The Mediterranean diet is not associated with neuroimaging or cognition in middle-aged adults: a cross-sectional analysis of the PREVENT dementia programme.

BACKGROUND AND PURPOSE: The Mediterranean diet (MedDiet) has been associated with reduced dementia incidence in several studies. It is important to understand if diet is associated with brain health in midlife, when Alzheimer's disease and related dementias are known to begin. METHODS: This study used data from the PREVENT dementia programme. Three MedDiet scores were created (the Pyramid, Mediterranean Diet Adherence Screener [MEDAS] and MEDAS continuous) from a self-reported food frequency questionnaire. Primary outcomes were hippocampal volume and cube-transformed white matter hyperintensity volume. Secondary outcomes included cornu ammonis 1 and subiculum hippocampal subfield volumes, cortical thickness and measures of cognition. Sex-stratified analyses were run to explore differential associations between diet and brain health by sex. An exploratory path analysis was conducted to study if any associations between diet and brain health were mediated by cardiovascular risk factors for dementia. RESULTS: In all, 504 participants were included in this analysis, with a mean Pyramid score of 8.10 (SD 1.56). There were no significant associations between any MedDiet scoring method and any of the primary or secondary outcomes. There were no differences by sex in any analyses and no significant mediation between the Pyramid score and global cognition by cardiovascular risk factors. CONCLUSIONS: Overall, this study did not find evidence for an association between the MedDiet and either neuroimaging or cognition in a midlife population study. Future work should investigate associations between the MedDiet and Alzheimer's disease and related dementias biomarkers as well as functional neuroimaging in a midlife population.

Facilitating clinical use of the Amsterdam Instrumental Activities of Daily Living Questionnaire: Normative data and a diagnostic cutoff value.

OBJECTIVE: The Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q) is well validated and commonly used to assess difficulties in everyday functioning regarding dementia. To facilitate interpretation and clinical implementation across different European countries, we aim to provide normative data and a diagnostic cutoff for dementia. METHODS: Cross-sectional data from Dutch Brain Research Registry (N = 1,064; mean (M) age = 62 ± 11 year; 69.5% female), European Medial Information Framework-Alzheimer's Disease 90 + (N = 63; Mage = 92 ± 2 year; 52.4% female), and European Prevention of Alzheimer's Dementia Longitudinal Cohort Study (N = 247; Mage = 63 ± 7 year; 72.1% female) were used. The generalized additive models for location, scale, and shape framework were used to obtain normative values (Z-scores). The beta distribution was applied, and combinations of age, sex, and educational attainment were modeled. The optimal cutoff for dementia was calculated using area under receiver operating curves (AUC-ROC) and Youden Index, using data from Amsterdam Dementia Cohort (N = 2,511, Mage = 64 ± 8 year, 44.4% female). RESULTS: The best normative model accounted for a cubic-like decrease of IADL performance with age that was more pronounced in low compared to medium/high educational attainment. The cutoff for dementia was 1.85 standard deviation below the population mean (AUC = 0.97; 95% CI [0.97-0.98]). CONCLUSION: We provide regression-based norms for A-IADL-Q and a diagnostic cutoff for dementia, which help improve clinical assessment of IADL performance across European countries.

Nutrition for dementia prevention: a state of the art update for clinicians.

BACKGROUND AND OBJECTIVES: Dementia prevalence continues to rise. It is therefore essential to provide feasible and effective recommendations to encourage healthy brain ageing and reduce dementia risk across the population. Appropriate nutrition represents a potential strategy to mitigate dementia risk and could be recommended by clinicians as part of mid-life health checks and other health initiatives to reduce dementia prevalence. The purpose of this review is to provide a clinician-focused update on the current state of the knowledge on nutrition and dementia prevention. METHODS: Narrative review. RESULTS: Strong evidence exists to support the consumption of healthy, plant-based dietary patterns (e.g. Mediterranean, MIND or Nordic diet) for maintaining cognitive function and reducing dementia risk in later life and is supported by dementia prevention guideline from leading public health bodies (e.g. World Health Organization). Emerging evidence suggests potential cognitive benefits of consuming specific nutrients/foods (e.g. n-3 fatty acids or fish, flavonols and B-vitamins) and multi-nutrient compounds (e.g. Fortasyn Connect). Challenges and opportunities for integrating nutritional/dietary interventions for dementia prevention into clinical practice are explored in this review. CONCLUSIONS: Appropriate nutrition represents an important factor to help facilitate healthy cognitive ageing and allay dementia risk. The information provided in this article can help clinicians provide informed opinions on appropriate nutritional strategies as part of mid-life Health Checks and other risk reduction initiatives.

