AAIC Neuroscience Next 2026

BACKGROUND:

Tau aggregation is a defining feature of tauopathies, yet its early impact on nuclear and nucleolar organisation remains unclear. The nucleolus, a key site of ribosomal biogenesis, is sensitive to cellular stress and can undergo structural alterations during neurodegenerative processes. This study examined how mutant tau expression influences the nuclear and nucleolar distribution of non-phosphorylated tau (nP-Tau) and associated changes in nucleolar morphology.

METHODS:

A tetracycline-inducible SH-SY5Y cell line expressing 4R-P301S tau was used to model early events in tau-induced stress. Tau expression was induced with 1 µg/mL tetracycline for 1 hour and 48 hours. High-content immunofluorescence imaging (Operetta CLS) combined with in-house 3D analysis pipelines enabled quantitative compartmental assessment (cytoplasm, nucleus, nucleolus) of fluorescence intensity and localisation for 4R Tau and nP-Tau (Tau 1 antibody). Nucleolar size and number were also quantified. Statistical tests included Shapiro-Wilk, Levene’s, one-way ANOVA with Tukey’s post-hoc, and Mann-Whitney U, as appropriate.

RESULTS:

Induction with tetracycline led to a significant increase in 4R Tau expression as early as 1 hour, confirming rapid activation of the model (p < 0.001). At both 1 hour and 48 hours, nP-Tau intensity was markedly elevated within the nucleus and nucleolus (p < 0.01), indicating early tau redistribution. While nucleolar size remained unchanged, there was a non-significant trend towards reduced nucleolar number at both time points compared with uninduced controls. CONCLUSION: Mutant tau expression rapidly induces nuclear and nucleolar accumulation of nP-Tau in SH-SY5Y cells, preceding overt morphological nucleolar stress. These findings suggest that nuclear and nucleolar redistribution of nP-Tau may represent an early molecular event in tau-associated cellular stress, potentially preceding measurable changes in nucleolar structure.

BACKGROUND:

Chronic alcohol consumption, the resulting neurotoxic effects and the long-term neurological issues in particular due to altering brain functions can considerably enhance progressive decline in executive functions. While some believe that alcohol has benefits for the body, research findings have increasingly challenged this common belief. Brain studies have especially highlighted neuronal degeneration caused by alcohol intake; however, the impact of alcohol intoxication on the volumetric characteristics of subcortical regions remains underexplored.

METHODS:

Given the involvement of subcortical structures in cognitive decline, we examined the volumetric alterations in grey matter and utilized high-resolution T1-weighted structural brain data of 7,690 participants from the UK Biobank who drink alcohol regularly. We also included 3,019 individuals who never drink alcohol from the same cohort as the control group. We focused on the volumes of the Brain Stem, Thalamus, Caudate, Putamen, Amygdala, Hippocampus, and Pallidum, and we performed a multifactor Multivariate Analysis of Variance to examine differences in the combined mean of the grey matter volume of the above-mentioned regions between these two groups of participants. Post hoc tests were subsequently carried out and Holm’s Sequential Bonferroni procedure was used to correct for multiple comparisons.

RESULTS:

After adjusting for biological sex and age, our findings revealed significant shrinkage of the Brain Stem due to alcohol intoxication, while the Putamen demonstrated resilience. Importantly, we observed alcohol-induced inflammation in the Thalamus, Caudate, Amygdala, Hippocampus, and Pallidum.

CONCLUSION:

Given that neuroinflammatory conditions in subcortical regions can contribute to the development of Multiple Sclerosis, the inflammation observed in the Thalamus, Caudate, Amygdala, Hippocampus, and Pallidum highlights a heightened risk for neurodegenerative diseases linked to alcohol-induced neurotoxicity. Moreover, while age-related brain degeneration does not affect all individuals in later life, alcohol consumption introduces an additional risk factor that accelerates neurodegenerative processes. The association between brain stem shrinkage and frontotemporal dementia further suggests that alcohol may act as an early driver of neurodegeneration, shedding light on the long-term impact of sustained alcohol use on subcortical brain structures.

BACKGROUND:

Age-related cognitive decline has inevitable consequences for one’s self-sufficiency and life expectancy; yet, the associated brain structural changes have not been fully documented. Given the involvement of subcortical areas in deterioration of cognitive abilities, in this study we aimed to map the age-related volumetric characteristics of grey matter in subcortical brain.

METHODS:

We used T1-weighted structural brain scans data from 46,111 healthy participants; they were divided into the middle-aged group (ages 44-60) and the older group (ages 61-83). A path analysis was performed to assess the relationship between the age and the volumes of subcortical areas. The goodness-of-fit of the model was evaluated using several fit indices, including the RMSEA, the CFI and the TLI. Based on modification indices, multi-collinearities were adjusted and the model was re-estimated to achieve a better fit.

RESULTS:

According to our findings, age had significant positive direct effects resulting in increased volumes in the right and left Caudate, and Pallidum, and in the left Putamen; besides, age had significant negative direct effects and thus shrinkage in the volumes of the Brain Stem, the left Thalamus, the right and the left Amygdala, and Hippocampus in the older group.

CONCLUSION:

The analyses reveal that shrinkage of grey matter volume in subcortical areas is not the only reason behind age-related changes in structural brain characteristics; increases in the volumes of the left and right Caudate and Pallidum and the left Putamen in the older group demonstrate age-related brain inflammation due to immune system alterations, probably preceding pathogenesis of neurodegenerative diseases in some individuals.

BACKGROUND:

Dementia is a common symptom in Parkinson’s disease (PD), occurring in up to 80% of PD patients within 20 years following initial diagnosis, resulting in a condition known as Parkinson’s disease dementia (PDD). It is currently unknown why some individuals with PD go on to develop PDD while others remain free of cognitive decline until death. One possible contributor is metallomic dysfunction, with previous studies showing metallic alterations across the PDD brain—most notably, widespread Cu decreases. In this study, we set out to ascertain whether similar alterations were also present in the PD brain.

METHODS:

Levels of the essential metals Na, Mg, K, Ca, Mn, Fe, Cu, and Zn and the metalloid Se were determined in tissues from seven brain regions obtained from nine confirmed PD cases and 15 matched controls using inductively coupled plasma mass spectrometry (ICP-MS). Multiple linear regression was used to determine potential confounder effects from variables such as age, post-mortem delay, and α-synuclein Braak stage. Results were compared with findings previously obtained in PDD brains using the same methods.

RESULTS:

Only one significant case-control difference was found in the PD brain: decreased Cu in the medulla oblongata. This contrasts markedly with the widespread metallic dysfunction observed in the PDD brain. PD and PDD cases were well-separated by PCA analysis. In the PD cohort, tau Braak stage correlated with Cu levels in several brain regions; however, these correlations were not retained when PDD cases were included in the analysis.

CONCLUSION:

In contrast to PDD cases, PD cases show a striking lack of metallic changes in the brain. This data suggests that a resistance to metallomic dysfunction may contribute to resilience against cognitive impairment in those who do not go on to develop dementia in PD.

BACKGROUND:

Biotin, also known as vitamin B7, is an essential dietary micronutrient that acts as a carboxylase enzyme cofactor, participating in a range of essential molecular processes ranging from gluconeogenesis and lipogenesis to amino acid metabolism and TCA cycle activity—many of which have been reported to be dysregulated in Alzheimer’s disease (AD). There is some evidence that lower levels of biotin intake are linked with increased risk of dementia and that concentrations are reduced in AD patient serum. This study aimed to ascertain whether biotin levels are similarly perturbed in the AD brain.

METHODS:

Biotin concentrations were determined in brain tissues from five regions including the motor cortex, middle temporal gyrus, cingulate gyrus, hippocampus), and sensory cortex from nine neuropathologically and clinically confirmed AD cases and nine matched controls using ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Case-control differences were determined by multiple Mann-Whitney U tests with 10% FDR correction and any potential confounding effects from variables such as age, sex, tau Braak stage, etc., were determined by multiple linear regression.

RESULTS:

Biotin levels were decreased in AD cases in every investigated region, with an average decrease of ~40%. Multiple linear regression showed an effect of post-mortem delay and brain weight on biotin concentrations in the motor cortex, suggesting potential confounding effects within this region; however, no confounding effects were observed in any other brain region.

CONCLUSION:

Biotin levels appear to be diminished across the AD brain. These changes may contribute to downstream metabolic disturbances observed in AD such as altered TCA cycle activity and glucose metabolism in conjunction with other metabolic alterations which show the same pattern of dysregulation in the AD brain, such as those previously reported in pantothenic acid, TCA cycle components, and metabolites involved in glucose metabolism.

