bluuebunny/crossref_metadata_2025 huggingface dataset:
Cross‐cultural adaptation, validity and reliability of the Everyday Cognition Scale in Mexico M‐ECog in Older Adults with Subjective Cognitive Decline, Mild Cognitive Impairment and Alzheimer’s Dementia
Authors: Mimenza Alberto , Pillajo Brenda , Gutiérrez Lidia Antonia , Trejo Natalia Arias , Aguilar‐Navarro Sara Gloria
Published: December 2023

Background

The Everyday Cognition (ECog) scale was created to assess the functional abilities of older adults across a wide range of abilities between normal aging and dementia. The original ECog was shown to have convergent and divergent external validity. Developed in 2008 by Farias et al and updated in 2021. This scale screens early cognitive alterations such as Subjective Cognitive Decline (SCD), Mild Cognitive Impairment (MCI) and Alzheimer’s dementia (AD) through the decline of basic activities and instruments of daily life (DLA)To establish validity, reliability, and cross‐cultural adaptation of the ECog in Spanish (M‐ECog) to identify: SCD, MCI, and Alzheimer’s‐type dementia in older Mexican adults.

Method

200 patients and 200 informants in a memory clinic of a third level hospital in Mexico City. Four groups were formed: 50 cognitively healthy (CH), 50 SQD, 50 MCI and 50 AD. The clinical evaluation included: sociodemographic aspects, cognitive status by the Mini‐Mental State Evaluation (MMSE) and Montreal Cognitive Evaluation Spanish version (MoCA‐E). The informants rated the functional status measured through the KATZ and Lawton & Brody scales, as well as the ECog Spanish version (M‐ECog).

Result

The internal consistency of the overall function of the M‐ECog (Cronbach’s alpha) was 0.881. The intraclass correlation coefficient was 0.877 (95% CI, 0.850‐0.902; p<0.001). M‐ECog was significantly correlated with DLA 0.40 (95% CI, 0.320‐0.471; p<0.001), MMSE 0.68; (95% CI, 0.650‐0.710; p<0.001) and MoCA‐E 0.70 (95% CI, 0.620‐0.892; p<0.001). And it differentiated patients with SCD, MCI and AD from CH (p < 0.002). The area under the curve (AUC) for SQD was 0.70 (95% CI, 0.58‐0.82), p < 0.005 with a cut‐off value of 46 points, (Sensitivity (S) 99%, and Specificity (E) of 96%; the AUC for MCI was 0.94 (95% CI, 0.89‐0.99), p < 0.001 with a cut‐off point of 52 points, (S: 97%, E: 27%); and for the dementia group, the AUC was 0.86 (95% CI, 0.79‐0.92), p <0.001 with a cut‐off value of 85 points, with (S: 97%, E: 51%).

Conclusion

M‐ECog is a valid, reliable, useful instrument that measures daily skills mediated by cognition in older Mexican adults, self‐applicable (patients and informants) with SCD, MCI and Alzheimer’s Dementia
Re‐calibration and performance of a proteomic prognostic test for 5‐year dementia risk
Authors: Paterson Clare , Loupy Kelsey , Biegel Hannah , Hagar Yolanda , Ostroff Rachel , Sampson Laura , Bogren Lori K , Williams Stephen A
Published: December 2023

Background

Proteomics‐driven health and wellness tests can provide personalized insight into individual risk for disease that is sensitive to change across time. The SomaSignalTM Mid‐Life Dementia Risk Test is a blood‐based, protein‐only prognostic model developed using SomaScan® Assay v4.0 (measuring ∼5,000 proteins) combined with machine learning methods to predict 20‐year risk for dementia in individuals aged 49 years and older. However, shorter term risk stratification for dementia may better enable early detection of emerging changes in cognition, enrich clinical trial enrollment for novel interventions, and eventually improve precision medicine prescribing of therapeutics. Thus, the 20‐year dementia risk test was re‐calibrated to maximize performance of 5‐year prediction in an older population.

Method

The 25‐protein Mid‐Life Dementia Risk model was re‐calibrated to predict 5‐year risk for a dementia diagnosis in adults aged 65 and older. We utilized plasma samples from ARIC visit 5 (n = 4985; median age 75 years) for the re‐calibration, which included a total of 391 total incident dementia diagnoses occurring within 5 years of blood draw. Re‐calibrated models were assessed in a training dataset consisting of 70% of the ARIC visit 5 data to identify the optimal 5‐year risk model. The final model was tested for robustness in a 15% holdout sample and validated independently in the remaining 15% samples.

Result

The AUC of the re‐calibrated 5‐Year Dementia Risk model was equal to 0.778, 0.735, and 0.776, in training, verification, and validation datasets, respectively. Individuals were stratified by relative risk into Low‐, Medium‐Low‐, Medium‐High‐, and High‐risk bins, with a 5‐year dementia diagnosis rate of 1.510% in the Low‐risk bin vs 20.337% in the High‐risk bin. The performance of the proteomic model was superior to that of APOE genotype or age in predicting 5‐year dementia risk as evaluated by AUC and dynamic range.