Generating real-world evidence in Alzheimer's disease: Considerations for establishing a core dataset.

Ongoing assessment of patients with Alzheimer's disease (AD) in postapproval studies is important for mapping disease progression and evaluating real-world treatment effectiveness and safety. However, interpreting outcomes in the real world is challenging owing to variation in data collected across centers and specialties and greater heterogeneity of patients compared with trial participants. Here, we share considerations for observational postapproval studies designed to collect harmonized longitudinal data from individuals with mild cognitive impairment or mild dementia stage of disease who receive therapies targeting the underlying pathological processes of AD in routine practice. This paper considers key study design parameters, including proposed aims and objectives, study populations, approaches to data collection, and measures of cognition, functional abilities, neuropsychiatric status, quality of life, health economics, safety, and drug utilization. Postapproval studies that capture these considerations will be important to provide standardized data on AD treatment effectiveness and safety in real-world settings.

Entorhinal-based path integration selectively predicts midlife risk of Alzheimer's disease.

INTRODUCTION: Entorhinal cortex (EC) is the first cortical region to exhibit neurodegeneration in Alzheimer's disease (AD), associated with EC grid cell dysfunction. Given the role of grid cells in path integration (PI)-based spatial behaviors, we predicted that PI impairment would represent the first behavioral change in adults at risk of AD. METHODS: We compared immersive virtual reality (VR) PI ability to other cognitive domains in 100 asymptomatic midlife adults stratified by hereditary and physiological AD risk factors. In some participants, behavioral data were compared to 7T magnetic resonance imaging (MRI) measures of brain structure and function. RESULTS: Midlife PI impairments predicted both hereditary and physiological AD risk, with no corresponding multi-risk impairment in episodic memory or other spatial behaviors. Impairments associated with altered functional MRI signal in the posterior-medial EC. DISCUSSION: Altered PI may represent the transition point from at-risk state to disease manifestation in AD, prior to impairment in other cognitive domains.

Mediterranean diet adherence is associated with lower dementia risk, independent of genetic predisposition: findings from the UK Biobank prospective cohort study.

BACKGROUND: The identification of effective dementia prevention strategies is a major public health priority, due to the enormous and growing societal cost of this condition. Consumption of a Mediterranean diet (MedDiet) has been proposed to reduce dementia risk. However, current evidence is inconclusive and is typically derived from small cohorts with limited dementia cases. Additionally, few studies have explored the interaction between diet and genetic risk of dementia. METHODS: We used Cox proportional hazard regression models to explore the associations between MedDiet adherence, defined using two different scores (Mediterranean Diet Adherence Screener [MEDAS] continuous and Mediterranean diet Pyramid [PYRAMID] scores), and incident all-cause dementia risk in 60,298 participants from UK Biobank, followed for an average 9.1 years. The interaction between diet and polygenic risk for dementia was also tested. RESULTS: Higher MedDiet adherence was associated with lower dementia risk (MEDAS continuous: HR = 0.77, 95% CI = 0.65-0.91; PYRAMID: HR = 0.86, 95% CI = 0.73-1.02 for highest versus lowest tertiles). There was no significant interaction between MedDiet adherence defined by the MEDAS continuous and PYRAMID scores and polygenic risk for dementia. CONCLUSIONS: Higher adherence to a MedDiet was associated with lower dementia risk, independent of genetic risk, underlining the importance of diet in dementia prevention interventions.