BACKGROUND:

Alzheimer’s disease (AD), Parkinson’s disease (PD), and dementia with Lewy bodies (DLB) are major neurodegenerative disorders that collectively affect millions worldwide. Despite distinct clinical features, these conditions share overlapping genetic risk factors, including apolipoprotein-E (ApoE) and alpha-synuclein (aSyn). ApoE has protective (E2, Christchurch) and risk-related (E3, E4) isoforms, while aSyn mutations (A53T, E46K) promote early aggregation and neurotoxicity. How the protein interaction networks of ApoE and aSyn converge on healthy vs disease mechanisms remains unclear.

METHODS:

We are applying TurboID proximity labeling proteomics to define the in vivo isoform interactomes of ApoE and aSyn. Using AAV delivery, TurboID-tagged ApoE (E2, E3, E4, Christchurch) is expressed in astrocytes, and aSyn (WT, A53T, E46K) in neurons, to identify cell and isoform-specific protein networks. Western blot and immunofluorescence microscopy are used to confirm TurboID probe expression and candidate-interactor biotin labeling. Biotin-labeled candidate interaction partners are enriched using streptavidin magnetic beads and purified for precision LFQ mass spectrometry.

RESULTS:

Preliminary data in pilot animals indicate that wild-type aSyn and ApoE3 may share many interacting proteins enriched in axonal components, neurofilament structures, and neurodegeneration-related pathways. This unexpected overlap suggests that ApoE and aSyn may influence common axonal integrity networks essential for neuronal health. We hypothesize that protective variants (ApoE2/Christchurch, WT aSyn) preserve these axonal networks, while risk variants (ApoE4, mutant aSyn) destabilize them, contributing to early axonal dysfunction.

CONCLUSION:

Axonal dysfunction represents a potentially reversible, early event in neurodegeneration, distinct from the irreversible aggregation observed in late disease stages. By mapping how ApoE and aSyn variants differentially regulate axonal protein-protein interaction networks, this work aims to establish a unifying molecular framework linking genetic risk to shared cellular pathology across AD, PD, and DLB.

BACKGROUND:

Proxies for cognitive reserve, including physical and cognitive activity, have been shown to mitigate disease progression in various forms of neurodegeneration. In this study, we examined whether lower levels of physical and/or cognitive activity were associated with greater clinical impairment in familial frontotemporal dementia (FTD), suggesting a potential protective effect of leisure activities against cognitive decline.

METHODS:

A total of 284 presymptomatic C9orf72, GRN, or MAPT mutation carriers and 193 non-carrier family relatives from the Genetic Frontotemporal Dementia Initiative (GENFI) completed the Physical Activity Scale for the Elderly (PASE) and Cognitive Activity Scale (CAS). The Clinical Dementia Rating scale plus NACC FTLD neuropsychiatric and motor domains (CDR plus NACC FTLD-NM) was used as a marker of clinical progression. Based on PASE and CAS scores,presymptomatic carriers were stratified into age-adjusted high, medium, and low activity groups. Group comparisons were conducted using Wilcoxon rank-sum tests.

RESULTS:

For physical activity, the high and low PASE groups had mean (SD) scores of 300 (76) and 104 (30), respectively. For cognitive activity, the high and low CAS groups had mean (SD) scores of 27 (5) and 12 (3). Participants in the low PASE group had significantly higher CDR+NACC FTLD-NM scores (mean ± SD: 0.59 ± 1.04) compared to the high group (0.29 ± 0.67; Wilcoxon rank-sum test: p=0.005). Similarly, the low CAS group had significantly higher CDR+NACC FTLD-NM scores (0.60 ± 0.88) than the high group (0.38 ± 0.90; p=0.018).

CONCLUSION:

These findings suggest that lower levels of physical and cognitive activity are associated with greater clinical impairment in presymptomatic familial FTD. Ongoing analyses will explore associations with neuropsychological features, potential synergistic interactions between activities in moderating clinical progression, and longitudinal trajectories to determine causal effects.

BACKGROUND: Apathy is a key symptom of frontotemporal dementia (FTD) and has a substantial impact on patients and caregivers. The brief informant-rated Dimensional Apathy Scale (b-DAS) assesses apathy severity across emotional, executive and initiation domains. However, its application in FTD remains limited, and the trajectories of apathy across disease stages and genetic subtypes remain poorly characterised.

METHODS:

We examined b-DAS scores in 515 participants from the GENFI cohort (mean age 50.3 [13.4] years; 43% male; education 15.1[3.25] years), including 184 C9orf72, 104 GRN, 53 MAPT mutation carriers, and 174 non-carriers. Mutation carriers were classified as asymptomatic (FTLD-CDR+NM=0), prodromal (0.5), or symptomatic (≥1). Cross-sectional analyses compared b-DAS total and subdomain scores across disease stages and genetic groups using linear regressions adjusted for age, sex, and education, with bootstrapping to account for non-normality. In a subset of participants (N = 353), associations between apathy (b-DAS total scores) and cognition were assessed using correlations with an executive function z-score composite derived from standardised measures (TMT-B Time, Digit Symbol, Digit Span Backwards, Stroop Ink Naming).

RESULTS:

Apathy progressively increased across disease stages in all mutation groups. Symptomatic carriers exhibited significantly higher b-DAS total and subdomain scores (p< .001), and prodromal carriers also demonstrated elevated scores on b-DAS total and Initiation subdomain scores, compared with non-carriers (p< .05). Notably, MAPT carriers showed increased Initiation-Apathy relative to non-carriers even at the asymptomatic stage (p=.025). Across all genetic groups, higher total and subdomain apathy scores were associated with poorer executive function (p< .001), although the effect size was modest.

CONCLUSION:

Apathy emerges early in genetic FTD, progressing from the prodromal phase, and is associated with executive dysfunction. These findings support the b-DAS as a sensitive tool for early detection and disease monitoring, although further analyses across longitudinal data are required.

BACKGROUND:

Frontotemporal dementia (FTD) has a genetic cause in 20% of cases, knowledge of which can affect a person’s mental health. Commonly, the General Anxiety Disorder 7 (GAD-7) and Patient Health Questionnaire 9 (PHQ-9) are used to assess anxiety and depression, however there is evidence that the Warwick-Edinburgh Mental Health Wellbeing Scale (WEMWBS) could be a more sensitive and comprehensive alternative. This study explores how genetic status and awareness of that status affect mental health in people at risk of FTD and evaluates which questionnaire best captures these differences.

METHODS:

Using data from the Genetic Frontotemporal Dementia Initiative (GENFI), depression, anxiety and general wellbeing scores were analysed in symptomatic carriers of pathogenic FTD mutations and an at-risk cohort (presymptomatic mutation carriers and non-carriers) using the GAD-7, PHQ-9 and WEMWBS test. The at-risk cohort was further classified as either aware or unaware of their genetic status. Data (n = 705) was analysed using descriptive statistics and Wilcoxon tests to assess group differences and the effects of both genetic status and awareness.

RESULTS:

Symptomatic carriers showed significantly lower wellbeing (-3.9 WEMWBS points, p = 0.021) and higher depression scores (+2.7 PHQ-9 points, p = 0.021) than non-carriers. In the at-risk cohort, non-carriers who were aware of their genetic status reported higher wellbeing (+2.8 WEMWBS points, p = 0.026) compared with those unaware, with no significant differences in anxiety or depression scores. In contrast, knowledge of genetic status did not improve wellbeing in presymptomatic mutation carriers.

CONCLUSION:

Awareness of a positive FTD genetic status and symptom onset is associated with reduced wellbeing and increased depression, whereas awareness among non-carriers improves wellbeing without affecting depression or anxiety. These findings suggest that WEMWBS is a more sensitive tool for detecting subtle changes in mental health than GAD-7 or PHQ-9, particularly in at-risk cohorts and should be used in clinical assessments of mental health changes.

BACKGROUND:

Digital health technologies offer promising solutions for remote cognitive assessment in Frontotemporal Dementia (FTD). As part of the FTD Prevention Initiative, we compared two digital tools: the Genetic FTD Initiative (GENFI) Ignite iPad app (UCL) and the ALLFTD smartphone app (UCSF). We aimed to compare executive function measures across both platforms to validate these tools and identify the most suitable approach for early detection of cognitive change in FTD.

