistic regression was used to investigate the associations of pharmacokinetic biomarkers with EPS. Model-based predictions were used to simulate the dose adjustments needed to avoid EPS.Results: The model showed an age-related reduction in risperidone clearance (P < 0.0001), reduced renal elimination of 9-OH-risperidone (elimination half-life 27 h), and slower active moiety clearance in 22% of patients, (concentration-to-dose ratio: 20.2 (s.d. = 7.2) v. 7.6 (s.d. = 4.9) ng/mL per mg/day, Mann-Whitney U-test, P < 0.0001). Higher trough 9-OH-risperidone and active moiety concentrations (P < 0.0001) and lower Mini-Mental State Examination (MMSE) scores (P < 0.0001), were associated with EPS. Model-based predictions suggest the optimum dose ranged from 0.25 mg/day (85 years, MMSE of 5), to 1 mg/day (75 years, MMSE of 15), with alternate day dosing required for those with slower drug clearance.Conclusions: Our findings argue for age- and MMSE-related dose adjustments and suggest that a single measure of the concentration-to-dose ratio could be used to identify those with slower drug clearance. [ABSTRACT FROM AUTHOR]

Introduction: There is increasing emphasis on the importance of optimizing and standardizing clinical trials of agitation in Alzheimer’s disease (AD), but the risks of bias arising from published trials and the number and design of unpublished studies are poorly understood. Methods: Using the ClinicalTrials.gov database, we systematically reviewed all registered investigational clinical trials for agitation in AD to describe the landscape of agitation drug treatment trials and to assess their quality and generalizability. Results:We included 52 clinical studies registered over the past 25 years.Within published randomized controlled trials (RCTs), there was a high rate of participant dropout, poor reporting of randomization procedures, and inconsistent definitions of the sample included for analysis. There was also evidence of publication and funder bias. Discussion:We discuss factors that limit the internal and external validity of published RCTs and make additional recommendations for the conduct and reporting of future clinical trials of agitation in AD. [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]

The locus coeruleus (LC), the origin of noradrenergic modulation of cognitive and behavioral function, may play an important role healthy ageing and in neurodegenerative conditions. We investigated the functional significance of age-related differences in mean normalized LC signal intensity values (LC-CR) in magnetization-transfer (MT) images from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) cohort - an open-access, population-based dataset. Using structural equation modelling, we tested the pre-registered hypothesis that putatively noradrenergic (NA)-dependent functions would be more strongly associated with LC-CR in older versus younger adults. A unidimensional model (within which LC-CR related to a single factor representing all cognitive and behavioral measures) was a better fit with the data than the a priori two-factor model (within which LC-CR related to separate NA-dependent and NA-independent factors). Our findings support the concept that age-related reduction of LC structural integrity is associated with impaired cognitive and behavioral function. Alterations of locus coeruleus signal intensity have been associated with functional changes in health and disease. Here, the authors tested a pre-registered hypothesis on a large number of subjects as part of the Cam-CAN consortium. [ABSTRACT FROM AUTHOR]