The Mediterranean diet is associated with better cardiometabolic health for women in mid-life but not men: A PREVENT dementia cohort cross-sectional analysis.

BACKGROUND AND AIMS: The Mediterranean diet (MedDiet) has been associated with better cardiovascular health in a number of studies. This study aimed to explore cross-sectional associations between MedDiet adherence in the PREVENT Dementia (PREVENT) programme, stratified by sex. METHODS AND RESULTS: Three MedDiet scores were calculated (MEDAS, MEDAS continuous and Pyramid) alongside a Western diet score. We used linear regression and linear mixed effects models to test for associations between the MEDAS score and cardiovascular health. Propensity scores were calculated to strengthen causality inferences from the data, and used as covariates along with total energy intake and Western diet scores. Exploratory analysis repeated the linear regression models for each individual food component. This study included 533 participants, with a mean age 51.25 (±5.40) years, and a majority of women (60.0%). Women had higher MedDiet scores across all three scoring methods, had a lower Western diet score and consumed fewer total calories. Higher MedDiet scores were associated with lower blood pressure, body mass index (BMI) and lower cardiovascular risk scores. When stratified by sex, women had significant positive associations between MedDiet scores and lower blood pressure, BMI and glycemia, whereas men only had a significant association with lower BMI. CONCLUSION: There were significant associations between higher MedDiet scores and a number of cardiovascular health outcome measures. These associations were seen more consistently for women compared to men, which may have implications for the development of personalised nutritional recommendations to improve cardiovascular health.

Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial.

Importance: There are limited efficacious treatments for Alzheimer disease. Objective: To assess efficacy and adverse events of donanemab, an antibody designed to clear brain amyloid plaque. Design, Setting, and Participants: Multicenter (277 medical research centers/hospitals in 8 countries), randomized, double-blind, placebo-controlled, 18-month phase 3 trial that enrolled 1736 participants with early symptomatic Alzheimer disease (mild cognitive impairment/mild dementia) with amyloid and low/medium or high tau pathology based on positron emission tomography imaging from June 2020 to November 2021 (last patient visit for primary outcome in April 2023). Interventions: Participants were randomized in a 1:1 ratio to receive donanemab (n = 860) or placebo (n = 876) intravenously every 4 weeks for 72 weeks. Participants in the donanemab group were switched to receive placebo in a blinded manner if dose completion criteria were met. Main Outcomes and Measures: The primary outcome was change in integrated Alzheimer Disease Rating Scale (iADRS) score from baseline to 76 weeks (range, 0-144; lower scores indicate greater impairment). There were 24 gated outcomes (primary, secondary, and exploratory), including the secondary outcome of change in the sum of boxes of the Clinical Dementia Rating Scale (CDR-SB) score (range, 0-18; higher scores indicate greater impairment). Statistical testing allocated α of .04 to testing low/medium tau population outcomes, with the remainder (.01) for combined population outcomes. Results: Among 1736 randomized participants (mean age, 73.0 years; 996 [57.4%] women; 1182 [68.1%] with low/medium tau pathology and 552 [31.8%] with high tau pathology), 1320 (76%) completed the trial. Of the 24 gated outcomes, 23 were statistically significant. The least-squares mean (LSM) change in iADRS score at 76 weeks was -6.02 (95% CI, -7.01 to -5.03) in the donanemab group and -9.27 (95% CI, -10.23 to -8.31) in the placebo group (difference, 3.25 [95% CI, 1.88-4.62]; P < .001) in the low/medium tau population and -10.2 (95% CI, -11.22 to -9.16) with donanemab and -13.1 (95% CI, -14.10 to -12.13) with placebo (difference, 2.92 [95% CI, 1.51-4.33]; P < .001) in the combined population. LSM change in CDR-SB score at 76 weeks was 1.20 (95% CI, 1.00-1.41) with donanemab and 1.88 (95% CI, 1.68-2.08) with placebo (difference, -0.67 [95% CI, -0.95 to -0.40]; P < .001) in the low/medium tau population and 1.72 (95% CI, 1.53-1.91) with donanemab and 2.42 (95% CI, 2.24-2.60) with placebo (difference, -0.7 [95% CI, -0.95 to -0.45]; P < .001) in the combined population. Amyloid-related imaging abnormalities of edema or effusion occurred in 205 participants (24.0%; 52 symptomatic) in the donanemab group and 18 (2.1%; 0 symptomatic during study) in the placebo group and infusion-related reactions occurred in 74 participants (8.7%) with donanemab and 4 (0.5%) with placebo. Three deaths in the donanemab group and 1 in the placebo group were considered treatment related. Conclusions and Relevance: Among participants with early symptomatic Alzheimer disease and amyloid and tau pathology, donanemab significantly slowed clinical progression at 76 weeks in those with low/medium tau and in the combined low/medium and high tau pathology population. Trial Registration: ClinicalTrials.gov Identifier: NCT04437511.