METHODS:

47 presymptomatic participants (mean age = 49.0 ± 1.8 years; 22 males) from UCL and UCSF completed both apps within four weeks. Each assessed executive function using analogous tasks: Stroop Ink Naming Test (inhibitory control), Wisconsin Card Sorting Test (set-shifting), Flanker Test (inhibitory control), and N-Back Test (working memory). Pearson correlations compared performance across platforms. Participants provided usability and feasibility feedback via online survey.

RESULTS:

Performance was significantly correlated across apps for Stroop (r = 0.67, p < 0.001), Wisconsin Card Sorting (r = 0.54, p < 0.001), Flanker (r = 0.63, p < 0.001), and N-Back tests (r = 0.33, p = 0.035). Participants rated both apps favorably, with no clear preference between smartphones (46.2%) and tablets (46.2%). Regarding usability, 23% reported the ALLFTD screen as somewhat small, while all found the Ignite screen satisfactory or ideal. However, 15% found Ignite sessions too long compared to 38% for ALLFTD, suggesting differences in perceived task burden.

CONCLUSION:

These findings support the validity and feasibility of digital executive function assessments across independent platforms. Comparable performance between Ignite and ALLFTD indicates that remote cognitive testing can reliably capture FTD-relevant measures. Both tools proved practical and acceptable for at-home use, though screen size remains a consideration. Session duration is already being adjusted to improve usability. Ongoing work will further optimize and align digital tools for large-scale remote FTD trials and monitoring.

BACKGROUND:

The Oxford Brain Health Clinic (OBHC) has scanned over 400 NHS memory clinic patients with a magnetic resonance imaging (MRI) protocol aligned with the UK Biobank (UKB). We also acquired the same data from healthy volunteers (HV) of a similar age range. This work explores the added value of UKB-aligned analysis of multimodal MRI to explain variability in cognition in a real-world memory clinic setting.

METHODS:

Six modalities from 140 OBHC patients and 92 HV (Table 1) were analysed with a UKB-aligned image analysis pipeline optimised for memory clinic use (Gillis <i>et al.</i>, 2025), yielding 3520 imaging-derived phenotypes (IDPs). Four models using different sets of IDPs were compared in terms of their ability to predict ACE-III total cognitive score (Table 2). Within a cross-validation framework, model performance (root mean squared error – RMSE) was compared with a Freidman rank and post-hoc Wilcoxon tests with Holm correction. To also explore the value of quantitative IDPs compared to visual ratings, we used the same method on OBHC patients for which both a neuroradiology report (including MTA and Fazekas scores) and structural IDPs were available (N=284).

RESULTS:

The “All IDPs” model outperformed the 3 other models (Figure 1). Upon inspection of IDPs importance within this PLS model, we observed that: 1) the 3 retained components reflect patterns of global brain health, unique vascular changes, and atrophy changes with preserved white matter integrity; 2) the most important IDPs were temporal and peripheral GM volumes, periventricular WMH volume, and inferior fronto-occipital and superior longitudinal fasciculus mean diffusivity. The model with hippocampal and WMH volumes performed slightly better than the visual ratings model (RMSE 0.90 vs 0.93), although not significantly (p=0.08).

CONCLUSION:

Including IDPs from dMRI, ASL, and rfMRI explains more variability in cognition than simpler models without these modalities. The model with hippocampal and WMH volumes performs as well or slightly better than the one with neuroradiologist visual ratings on these structures.

BACKGROUND:

Frontotemporal dementia (FTD) and related disorders are a heterogeneous group of neurodegenerative syndromes driven by distinct molecular pathologies (e.g., TDP-43, tau) that overlap clinically with Alzheimer’s disease (AD). Gaps remain in translating basic science discoveries about pathogenesis into accessible, early-detection tools, particularly for underrepresented populations. We present a translational, equity-focused research program that links mechanistic biology with scalable diagnostic approaches and community-based implementation to improve timely diagnosis and reduce disparities.

METHODS:

We conducted a multi-arm study combining (1) basic-science analyses of postmortem and induced pluripotent stem cell (iPSC)-derived neuronal models to map molecular cascades distinguishing TDP-43 vs tau pathology; (2) a prospective clinical cohort (n = 420) recruited with deliberate oversampling of historically underserved groups, undergoing multimodal assessment—plasma proteomics (neurofilament light, phosphorylated tau species, candidate TDP-43 peptides), structural and functional MRI, and brief smartphone-based cognitive and speech tasks; and (3) machine-learning integration to derive a multimodal early-detection algorithm. We evaluated diagnostic accuracy for FTD vs AD, profiled early pathophysiologic signatures, and assessed barriers to equitable access through mixed-methods community interviews.

RESULTS:

Mechanistic studies identified convergent pathways of synaptic dysfunction and proteostasis imbalance that differentiate TDP-43 and tau phenotypes and nominate plasma peptide targets. In the clinical cohort, a combined biomarker + digital cognitive model demonstrated high discrimination between FTD and AD and detected disease-stage changes prior to overt clinical impairment. Importantly, algorithm performance remained robust after stratifying by race, education, and socioeconomic status when community-informed calibration and local normative adjustments were applied. Qualitative findings revealed modifiable access barriers (service awareness, cost, mistrust) and community preferences for decentralized screening.

CONCLUSION:

Integrating basic pathogenesis research with multimodal biomarkers and community-centered implementation yields a feasible pathway for earlier, more equitable detection of FTD and related disorders and clarifies molecular targets for future therapeutic development.

BACKGROUND:

Parkinson’s disease (PD) is primarily characterised by motor symptoms, but dementia is a common outcome that signals poor prognosis and care home admission. Predicting who will develop dementia remains a clinical challenge. The NULISA TM platform is a multiplex proteomic assay that detects neurodegeneration-relevant proteins with high sensitivity.

METHODS:

We used the NULISAseq TM CSF Disease Panel 120 to quantify baseline serum proteins from 730 individuals with PD. Participants underwent serial cognitive assessments using the Montreal Cognitive Assessment (MoCA) over a mean of 3.9 ± 2.1 years, with an average of 3.4 ± 1.3 assessments per person. We used a Cox proportional hazards model to identify proteins associated with time-to-dementia, and a linear mixed model (LMM) to identify which proteins predict a decline in MoCA scores within the first 3 years of follow-up. Domain-specific cognitive decline was also evaluated. All models were adjusted for sex, age at serum sampling and batch. P-values were corrected using the Benjamini-Hochberg (BH) method.

RESULTS:

Age at baseline was 67.1 ± 8.9 years, with mean disease duration from diagnosis of 1.3 ± 0.9 years. The mean adjusted baseline MoCA score was 25.5 ± 3.8. Survival analysis revealed significant associations for phosphorylated Tau proteins (pTau-217, pTau-181 and pTau-231), NPTXR and FCN2. Adjusting for APOE4 status attenuated most signals, with only FCN2 surviving BH correction. Adding these proteins to a predictive model with age and sex improved the AUC from 0.70 to 0.75 (DeLong’s test, adjP = 0.041). The AUC further increased to 0.81 when adding the adjusted MoCA score at baseline (adjP = 0.020). The LMM revealed that higher levels of pTau-231, GFAP, pTau-181 and NFLH predicted faster MoCA decline within the first 3 years of follow-up. GFAP was linked to deterioration in attention, executive, and language domains, while CXCL10, pTau-181, and pTau-231 were associated with language decline over 5 years.

CONCLUSION:

We identified serum proteins associated with cognitive decline and time-to-dementia in PD. The attenuation of signals after APOE4 adjustment suggests that these markers may reflect Alzheimer’s co-pathology. Further studies in PD patients without AD co-pathology are needed to identify biomarkers specific to Lewy Body disease.

BACKGROUND:

Frontotemporal dementia (FTD) is a heterogeneous group of disorders involving frontal and temporal lobe degeneration, with overlapping clinical, genetic, and pathological features. Blood-based biomarkers, including Neurofilament Light Chain (NfL) and Glial Fibrillary Acidic Protein (GFAP), hold promise for improving differential diagnoses. NfL is consistently elevated in symptomatic carriers, rising sharply just prior to phenoconversion, whilst GFAP is commonly increased in certain subgroups such as those with GRN mutations. Biomarker validation across platforms is essential for diagnostic accuracy, disease monitoring, and evaluating emerging therapies. Despite comparisons between NULISA and established assays, no studies have focused solely on FTD.