European consensus for the diagnosis of MCI and mild dementia: Preparatory phase.

INTRODUCTION: Etiological diagnosis of neurocognitive disorders of middle-old age relies on biomarkers, although evidence for their rational use is incomplete. A European task force is defining a diagnostic workflow where expert experience fills evidence gaps for biomarker validity and prioritization. We report methodology and preliminary results. METHODS: Using a Delphi consensus method supported by a systematic literature review, 22 delegates from 11 relevant scientific societies defined workflow assumptions. RESULTS: We extracted diagnostic accuracy figures from literature on the use of biomarkers in the diagnosis of main forms of neurocognitive disorders. Supported by this evidence, panelists defined clinical setting (specialist outpatient service), application stage (MCI-mild dementia), and detailed pre-assessment screening (clinical-neuropsychological evaluations, brain imaging, and blood tests). DISCUSSION: The Delphi consensus on these assumptions set the stage for the development of the first pan-European workflow for biomarkers' use in the etiological diagnosis of middle-old age neurocognitive disorders at MCI-mild dementia stages. HIGHLIGHTS: Rational use of biomarkers in neurocognitive disorders lacks consensus in Europe. A consensus of experts will define a workflow for the rational use of biomarkers. The diagnostic workflow will be patient-centered and based on clinical presentation. The workflow will be updated as new evidence accrues.

Associations between cerebrospinal fluid markers and cognition in ageing and dementia: A systematic review.

A biomarker associated with cognition in neurodegenerative dementias would aid in the early detection of disease progression, complement clinical staging and act as a surrogate endpoint in clinical trials. The current systematic review evaluates the association between cerebrospinal fluid protein markers of synapse loss and neuronal injury and cognition. We performed a systematic search which revealed 67 studies reporting an association between cerebrospinal fluid markers of interest and neuropsychological performance. Despite the substantial heterogeneity between studies, we found some evidence for an association between neurofilament-light and worse cognition in Alzheimer's diseases, frontotemporal dementia and typical cognitive ageing. Moreover, there was an association between cerebrospinal fluid neurogranin and cognition in those with an Alzheimer's-like cerebrospinal fluid biomarker profile. Some evidence was found for cerebrospinal fluid neuronal pentraxin-2 as a correlate of cognition across dementia syndromes. Due to the substantial heterogeneity of the field, no firm conclusions can be drawn from this review. Future research should focus on improving standardization and reporting as well as establishing the importance of novel markers such as neuronal pentraxin-2 and whether such markers can predict longitudinal cognitive decline.

Self-reported diabetes is associated with allocentric spatial processing in the European Prevention of Alzheimer's Dementia Longitudinal Cohort Study.