METHODS:

Comparative analysis of blood NfL and GFAP in a genetic FTD cohort was performed (GENFI, n=448). Samples collected simultaneously were analysed on the nucleic acid linked immuno‐sandwich assay (NULISA) and the single molecule array (Simoa). Comparisons were grouped by genetic mutation (C9ORF72, MAPT, and GRN), genetic status (non-carrier vs carrier) and symptom status (control, pre-symptomatic, and fully symptomatic on the CDR + NACC FTLD rating scale).

RESULTS:

NfL and GFAP showed strong agreement (ρ = 0.84-0.98), with correlations increasing with clinical severity (NfL ρ = 0.87 (controls), 0.93 (presymptomatic), 0.96 (symptomatic); GFAP ρ = 0.82, 0.90, 0.93). Both biomarkers showed highest correlation in GRN mutations (ρ = 0.98 for both) and stronger correlations in mutation carriers vs non-carriers (NfL ρ = 0.96 vs 0.91; GFAP ρ = 0.92 vs 0.84). ROC analyses showed comparable discrimination between mutation carriers and non-carriers (AUC = 0.61-0.68) and excellent accuracy for distinguishing non-carriers from symptomatic individuals (AUC = 0.82-0.93).

CONCLUSION:

NfL and GFAP exhibited strong platform correlations, increasing alongside clinical severity and supporting stage-specific diagnosis. ROC analysis confirmed excellent accuracy in identifying symptomatic individuals. Findings support NfL and GFAP as robust biomarkers for FTD diagnosis and monitoring, with clinical and research applications.

BACKGROUND:

The apolipoprotein E (APOE) locus is the strongest genetic risk factor for late-onset Alzheimer’s disease and related dementias (ADRD). Variation in ApoE isoforms is known to have diverse pleiotropic effects on circulating lipids and other metabolites, but effects on the circulating proteome across the life course are not well characterised. We therefore aimed to compare the specific effects of APOE ε4 and APOE ε2 carriage on the proteome in middle and later life.

METHODS:

We compared the proteomic profiles of APOE ε4 and ε2 carriers with ε3 homozygotes in UK Biobank participants (N = 42,642; age = 39.1 to 70.9 years). Using multivariable linear regression, we conducted ancestry-specific analyses of 2,922 assayed plasma proteins across individuals of European (EUR), African (AFR), and South Asian (SAS) ancestry. To explore age-dependent effects, stratified analyses were performed with the sample split into age tertiles (youngest = 40.2-54.4 years; middle = 54.4-62.6 years; oldest = 62.7-70.9 years). We then performed replication analyses of APOE-associated proteins in age-matched tertiles, using data from two independent cohorts.

RESULTS:

We identified 331 proteins associated ε2 carriage and 443 with ε4 carriage; 149 of these were associated with both ε2 and ε4 carriage. These included established biomarkers of ADRD (GFAP and NEFL), and other proteins implicated by ADRD risk loci (e.g., TREM2, CTSB, IDUA, SORT1, GRN); though many of these proteins have been linked to neurodegenerative diseases more broadly. Several strong associations were consistent across age tertiles and ancestries. In multiple age tertiles, ε4 carriage was strongly associated with directionally consistent differences in APOE, MENT, and SNAP25 levels across ancestries, while ε2 carriers had lower PLA2G7 levels in both EUR and AFR populations.

CONCLUSION:

APOE ε4 and ε2 exert broad, often age-dependent effects on the plasma proteome, detectable decades before typical ADRD diagnosis. Further research is needed to determine their relevance to ADRD pathophysiology and prediction.

BACKGROUND:

Fluid biomarkers are useful tools in disease detection, monitoring, and treatment. However, current sampling methodologies are invasive and timely procedures that require patients to travel to clinics, trained staff, and resources costly to the healthcare system. The use of micro-sampling offers a solution: it requires only a finger-prick blood sample which can be performed at home and mailed to a lab for analysis. However, thorough validation of micro-samples for biomarker detection and assessment of the feasibility of at-home sampling are needed.

METHODS:

Quanterix’s Single Molecule Array (SIMOA) platform was used to compare pTau-217, NfL, and GFAP concentrations in Capitainer SEP-10 DPS made from venous (DPS ven) blood against matched plasma. Each Capitainer SEP-10 card uses ~70uL of whole blood and performs on-board plasma separation to produce two 10uL DPS ven. Different storage conditions and extraction protocols involving the use of one (1x DPS ven) or two (2x DPS ven) DPS were assessed.

RESULTS:

Concentrations of pTau-217, GFAP and NfL were detectable in 1x DPS ven stored at RT. Concentration of pTau-217 and GFAP correlated to concentrations measured in matched plasma (R 2 = 0.82 from 2x DPS ven and 0.78 from1x DPS ven), respectively), but not NfL (R 2 = 0.37 from 1x DPS ven). Concentrations of pTau-217, were detectable in DPS ven stored at room temperature (RT) for up to 6 weeks. Storage at -70°C saw no significant difference in DPS ven pTau-217 concentration compared to RT (p = 0.73, from 2x DPS ven).

CONCLUSION:

These results display that DPS can be used to detect pTau-217, NfL and GFAP in plasma, and suggests that DPS have potential to be used as a screening tool for some neurodegenerative diseases. However, further validation is required for different biomarkers, immunoassays, and card types, as well as assessing the feasbility and challenges of at-home sampling.

BACKGROUND:

Clinical translation of blood-based biomarkers for dementia diagnosis requires a robust understanding of their stability under real-world pre-analytical handling conditions. We investigated the effects of varied pre-analytical handling conditions on quantification of 124 brain-derived proteins relevant to dementia research in human plasma.

METHODS:

Plasma samples from symptomatic individuals and asymptomatic relatives attending two specialist cognitive clinics were subjected to a range of pre-analytical conditions (n=10 each), including: pre-centrifugation delay at room temperature (RT) for 30 minutes, 1 or 3 hours, or at 2-8°C for 3 or 24 hours; post-centrifugation delay prior to -80°C storage for 0, 4 or 24 hours at RT; 4, 24 hours or 2 weeks at 2-8°C; or 2 weeks at -20°C; 1-4 freeze/thaw cycles; and post-centrifugation storage for up to 2 weeks at -20°C and transport in a Bio-Freeze device or storage at -80°C and transport on dry ice. Protein abundance was quantified using the NULISAseq CNS Disease 120 Panel (ARGO immunoassay platform; Alamar Biosciences). Non-parametric Friedman or Wilcoxon tests (p<0.05) assessed statistical significance, and a ±10% median relative change threshold defined likely clinical significance.

RESULTS:

ANXA5 values reduced by a median of 10% with 3-hour pre-centrifugation delay at RT. Across post-centrifugation delays, concentrations of six proteins (ANXA5, ARSA, NRGN, oligo-SNCA, RUVBL2, YWHAZ) showed increases of>10% with intermediate storage at -20°C for 2 weeks, five (ANXA5, APOE4, ARSA, ENO2, HBA1) increased and one (Aβ42) reduced with storage at 2-8°C for 2 weeks and 2 (ENO2, HBA1) increased with storage at RT for 24 hours. No analyte showed clinically significant differences for either pre-centrifugation delays at 2-8°C, or for up to four freeze-thaw cycles, or between the two storage and transport conditions.

CONCLUSION:

Plasma measurements on the NULISAseq CNS panel are mostly robust to pre-centrifugation delays of up to 3 hours at RT and 24 hours at 2-8°C, but some proteins quantifications are significantly altered with post-centrifugation intermediate storage at either 2-8 °C or -20°C for 2 weeks. Recently developed standardised sample handling protocols may need to be updated to ensure the reliability and reproducibility of blood-based biomarker measurements on this multiplexed panel.

BACKGROUND:

A leading explanation for translational failure in neurodegenerative disease is that new drugs are evaluated late in the disease course when clinical features have become irreversible.

METHODS:

Here, to address this gap, we cognitively profiled 21,051 people aged 17-85 years as part of the Genes and Cognition cohort within the National Institute for Health and Care Research BioResource across England. We describe the cohort, present cognitive trajectories and show the potential utility.

RESULTS:

Surprisingly, when studied at scale, the APOE genotype had negligible impact on cognitive performance. Different cognitive domains had distinct genetic architectures, with one indicating brain region-specific activation of microglia and another with glycogen metabolism. Thus, the molecular and cellular mechanisms underpinning cognition are distinct from dementia risk loci, presenting different targets to slow down age-related cognitive decline.

CONCLUSION:

Participants can now be recalled stratified by genotype and cognitive phenotype for natural history and interventional studies of neurodegenerative and other disorders.

BACKGROUND:

Treatment guidelines for amyloid therapies mandate MRI scans to monitor for ARIA at regular intervals. As a non-contrast MRI technique that measures cerebral perfusion, arterial spin labelling (ASL) can be readily included in existing ARIA monitoring sessions with little change to workflows. This abstract builds upon prior work to demonstrate the suitability of ASL MRI to track and predict cognitive change during amyloid therapy.

METHODS:

Data were collected from 13 patients (5M 8F, aged 73.4 ± 8.6 years) undergoing amyloid therapy at Weill Cornell Medicine, New York, USA. T1-weighted structural and ASL images were acquired at baseline and during ARIA monitoring sessions on GE 3T scanners. Pseudo-continuous ASL (PCASL) was used with a 1.8s label duration, 2.025s post-label delay, 3D readout and TR/TE = 5.338s/53.6ms. Cognition was assessed using MOCA before and during treatment, with change in MOCA used to measure treatment response. T1w images were processed using recon-all-clinical from FreeSurfer 7.4.1 to segment the Desikan-Killiany-Tourville (DKT) atlas structures. ASL images were processed using the QASL pipeline (Quantified Imaging, UK), a derivative of FSL’s BASIL to quantify cerebral blood flow (CBF). To mitigate the effect of demographics on baseline CBF, each subject’s map was normalised to a value of 60 units using a reference region method. Pearson’s correlation was calculated between MOCA change and mean whole-brain cortical CBF change. Additionally, baseline regional CBF was correlated against cognition change to assess the predictability of treatment response.

RESULTS:

Change in mean whole-brain cortical CBF correlated significantly with change in cognition (r=0.90, p<0.001). Among the 62 cortical structures in the DKT atlas, the right entorhinal cortex showed the strongest correlation between baseline CBF and change in MOCA (r=0.75, p=0.003).

CONCLUSION:

In a small cohort, changes in cortical CBF from ASL MRI showed an excellent correlation with changes in MOCA during amyloid therapy. Further, right entorhinal CBF at baseline correlated well with future cognition change, demonstrating that ASL may be used to predict treatment response. Further work is needed to validate these findings in a larger cohort, with the aim of establishing ASL as a valuable tool for monitoring and predicting treatment outcomes.

BACKGROUND:

Frontotemporal dementia (FTD) is a neurodegenerative disease which causes grey matter atrophy within the frontal and/or temporal lobes of the brain. Using novel Wave-CAIPI technology, rapid MRI sequences could reduce costs and save time, being 70% faster than classical T1 scans. This project investigated rapid T1 MRI scans’ potential to dissociate presymptomatic and symptomatic participants with FTD from controls in comparison to classical scans.

METHODS:

Classical T1 (5 mins) and rapid T1 (1 min) scans were acquired on a SIEMENS Prisma scanner for 28 participants, including carriers of mutations causal of FTD (3 symptomatic carriers and 21 presymptomatic carriers) and 4 mutation-negative controls. Data was preprocessed using FreeSurfer with grey matter volumes and thickness extracted for the frontal and temporal lobes. For each brain region and metric, we correlated the volume and thickness values for rapid and classical scans across all participants. For each sequence, we performed receiver-operating characteristic (ROC) analyses assessing the sensitivity and specificity of frontal and temporal lobe volumes and thickness for distinguishing all carriers from controls, symptomatic carriers from controls and presymptomatic carriers from controls. We compared area under the curve (AUC) for each sequence using DeLong’s test.

RESULTS:

Temporal, frontal and frontotemporal brain volumes and thickness were highly correlated between rapid and classical T1 scans. R 2 values ranged from 0.82 to 0.94 for thickness and 0.92 to 0.98 for volumes, with temporal lobe volume showing the highest correlation and frontal lobe thickness the lowest. Though AUCs dissociating presymptomatic carriers from controls remained modest, these did not significantly differ between rapid and classical scans.

CONCLUSION:

Rapid T1 scans offer a compelling alternative, demonstrating comparability to classical even at the presymptomatic disease stage. By substantially reducing scan time and cost while preserving data quality and clinical relevance, this approach holds strong promise for broad application across research and clinical settings.

BACKGROUND:

Dementia remains a major global health challenge characterized by progressive neurodegeneration, cognitive impairment, and psychosocial decline. Traditional pharmacological and non-pharmacological treatments yield limited improvements. The vagus nerve’s extensive projections offer a pathway to enhance neuroplasticity, regulate mood, and restore cognitive and emotional control disrupted in dementia.​ Vagal nerve stimulation (VNS), encompassing both invasive and non-invasive modalities such as transcutaneous auricular VNS (taVNS), has emerged as a promising adjunctive intervention for dementia-related cognitive decline and psychosocial dysfunction.

METHODS:

Systematic review: PubMed/MEDLINE, Cochrane Library, Web of Science, Embase,PsycINFO and Scopus. Search terms: “vagus nerve stimulation” OR “VNS” OR “vagal stimulation” OR “transcutaneous vagus nerve stimulation” OR “taVNS” OR “cervical VNS” OR “auricular VNS” OR “cranial nerve stimulation” AND “dementia” OR “Alzheimer’s disease” OR “cognitive impairment” OR “memory loss” OR “MCI” AND “psychosocial” OR “quality of life” OR “carer support” OR “social engagement” OR “therapy” OR “behavioral symptoms” OR “depression” OR “anxiety”.

RESULTS:

Evidence consistently supports VNS’s capacity to enhance cognitive functions and neural connectivity within memory networks such as the hippocampal-temporal-parietal circuits. Mechanistically, VNS activates the locus coeruleus-noradrenergic system, improving attention and memory while modulating neuroinflammation and tau pathology. Studies further reveal psychosocial benefits, with VNS promoting emotional regulation, reducing anxiety symptoms, and enhancing social interaction, effects that are particularly relevant within the neurovisceral integration and social health models of dementia care.​ From a biopsychosocial standpoint, the integration of VNS with interventions like cognitive stimulation and reminiscence therapy presents new opportunities for holistic dementia management. By linking autonomic regulation to social behavior, VNS may strengthen interpersonal engagement and caregivers’ relational experiences, supporting both patient wellbeing and care outcomes.​Studies largely based in high-income settings, examined the influence of invasive and non-invasive VNS protocols on cognition, memory, emotional regulation, and social engagement among populations with Alzheimer’s disease, vascular dementia, and mild cognitive impairment.​

CONCLUSION:

Clinical evidence suggests VNS may not only mitigates neurodegenerative processes but also fosters emotional and social resilience. Future research should focus on optimizing stimulation protocols, assessing long-term psychosocial outcomes, and embedding VNS within integrative dementia care frameworks aimed at maximizing both cognitive and relational quality of life.

BACKGROUND:

Dementia is a neurodegenerative condition with no known cure, so far. In 2021, 57 million people were living with dementia worldwide, with almost 10 million new cases recorded every year. In 2019, dementia’s global economic burden reached US$1.3 trillion. Given this, addressing the modifiable risk factors remains one of the critical aspects of dementia prevention. This umbrella review examines the psychosocial and behavioural factors associated with increased risk or protective effects for dementia and cognitive impairment.

METHODS:

The study adhered to the Preferred Reporting Items of Systematic Review and Meta-Analysis (PRISMA) guidelines. Search was performed in PubMed, on 11 November 2024, from 01 September 2020, right after the publication of the 2020 update Lancet Commission on dementia prevention. Abstracts and full-texts were screened based on inclusion-exclusion criteria and 90 systematic reviews were retained.

RESULTS:

Psychosocial risk factors include hearing loss, depression, social isolation, low levels of education, vision impairment, poor sleep quality, psychotic disorders, childhood adversity and neuroticism. On the other hand, engagement in social activities, treatment of vision impairment, higher cognitive reserve and participation in cognitively stimulating activities, a strong sense of meaning, purpose in life, and overall psychological well-being along with leisure activities and visual art therapy, optimism and positive affect have also been linked to protective effects. Evidence remains inconclusive regarding anxiety, stress and PTSD. Behavioural risk factors include physical inactivity, alcohol use disorder, impaired mastication and playing professional football/soccer, involving head trauma. Protective factors encompass regular physical activity, moderate alcohol consumption, smoking cessation, adherence to a Mediterranean diet, use of nutritional supplements for vitamin B and iron, tea consumption, moderate coffee intake, and participation in multidomain non-pharmacological interventions. Evidence remains inconclusive about the effects of milk/dairy consumption, the caffeine component of tea/coffee and sleep duration. There is insufficient evidence about the impact of dental prostheses, gum chewing, Vitamin C and protein supplements, bilingualism, musical abilities and traditional board game playing.