Type 2 diabetes is a robust predictor of cognitive impairment. Impairment in allocentric processing may help identify those at increased risk for Alzheimer's disease dementia. The objective of this study was to investigate the performance of participants with and without diabetes on a task of allocentric spatial processing. This was a cross-sectional secondary data analysis study using baseline data from the European Prevention of Alzheimer's Dementia Longitudinal Cohort Study (EPAD LCS). Participants were aged 50 years and above and were free of dementia at baseline. Participants with no missing data on the variables of interest were included in this study. Our exposure variable was diabetes reported in the medical history. Our primary outcome was the Four Mountains Test (4MT), a novel task of allocentric processing. Covariates included demographics (age, sex, family history of dementia and years of education), APOEε4 carrier status, cognitive status (Clinical Dementia Rating scale), cerebrospinal fluid phosphorylated tau and amyloid-beta 1-42. Of 1324 participants (mean age = 65.95 (±7.45)), 90 had diabetes. Participants with diabetes scored 8.32 (±2.32) on the 4MT compared with 9.24 (±2.60) for participants without diabetes. In a univariate model, diabetes was significantly associated with worse 4MT total scores (ß = -.92, p = .001), remaining significant in a fully adjusted model (ß = -.64, p = .01). Cerebrospinal fluid phosphorylated tau was significantly higher in participants with diabetes compared with those without. Novel cognitive tests, such as the 4MT, may be appropriate to identify early cognitive changes in this high-risk group. Identifying those at greatest risk for future neurodegeneration is key to prevention efforts.

CAIDE dementia risk score relates to severity and progression of cerebral small vessel disease in healthy midlife adults: the PREVENT-Dementia study.

BACKGROUND: Markers of cerebrovascular disease are common in dementia, and may be present before dementia onset. However, their clinical relevance in midlife adults at risk of future dementia remains unclear. We investigated whether the Cardiovascular Risk Factors, Ageing and Dementia (CAIDE) risk score was associated with markers of cerebral small vessel disease (SVD), and if it predicted future progression of SVD. We also determined its relationship to systemic inflammation, which has been additionally implicated in dementia and SVD. METHODS: Cognitively healthy midlife participants were assessed at baseline (n=185) and 2-year follow-up (n=158). To assess SVD, we quantified white matter hyperintensities (WMH), enlarged perivascular spaces (EPVS), microbleeds and lacunes. We derived composite scores of SVD burden, and subtypes of hypertensive arteriopathy and cerebral amyloid angiopathy. Inflammation was quantified using serum C-reactive protein (CRP) and fibrinogen. RESULTS: At baseline, higher CAIDE scores were associated with all markers of SVD and inflammation. Longitudinally, CAIDE scores predicted greater total (p<0.001), periventricular (p<0.001) and deep (p=0.012) WMH progression, and increased CRP (p=0.017). Assessment of individual CAIDE components suggested that markers were driven by different risk factors (WMH/EPVS: age/hypertension, lacunes/deep microbleeds: hypertension/obesity). Interaction analyses demonstrated that higher CAIDE scores amplified the effect of age on SVD, and the effect of WMH on poorer memory. CONCLUSION: Higher CAIDE scores, indicating greater risk of dementia, predicts future progression of both WMH and systemic inflammation. Findings highlight the CAIDE score's potential as both a prognostic and predictive marker in the context of cerebrovascular disease, identifying at-risk individuals who might benefit most from managing modifiable risk.

An epigenetic predictor of death captures multi-modal measures of brain health.

Individuals of the same chronological age exhibit disparate rates of biological ageing. Consequently, a number of methodologies have been proposed to determine biological age and primarily exploit variation at the level of DNA methylation (DNAm). A novel epigenetic clock, termed 'DNAm GrimAge' has outperformed its predecessors in predicting the risk of mortality as well as many age-related morbidities. However, the association between DNAm GrimAge and cognitive or neuroimaging phenotypes remains unknown. We explore these associations in the Lothian Birth Cohort 1936 (n = 709, mean age 73 years). Higher DNAm GrimAge was strongly associated with all-cause mortality over the eighth decade (Hazard Ratio per standard deviation increase in GrimAge: 1.81, P < 2.0 × 10-16). Higher DNAm GrimAge was associated with lower age 11 IQ (ß = -0.11), lower age 73 general cognitive ability (ß = -0.18), decreased brain volume (ß = -0.25) and increased brain white matter hyperintensities (ß = 0.17). There was tentative evidence for a longitudinal association between DNAm GrimAge and cognitive decline from age 70 to 79. Sixty-nine of 137 health- and brain-related phenotypes tested were significantly associated with GrimAge. Adjusting all models for childhood intelligence attenuated to non-significance a small number of associations (12/69 associations; 6 of which were cognitive traits), but not the association with general cognitive ability (33.9% attenuation). Higher DNAm GrimAge associates with lower cognitive ability and brain vascular lesions in older age, independently of early-life cognitive ability. This epigenetic predictor of mortality associates with different measures of brain health and may aid in the prediction of age-related cognitive decline.