CONCLUSION:

Interventions to mitigate risk factors and promoting protective factors would help reducing the incidence of dementia/cognitive decline. More studies are required to enhance the understanding of the factors that have inconclusive or insufficient evidence.

BACKGROUND:

Recent studies have shown that almost half of all dementia cases could have been prevented or delayed by managing modifiable risk factors. However, there is a paucity of results from longitudinal studies that have analysed the association between the inflammatory potential of the diet, assessed by the Dietary Inflammatory Index (DII®), and the risk of dementia. We aimed to analyse whether a diet with a higher inflammatory potential is a risk factor for the incidence of dementia in a three-year follow-up.

METHODS:

Data from a total of 2,346 participants from the English Longitudinal Study of Ageing (ELSA Study) aged ≥ 50 were included. The DII was calculated from dietary intake data collected using the Oxford WebQ questionnaire and the energy-adjusted Dietary Inflammatory Index (E-DII™) to exclude the effect of energy intake on nutrients. The E-DII score was stratified by sex and divided into tertiles, where the lowest tertile represents a diet with lower inflammatory potential (≤ -0.375 for women and ≤ 0.419 for men), the second tertile (> -0.375 and ≤ 1.441 for women, > 0.419 and ≤ 1.863 for men) represents a medium inflammatory potential, and the highest tertile (> 1.441 and > 1.863 for women and men, respectively) represents the highest inflammatory potential of the diet. The incidence of dementia was defined as the presence of physician-diagnosed dementia or the coexistence of cognitive impairment (global cognition z-score lower than 1.5 standard deviations compared to the sample mean) and functional impairment (difficulty in performing one or more basic activities of daily living). Poisson regression models were performed to analyse the incidence of dementia, adjusted for socioeconomic, behavioural, anthropometric and clinical variables.

RESULTS:

Participants with a higher dietary inflammatory potential, classified in the third tertile, had a higher risk of dementia incidence over the three years of follow-up (IRR = 1.90, 95%CI 1.08-3.32) compared to individuals classified in the first tertile.

CONCLUSION:

The greater the inflammatory potential of the diet, the greater the risk of dementia. Given that diet is a modifiable factor, it may be adjusted to reduce its inflammatory potential and, consequently, reduce the risk of dementia.

BACKGROUND:

Social isolation is a known reversible risk factor for dementia and is sometimes responsible for accelerated cognitive decline. Memory clinics offer an important opportunity for early identification and intervention of social isolation.

METHODS:

This study aimed to perform a literature review using Google Scholar and PubMed to identify available and validated social isolation screening tools relevant to working-age memory clinic populations.

RESULTS:

Most studies reviewed prioritised older adult populations and were community-based, with limited inclusion of working-age individuals, reducing the relevance to the target population. Among the screening tools analysed, there was considerable variation in administration time, with the Duke Social Support Index taking the longest (25 minutes) and the UCLA-3 the shortest (under 5 minutes), making the latter more suitable for time-limited consultations. Tools were categorised as subjective, objective, or mixed, with mixed-method tools being the least common. Despite differences in design and focus, several tools, including the UCLA-3 and Lubben Scale, have been validated across age groups and settings.

CONCLUSION:

Integrating evidence-based social isolation screening tools into working-age memory clinics may support earlier intervention, reduce the impact of a cognitive impairment and thus improve patient outcomes; However, standardised clinical guidelines are necessary to ensure consistent uptake across services.

BACKGROUND:

Digital health technologies (DHTs) offer promising tools for remote symptom monitoring, contributing to the early detection of frontotemporal dementia (FTD). The Genetic FTD Initiative (GENFI) has implemented DHTs to enhance detection and develop outcome measures for clinical trials. One approach is the use of wearables to monitor heart rate variability (HRV), which reflects changes in parasympathetic nervous system function.

METHODS:

Participants attended their GENFI research visit at UCL and completed the CDR+NACC-FTLD during their clinical examination. After the visit, a Fitbit was provided for at home use. Resting HRV was measured through average root mean square of successive differences (RMSSD) per person over 28-days. Mutation carriers were classified based on CDR+NACC-FTLD stages: asymptomatic (0; n = 18, mean age = 34.8, SD = 8.5), prodromal (0.5; n = 40, mean age = 44.2, SD = 10.7), and symptomatic (≥1; n = 7, mean age = 62.9, SD = 5.7). Differences in average RMSSD between these groups and 27 mutation-negative controls (mean age = 46.2, SD = 13.0) were analysed using a linear regression model, adjusting for age.

RESULTS:

Asymptomatic mutation carriers had greater HRV with significantly higher RMSSD scores (mean=49.2, SD=23.7), compared to mutation negative controls (mean=30.6, SD=9.80, p<0.01). No significant differences were found between controls and prodromal mutation carriers (mean=32.8, SD=12.7, p=0.93) or between controls and symptomatic mutation carriers (mean=20.5, SD=2.60, p=0.36), although there was a trend to a lower RMSSD in the latter group.

CONCLUSION:

Significant differences in HRV were observed at the asymptomatic stage, with carriers showing increased HRV compared to controls. This variability may reflect heightened physiological stress in response to early neurodegenerative changes. However, HRV declined at later disease stages, suggesting progressive parasympathetic dysfunction. This is the first study exploring stage-specific HRV changes in FTD, highlighting the potential of DHTs as early biomarkers.

BACKGROUND:

Social isolation is a known reversible risk factor for dementia and is sometimes responsible for accelerated cognitive decline. Memory clinics offer an important opportunity for early identification and intervention of social isolation.

METHODS:

This study aimed to perform a literature review using Google Scholar and PubMed to identify available and validated social isolation screening tools relevant to working-age memory clinic populations.

RESULTS:

Most studies reviewed prioritised older adult populations and were community-based, with limited inclusion of working-age individuals, reducing the relevance to the target population. Among the screening tools analysed, there was considerable variation in administration time, with the Duke Social Support Index taking the longest (25 minutes) and the UCLA-3 the shortest (under 5 minutes), making the latter more suitable for time-limited consultations. Tools were categorised as subjective, objective, or mixed, with mixed-method tools being the least common. Despite differences in design and focus, several tools, including the UCLA-3 and Lubben Scale, have been validated across age groups and settings.

CONCLUSION:

Integrating evidence-based social isolation screening tools into working-age memory clinics may support earlier intervention, reduce the impact of a cognitive impairment and thus improve patient outcomes; However, standardised clinical guidelines are necessary to ensure consistent uptake across services.

BACKGROUND:

Stroke, defined by NICE as a vascular syndrome characterised by rapid-onset disturbance of cerebral function, affects approximately 100,000 people each year, with over 1.4 million survivors in the UK. Cognitive impairment is a common sequela of stroke that impedes recovery and requires systematic assessment as part of rehabilitation. The Montreal Cognitive Assessment (MoCA) is widely used for this purpose but has several limitations, including a disregard for physical disability, the need for trained staff and a lack of an integrated mood assessment. CognoStroke, a component of the CognoSpeak digital assessment platform, was developed to address these limitations. It replicates the cognitive domains assessed by the MoCA, while incorporating mood screening using the GAD-7 and PHQ-9, removing the need for staff presence and accommodating individual patient needs. CognoStroke provides automated scoring and longitudinal performance tracking, via the use of artificial intelligence, supporting clinical decision-making and subsequently, aiding stroke rehabilitation.

METHODS:

Patients with confirmed strokes, TIAs, or stroke mimics were recruited from inpatient and outpatient settings (n=28). Following capacity assessment and consent, participants completed both CognoStroke and MoCA assessments, either in person or remotely, and provided feedback on usability and attitudes towards artificial intelligence.

RESULTS:

Preliminary findings indicate high user acceptability, with 96.3% of participants reporting that they liked or felt neutrally towards speaking to the digital agent. Signs of severe anxiety were detected in 7.1% of participants and signs of moderately severe depression were detected in 10.7% of participants, suggesting that CognoStroke may be a more feasible and holistic digital alternative for post-stroke cognitive assessment. Challenges remain regarding accessibility and technological literacy amongst stroke survivors, with only 33.3% of participants completing the CognoStroke assessment independently. However, ongoing system adaptations are aiming to enhance user autonomy and inclusivity.

CONCLUSION:

CognoStroke shows strong potential as a scalable and clinically meaningful digital cognitive assessment tool for stroke survivors, pending further validation to support clinical implementation.

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BACKGROUND:

There is a need for sensitive cognitive measures that can detect subtle cognitive decline in the preclinical stages of Alzheimer’s disease (AD). The ‘Insight 46’ study provides an opportunity to investigate longitudinal associations between biomarkers of preclinical AD and early cognitive decline in a British cohort of identical age (all born in the same week in 1946).

METHODS:

Participants were assessed at ages ~70, ~73, and ~77 years (max n=702). Cognitive tests included the Preclinical Alzheimer Cognitive Composite (PACC), 7-day ‘accelerated forgetting’, Addenbrookes Cognitive Exam (ACE-III), Digit Symbol Substitution test (enhanced at age 77 with smartpens to capture novel process metrics including “think time vs. ink time”), and (at age 77) unsupervised remote digital testing using the Cognitron platform. Biomarker measures included β-amyloid-PET, plasma phosphorylated tau-217 (p-tau-217) and brain MRI. Linear regression models were used to investigate associations between cognitive outcomes and biomarker predictors including amyloid status (positive/negative), p-tau-217 status (low/intermediate/positive) and rates of whole-brain and hippocampal atrophy between ages ~70-73 and ~70-77, adjusting for relevant covariates.

RESULTS:

Between ages 70-73, there was little cognitive change overall, but we observed practice effects on memory tests and age-related declines on speed measures. Among amyloid-positive participants, faster rates of whole-brain and hippocampal atrophy between ages 70-73 were associated with reduced practice effects on memory measures. By age 77, there was clear divergence in cognitive trajectories with poorer performance among those with elevated amyloid and ptau-217 on a range of measures including PACC, ACE-III and Cognitron ‘delayed visual memory’ accuracy and speed (effect sizes d≈0.30-0.55), and associations between rates of atrophy and cognitive decline. At age ~73 amyloid-positive participants showed accelerated forgetting after 7 days, but at age ~77 even their immediate recall was poorer. DSST “think time” was sensitive to rates of atrophy whereas the standard ‘total score’ was not, suggesting that neurodegeneration initially comprises strategic efficiency on this task.

CONCLUSION:

Subtle cognitive decline is detectable among clinically-normal adults with evidence of preclinical AD pathology in their 70s, particularly in the memory domain. Speed and process metrics hold promise for enhancing detection of early deficits.

BACKGROUND:

Timely access to memory assessment is essential for accurate diagnosis and early intervention. Local Dementia Strategy recommends a maximum Referral to Treatment Time (RTT) of 18 weeks. However, the audit revealed an average RTT of 46 weeks, with significant delays for paper referrals and indirect pathways alongside possible inequities.

METHODS:

Six-month retrospective audit of 80 patients at a Memory Assessment Clinic. Audit scope included new and follow-up patients seen during the study period. Inclusion criteria were all patients referred for assessment of possible dementia with both referral and first appointment dates recorded in the clinical record. Exclusions applied to cases with missing or incomplete date fields and patients registered for non-memory related assessments. Data obtained from electronic clinical portal covering – referral source, referral method, demographic characteristics and clinical diagnosis. Waiting times were calculated from recorded referral date to the first scheduled or attended appointment. Referral dates documented in clinical letters were cross checked against the official referral date recorded in the electronic portal to assess consistency. Analyses compared waiting times across demographic groups, referral pathways, and diagnostic categories to identify factors contributing to delays.

RESULTS:

Mean waiting time from referral to first appointment 46 weeks, exceeding the 18-week target.Paper referrals showed delays of up to 300 days between receipt and electronic entry to the patient tracker list, whereas electronic referrals were promptly recorded.GP referrals routed via Neurology had the longest waits (>300 days). Males waited on average 79 days longer than females. Only 25% of patients were from Black, Asian and Minority Ethnic backgrounds despite comprising 52% of the local population. Asian and Black patients experienced longer waits. Interpreter provision was inconsistent, with family members used in all non-English-speaking cases. Shortest waiting times observed in dementia subtypes characterised by distinctive presentations, such as Lewy body dementia and longest for diagnostically uncertain cases.

CONCLUSION:

Delays in memory assessment are not just clinical inefficiencies, they are equity issues. Addressing them requires systemic change, digital transformation, and culturally competent care. Implementing the proposed recommendations will support earlier diagnosis, better care planning, reduce inequalities and improved outcomes.

BACKGROUND:

Repeat expansions in C9orf72 represent the most common genetic cause of frontotemporal dementia (FTD). Emerging evidence from genetic FTD cohort studies suggest subtle psychiatric and cognitive features may emerge in the presymptomatic stage, accompanied by structural and functional brain changes. Such findings raise the possibility of early, potentially neurodevelopmental alterations in C9orf72-associated FTD. However, few studies have systematically examined cognitive phenotypes in young adult presymptomatic carriers.

METHODS:

Cross-sectional data were available from 541 presymptomatic participants in the Genetic Frontotemporal dementia Initiative (GENFI) cohort who underwent comprehensive neuropsychology and clinical assessment. Presymptomatic C9orf72 expansion carriers (with a CDR® plus NACC FTLD-NM global score <0.5, N=284) were compared to mutation-negative controls (N=257). Linear regression models with bootstrapping, adjusting for education and sex, examined group differences on cognitive tasks across age deciles (“20s”, “30s”, “40s”, or “50s+”).

RESULTS:

Cognitive differences between C9orf72 carriers and non-carriers were evident in the 30s, in tasks assessing processing speed (Trail Making Test A: b=4.76, p=.001), and executive function (Trail Making Test B: b=11.35, p=.00; Stroop Ink Naming: b=6.45, p=.001; Digit Symbol: b=4.71, p=.009). By the 40s, additional group differences emerged in social cognition (Ekman Faces: b=1.14, p=.020) and episodic memory (FCSRT Delayed Free: b=1.21, p=.013), extending to broader semantic and executive domains by the 50s (Verbal Fluency Animals b=2.15 p=.015; Boston Naming Test b=1.17 p=.002; Camel and Cactus b=0.76 p=.008).

CONCLUSION:

Presymptomatic C9orf72 expansion carriers exhibit measurable cognitive differences compared to familial non-carriers as early as the third decade of life, greatly preceding expected age of symptom onset. These findings suggest that disease-related processes manifest earlier than anticipated and may represent a neurodevelopmental phenotype. Ongoing work will incorporate neuroimaging and longitudinal follow-up to delineate trajectories of cognitive and structural change.

BACKGROUND:

The experience of interpersonal space may be altered in Alzheimer’s disease (AD) due to atrophy in brain systems that support emotion and reward processing.

METHODS:

Seventy participants (AD=36, healthy controls=34) underwent structural neuroimaging and completed a modified stop-distance paradigm, an established interpersonal distance task, in which they indicated at which distance they preferred to have a conversation with the experimenter. After estimating the distance between themselves and the experimenter, participants rated their emotional experience. Feelings of physical closeness were calculated as the discrepancy between the perceived and actual distance between the participant and experimenter. Participants also estimated their distance from the wall, which served as a non-social control task.

RESULTS:

Unlike the healthy controls, the participants with AD felt physically closer to the experimenter than they were (despite no differences in objective interpersonal distance) and reported greater positive emotional experience. Voxel-based morphometry analyses revealed greater feelings of physical closeness related to smaller gray matter volume in the right ventral striatum and right medial orbitofrontal cortex (pFWE<.05).

CONCLUSION:

These results suggest that reward system atrophy influences how people with AD experience interpersonal space. Individuals with AD may feel physically closer to others than they are and find social proximity more enjoyable than healthy controls

BACKGROUND:

Proper name anomia is a common experience that can become unpleasantly amplified in people with dementia (PWD). The Gotcha! app aims to provide practice-based therapy for PWD enabling them to spontaneously retrieve the names of key people in their lives.

METHODS:

Gotcha! is a digital confrontation naming therapy app. PWD supply images and names of the people they want to be able to name and train on one face per day for six weeks. We employed a single-case experimental design with weekly testing of free-naming in both six-week blocks (pre therapy and during therapy). A novel speech verifier was used to provide real-time feedback (Barbera et al. 2020). PWD also had an MEG scan before and after the therapy block where they attempt to name pictures of familiar (trained) and famous (untrained) faces. We interrogated the behavioural data in two ways: 1) a within-subject non-parametric analysis using Tau-U metric (Parker et al. 2011); 2) a parametric group analysis using an ANOVA. MEG data were analysed in SPM. We measured source localised gamma-band (30-80 Hz) power 0-3400 ms after the onset of a face. We ran a group-based 2×2 factorial analysis on the resultant images (familiar vs. famous; pre- vs. post-therapy) using a repeated-measures ANOVA to look for changes in power.