Identifying functional cognitive disorder: a proposed diagnostic risk model.

BACKGROUND: Functional cognitive disorders (FCD) are an important differential diagnosis of neurodegenerative disease. The utility of suggested diagnostic features has not been prospectively explored in "real world" clinical populations. This study aimed to identify positive clinical markers of FCD. METHODS: Adults with cognitive complaints but not dementia were recruited from memory, neurology, and neuropsychiatry clinics. Participants underwent structured interview, Mini International Neuropsychiatric Interview, Montreal Cognitive Assessment, Luria 3-step, interlocking fingers, digit span and Medical Symptom Validity Test, Patient Health Questionnaire 15, Hospital Anxiety and Depression Scale, Multifactorial Memory Questionnaire, and Pittsburgh Sleep Quality Inventory. Potential diagnostic variables were tested against expert consensus diagnosis using logistic regression. RESULTS: FCD were identified in 31/49 participants. Participants with FCD were younger, spoke for longer when prompted "Tell me about the problems you've been having," and had more anxiety and depression symptoms and psychiatric diagnoses than those without FCD. There were no significant differences in sex, education, or cognitive scores. Younger age and longer spoken response predicted FCD diagnosis in a model which explained 74% of diagnostic variability and had an area under the curve (AUC) of 94%. CONCLUSIONS: A detailed description of cognitive failure is a sensitive and specific positive feature of FCD, demonstrating internal inconsistency between experienced and observed function. Cognitive and performance validity tests appear less helpful in FCD diagnosis. People with FCD are not "worried well" but often perform poorly on tests, and have more anxiety, depression, and physical symptoms than people with other cognitive disorders. Identifying diagnostic profiles is an important step toward parity of esteem for FCDs, as differential diagnoses of neurodegenerative disease and an independent target for clinical trials.

The frequency and framing of cognitive lapses in healthy adults.

OBJECTIVE: Many people present to health services with concern about cognitive symptoms. In a significant proportion those symptoms are not the result of pathologically defined brain disease. In some they are part of a functional cognitive disorder (FCD). We assessed the frequency of cognitive lapses in a non-clinical sample in order to consider the utility of frequency of cognitive lapses in diagnosing cognitive disorders. METHODS: Healthy adults, who had never sought help for cognitive symptoms, completed a questionnaire, distributed via social media, about self-evaluation of cognitive function, frequency of cognitive lapses, and use of memory aids, including Schmitdke and Metternich's functional memory disorder (FMD) inventory. RESULTS: One hundred and twenty-four adults, aged 18-59 (median 23), most with further or higher education, responded. Thirty-one (25%) reported "fair" or "poor" memory. Forty-eight (39%) reported memory worse than 5 years ago, and 30 (24%) reported memory worse than others the same age. Participants endorsed a mean 13/18 specific cognitive lapses at least monthly. One hundred and eleven (89%) scored ≥4, the suggested cutoff for the FMD inventory. CONCLUSIONS: Cognitive lapses described in FCDs are common in highly educated adults. The high frequency of lapses in this healthy population suggests self-reported frequency of lapses alone cannot discriminate FCDs from "normal" experiences. Further research is required to clarify the role of abnormal metacognition in FCD. Better understanding of the factors moderating subjective interpretation of cognitive failures will also aid development of better clinical risk-stratification methods in people concerned about future dementia.

Measuring axial length of the eye from magnetic resonance brain imaging.