RESULTS:

Results from the first 38 PWD to complete the trial demonstrate: 1) Within-subjects, non-parametric results 89% (34/38) showed a positive trend with better naming during the training phase with 20/38 reaching statistical significance at the individual subject level (Tau-U) 2) ANOVA showed a significant effect at the group level of training F(1,32) = 44.79, p = 0.01 We identified a large cluster of 2876 voxels situated in the left anterior temporal lobe (MNI: -54 10 -6, F=8.37, p=0.001) where gamma reduction was associated with training (pre-post) of familiar faces, but not (untrained) famous faces.

CONCLUSION:

Gotcha! app-based therapy for proper name anomia works for the majority of PWD in our trial thus far.Being able to freely produce the name of a relative or loved one has a big impact on people’s lives.

BACKGROUND:

Alzheimer’s disease (AD) is a proteinopathy characterized by amyloid-β (Aβ) deposition and hyperphosphorylated tau aggregation, leading to amyloid plaques and neurofibrillary tangles. Dysregulation of the ubiquitin-proteasome system has been implicated in these processes. Ubiquitin C-terminal hydrolase L5 (UCHL5), a deubiquitinase that regulates proteasomal activity, plays a key role in the degradation of damaged proteins. However, its involvement in AD progression remains poorly understood. This study investigated associations between cerebrospinal fluid (CSF) UCHL5 levels and AD biomarkers across Aβ status and clinical diagnostic groups.

METHODS:

We compared CSF UCHL5 levels between 168 cognitively unimpaired (CU) and 540 cognitively impaired (CI) individuals (Table.1A), using ANCOVA adjusted for age and sex. To assess relationships with Aβ pathology, 460 individuals with CSF and PET measures were stratified into four Aβ status groups (190 A−A−, 12 A+A−, 44 A−A+, 214 A+A+; Table.1B), and ANCOVA was applied across them. The first “A” denotes tau ratio status and the second to Aβ-PET. Associations between UCHL5 and AD biomarkers (CSF Aβ42, p-tau181, hippocampal volume, AV45 and FDG) were assessed using generalized linear mixed models adjusted for age and sex. Voxel-wise analyses explored relationships with FDG- and Aβ-PET signals according to clinical diagnosis.

RESULTS:

CSF UCHL5 levels were higher in CU compared to CI individuals (Fig.1A). A−A− participants showed elevated UCHL5, with significant differences versus A+A+ and between A−A+ and A+A+ groups (Fig.1B). In CU and A−A− groups, UCHL5 was positively associated with p-tau181 (Figs.2A/H). Conversely, in CI and A+A+ individuals, UCHL5 correlated positively with CSF Aβ42 and hippocampal volume (Figs.2B/I/C/J). In CI individuals, UCHL5 was negatively associated with AV45 SUVRs reflecting Aβ burden in occipital, temporal, parietal, and frontal cortices (Figs.2D/E), while positive correlations were observed with FDG SUVRs, in prefrontal, temporal and parietal regions, as supported by voxel-wise FDG-PET analyses (Figs.2G/F).

CONCLUSION:

A consistent pattern in CSF UCHL5 levels was observed across amyloid-β status and clinical diagnosis, with higher levels in A−A− and cognitively unimpaired individuals. These findings suggest potential differences in UCHL5 across disease stages and Aβ profiles. Analyses are warranted to elucidate the underlying mechanisms and clarify the role of UCHL5 in AD pathology.

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BACKGROUND:

Whilst recent work has shown the potential of cerebrospinal fluid (CSF) biomarkers for frontotemporal dementia (FTD), less invasive plasma biomarkers are limited. We investigated plasma-derived extracellular vesicles (EVs) and analysed the synaptic protein neuronal pentraxin 1 (NPTX1). Previous work from our group identified mutation-associated NPTX1 changes in CSF from symptomatic genetic FTD carriers compared to non-carriers. The ability to measure peripheral NPTX1 changes in EVs, reflecting brain pathophysiology, offers potential for minimally invasive FTD fluid biomarkers.

METHODS:

We first developed a protocol to isolate EVs from human plasma via size exclusion chromatography, validating EV enrichment by western blot (CD9, flotillin-1, ApoB), and EV size and count by nanoparticle tracking analysis (NTA). Using a commercially available mesoscale discovery (MSD) platform kit, we then quantified the levels of NPTX1 in paired plasma and EV samples from a pilot cohort of 30 FTD mutation carriers (GRN, MAPT, C9orf72) and age- and sex-matched non-carrier controls from the GENetic FTD Initiative.

RESULTS:

Preliminary investigation first confirmed reliable detection of NPTX1 in plasma-derived EVs, and suggested it is contained within EVs. Analysis of plasma-derived EVs in the pilot cohort found no significant differences in EV size (p=0.197) or NPTX1/particle (p=0.339) between FTD mutation carriers and controls, or between specific mutation carrier groups (p=0.719, 0.727 respectively). Plasma NPTX1 similarly showed no group differences (carriers vs. non-carriers p=0.998, between mutation carrier groups p=0.806), but was significantly higher than paired EV NPTX1/particle for all individuals (p<2.2e-16).

CONCLUSION:

Our findings support the feasibility of measuring synaptic proteins in plasma-derived EVs and highlight their potential for minimally invasive biomarkers in genetic FTD with the appropriate lysis conditions. Our next steps will be to refine our approach to target brain-derived EVs from plasma, and further investigate FTD mutation-associated differences in a larger cohort. This work may offer new insight into early synaptic changes and aid in future biomarker development.

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BACKGROUND:

Family members and caregivers play a vital role in the dementia diagnostic pathway, often being the first to notice subtle changes and later providing essential information through informant reports. These accounts capture everyday cognitive, behavioural, and functional changes that may not be apparent during clinical assessment. Despite their value, such reports are often inconsistently collected and underutilised due to limited appointment time and variability in clinician interpretation. Advances in Large Language Models (LLMs) offer new opportunities to automate and standardise the analysis of this information. This study investigates whether caregiver-provided information (known as a collateral history) can be automatically analysed using an LLM to support dementia diagnosis.

METHODS:

Forty structured interviews will be conducted with family members and caregivers of individuals with Mild Cognitive Impairment (MCI) or dementia. Interviews will capture observations and insights into early cognitive, behavioural, and functional changes. Transcripts will be anonymised and analysed by two expert raters (a consultant neurologist and an old age psychiatrist) to assess inter-rater reliability, followed by analysis using an LLM (LLaMA 3.2-3B Instruct). The model will be evaluated on its ability to: (1) identify evidence of cognitive impairment, (2) describe domain-specific deficits, (3) suggest differential diagnoses, and (4) detect signs of caregiver stress. LLM outputs will be compared with clinician analyses to assess concordance and thematic accuracy.

RESULTS:

Data collection and analysis are ongoing. Early pilot work has focused on refining the interview structure, optimising LLM prompts, and ensuring clinical relevance in model outputs. Preliminary findings suggest the LLM can extract structured, clinically meaningful information from caregiver data.

CONCLUSION:

This study will assess whether LLMs can reliably interpret caregiver-reported observations to support earlier and more consistent dementia diagnosis. Integrating AI into diagnostic workflows could enhance efficiency, reduce clinician workload, and improve access to timely, remote assessments.

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INTRODUCTION:

Sexism is prevalent in academia and is a crucial factor driving women out of the academic workforce. However, sexism in dementia research remains  underexplored. This study aimed to understand the perceptions and experiences of early-career dementia researchers (ECDRs) with sexism in the field.

METHODS:

In September/October 2021, a global online survey was conducted targeting ECDRs. The survey assessed their career experiences, including sexism, and was distributed through networks, social media, and e-mail lists. Responses were analyzed using descriptive and inferential statistics.

RESULTS:

Of the 345 respondents, more than half of the female ECDRs (52%) reported facing sexism in their careers, ranging from overt discrimination to subtle biases. Experiences varied by career stage and location, and many ECDRs reported a lack of institutional support.

DISCUSSION:

These findings reveal the prevalent nature of sexism in dementia research and highlight the need for targeted interventions to foster a more inclusive research environment.

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