BACKGROUND: Metrics derived from the human eye are increasingly used as biomarkers and endpoints in studies of cardiovascular, cerebrovascular and neurological disease. In this context, it is important to account for potential confounding that can arise from differences in ocular dimensions between individuals, for example, differences in globe size. METHODS: We measured axial length, a geometric parameter describing eye size from T2-weighted brain MRI scans using three different image analysis software packages (Mango, ITK and Carestream) and compared results to biometry measurements from a specialized ophthalmic instrument (IOLMaster 500) as the reference standard. RESULTS: Ninety-three healthy research participants of mean age 51.0 ± SD 5.4 years were analyzed. The level of agreement between the MRI-derived measurements and the reference standard was described by mean differences as follows, Mango - 0.8 mm; ITK - 0.5 mm; and Carestream - 0.1 mm (upper/lower 95% limits of agreement across the three tools ranged from 0.9 mm to - 2.6 mm). Inter-rater reproducibility was between - 0.03 mm and 0.45 mm (ICC 0.65 to 0.93). Intra-rater repeatability was between 0.0 mm and - 0.2 mm (ICC 0.90 to 0.95). CONCLUSIONS: We demonstrate that axial measurements of the eye derived from brain MRI are within 3.5% of the reference standard globe length of 24.1 mm. However, the limits of agreement could be considered clinically significant. Axial length of the eye obtained from MRI is not a replacement for the precision of biometry, but in the absence of biometry it could provide sufficient accuracy to act as a proxy. We recommend measuring eye axial length from MRI in studies that do not have biometry but use retinal imaging to study neurodegenerative changes so as to control for differing eye size across individuals.

Assessing and disclosing test results for 'mild cognitive impairment': the perspective of old age psychiatrists in Scotland.

BACKGROUND: Mild cognitive impairment (MCI) is a condition that exists between normal healthy ageing and dementia with an uncertain aetiology and prognosis. This uncertainty creates a complex dynamic between the clinicians' conception of MCI, what is communicated to the individual about their condition, and how the individual responds to the information conveyed to them. The aim of this study was to explore clinicians' views around the assessment and communication of MCI in memory clinics. METHOD: As part of a larger longitudinal study looking at patients' adjustment to MCI disclosure, we interviewed Old Age Psychiatrists at the five participating sites across Scotland. The study obtained ethics approvals and the interviews (carried out between Nov 2020-Jan 2021) followed a semi-structured schedule focusing on [1] how likely clinicians are to use the term MCI with patients; [2] what tests clinicians rely on and how much utility they see in them; and [3] how clinicians communicate risk of progression to dementia. The interviews were voice recorded and were analysed using reflective thematic analysis. RESULTS: Initial results show that most clinicians interviewed (Total N = 19) considered MCI to have significant limitations as a diagnostic term. Nevertheless, most clinicians reported using the term MCI (n = 15/19). Clinical history was commonly described as the primary aid in the diagnostic process and also to rule out functional impairment (which was sometimes corroborated by Occupational Therapy assessment). All clinicians reported using the Addenbrooke's Cognitive Examination-III as a primary assessment tool. Neuroimaging was frequently found to have minimal usefulness due to the neuroradiological reports being non-specific. CONCLUSION: Our study revealed a mixture of approaches to assessing and disclosing test results for MCI. Some clinicians consider the condition as a separate entity among neurodegenerative disorders whereas others find the term unhelpful due to its uncertain prognosis. Clinicians report a lack of specific and sensitive assessment methods for identifying the aetiology of MCI in clinical practice. Our study demonstrates a broad range of views and therefore variability in MCI risk disclosure in memory assessment services which may impact the management of individuals with MCI.

Fear of Dementia and the Obligation to Provide Aggregate Research Results to Study Participants.

A general obligation to make aggregate research results available to participants has been widely supported in the bioethics literature. However, dementia research presents several challenges to this perspective, particularly because of the fear associated with developing dementia. The authors argue that considerations of respect for persons, beneficence, and justice fail to justify an obligation to make aggregate research results available to participants in dementia research. Nevertheless, there are positive reasons in favor of making aggregate research results available; when the decision is made to do so, it is critical that a clear strategy for communicating results is developed, including what support will be provided to participants receiving aggregate research results.

Proximity to dementia onset and multi-modal neuroimaging changes: The prevent-dementia study.

BACKGROUND: First-degree relatives of people with dementia (FH+) are at increased risk of developing Alzheimer's disease (AD). Here, we investigate "estimated years to onset of dementia" (EYO) as a surrogate marker of preclinical disease progression and assess its associations with multi-modal neuroimaging biomarkers. METHODS: 89 FH+ participants in the PREVENT-Dementia study underwent longitudinal MR imaging over 2 years. EYO was calculated as the difference between the parental age of dementia diagnosis and the current age of the participant (mean EYO = 23.9 years). MPRAGE, ASL and DWI data were processed using Freesurfer, FSL-BASIL and DTI-TK. White matter lesion maps were segmented from FLAIR scans. The SPM Sandwich Estimator Toolbox was used to test for the main effects of EYO and interactions between EYO, Time, and APOE-ε4+. Threshold free cluster enhancement and family wise error rate correction (TFCE FWER) was performed on voxelwise statistical maps. RESULTS: There were no significant effects of EYO on regional grey matter atrophy or white matter hyperintensities. However, a shorter EYO was associated with lower white matter Fractional Anisotropy and elevated Mean/Radial Diffusivity, particularly in the corpus callosum (TFCEFWERp < 0.05). The influence of EYO on white matter deficits were significantly stronger compared to that of normal ageing. APOE-ε4 carriers exhibited hyperperfusion with nearer proximity to estimated onset in temporo-parietal regions. There were no interactions between EYO and time, suggesting that EYO was not associated with accelerated imaging changes in this sample. CONCLUSIONS: Amongst cognitively normal midlife adults with a family history of dementia, a shorter hypothetical proximity to dementia onset may be associated with incipient brain abnormalities, characterised by white matter disruptions and perfusion abnormalities, particularly amongst APOE-ε4 carriers. Our findings also confer biological validity to the construct of EYO as a potential stage marker of preclinical progression in the context of sporadic dementia. Further clinical follow-up of our longitudinal sample would provide critical validation of these findings.

Functional cognitive disorder: dementia's blind spot.

An increasing proportion of cognitive difficulties are recognized to have a functional cause, the chief clinical indicator of which is internal inconsistency. When these symptoms are impairing or distressing, and not better explained by other disorders, this can be conceptualized as a cognitive variant of functional neurological disorder, termed functional cognitive disorder (FCD). FCD is likely very common in clinical practice but may be under-diagnosed. Clinicians in many settings make liberal use of the descriptive term mild cognitive impairment (MCI) for those with cognitive difficulties not impairing enough to qualify as dementia. However, MCI is an aetiology-neutral description, which therefore includes patients with a wide range of underlying causes. Consequently, a proportion of MCI cases are due to non-neurodegenerative processes, including FCD. Indeed, significant numbers of patients diagnosed with MCI do not 'convert' to dementia. The lack of diagnostic specificity for MCI 'non-progressors' is a weakness inherent in framing MCI primarily within a deterministic neurodegenerative pathway. It is recognized that depression, anxiety and behavioural changes can represent a prodrome to neurodegeneration; empirical data are required to explore whether the same might hold for subsets of individuals with FCD. Clinicians and researchers can improve study efficacy and patient outcomes by viewing MCI as a descriptive term with a wide differential diagnosis, including potentially reversible components such as FCD. We present a preliminary definition of functional neurological disorder-cognitive subtype, explain its position in relation to other cognitive diagnoses and emerging biomarkers, highlight clinical features that can lead to positive diagnosis (as opposed to a diagnosis of exclusion), and red flags that should prompt consideration of alternative diagnoses. In the research setting, positive identifiers of FCD will enhance our recognition of individuals who are not in a neurodegenerative prodrome, while greater use of this diagnosis in clinical practice will facilitate personalized interventions.