Conclusion

The 20‐Year Dementia Risk Test was successfully re‐calibrated to predict 5‐year dementia risk in individuals aged 65 years and older with more than a 13‐fold dynamic range for risk stratification. The proteomics‐based 5‐Year Dementia Risk Test outperforms leading risk factors for dementia, including APOE genotype and age.
Constrained Decoupled Dictionary Learning of Task fMRI data
Authors: Pillai Sreekrishna R. , Carmichael Owen T. , Bazzano Lydia
Published: December 2023

Background

Dictionary learning techniques have the potential to efficiently detect functional connectivity impairments in distributed brain networks associated with Alzheimer’s Disease (AD) when applied to task functional magnetic resonance imaging (tfMRI) data. However, traditional methods are constrained in what brain networks they can identify due to the statistical independence assumptions they make, and they do not leverage the structure of the tfMRI task when identifying networks. We used a new sparse dictionary learning technique to identify brain functional network correlates of cardiometabolic risk variables in a community‐based cohort.

Method

The Bogalusa Heart Study (BHS) is community‐based cohort study of atherosclerosis and risk factors for cardiovascular disease. fMRI data was collected from 100 participants of BHS during performance of a Stroop task. Spatially concatenated tfMRI data was factorized into a group‐wise temporal dictionary matrix and a set of scan‐level spatial patterns while biasing a subset of learned temporal patterns to be paradigm related. Scan‐level spatial patterns obtained as a result were aggregated and factorized to derive a group‐level spatial dictionary matrix and sparse loading coefficients. The sparse loading coefficients obtained from this Constrained Decoupled Dictionary Learning (CDDL) method were used as descriptive biomarkers, the relevance of which was established by using them to predict cardiometabolic variables including fasting glucose level, homeostatic model assessment for insulin resistance (HOMA‐IR) index and fasting insulin level using support vector regression and a leave‐one out cross‐validation. The performance of the algorithm was calculated in terms of Mean Absolute Percentage Error (MAPE) between actual and predicted cardiometabolic variable values

Result

The SVM regressor was able to predict the cardiometabolic variables with low MAPE. The prediction of glucose values achieved the least MAPE for all kernel types (Table 1).

Conclusion

Combining prior knowledge, decoupling of spatial and temporal patterns, and high‐dimensional regression, we generated brain functional network patterns from real‐world tfMRI data that associated with known cardiometabolic indicators of brain health. These brain functional network patterns thus have the potential to serve as indicators of brain health.
Alzheimer’s Disease Biomarkers: Roles of Type 2 Diabetes from the HABS‐HD Study
Authors: Yu Fang , Pituch Keenan A , Maxfield Molly , Basena Elsa , Geda Yonas E. , Pruzin Jeremy J. , Coon David W. , Shaibi Gabriel Q ,   Health and Aging Brain Study: Health Disparities (HABS‐HD) Study Team
Published: December 2023

Background

Alzheimer’s disease (AD) disproportionately affects Mexican Americans, however, reasons underlying this health disparity remain unknown. Type 2 diabetes (T2D) is a risk factor for AD and may contribute to AD pathogenesis. The purpose of this study was to examine the associations between T2D and AD blood biomarkers among Mexican Americans and non‐Hispanic Whites.

Methods

This study analyzed baseline data from the Health and Aging Brain Study: Health Disparities (HABS‐HD) that investigated AD differences among Mexican Americans and non‐Hispanic White. HABS‐AD participants were excluded from this study if they had missing data or were outliers (z‐scores >|4|) on a given AD biomarker (N = 1,552 for Aβ42/40 ratio, 1,570 for t‐tau, and 1,553 for NfL). AD biomarkers included plasma Aβ42/42 ratio, total tau (t‐tau), and neurofilament light (NfL) analyzed using Simoa. Predictors were blood glucose, HbA1c, and T2D diagnosis. Data were analyzed with regression analyses controlling for covariates (e.g., demographics, smoking, BMI, health status, diseases, cognition) and treating missing predictor data using Bayesian MCMC estimation.

Results

Mexican Americans differed significantly from non‐Hispanic Whites in age (66.6±8.7 vs. 69.5±8.6), sex (64.9% female vs. 55.1%), education (9.5±4.6 vs. 15.6±2.5), blood glucose (113.5±36.6 vs. 99.2±17.0), HbA1c (6.33±1.4 vs. 5.51±0.6), T2D diagnosis (35.3% vs. 11.1%), Aβ42/40 ratio (.051±.012 vs. .047±.011), t‐tau (2.56±.95 vs. 2.33±.90), and NfL (16.3±9.5 vs. 20.3±10.3). The models with the covariates and predictors accounted for 6% (p<.001), 15% (p<.001), and 36% (p<.001) of the variation in Aβ42/40 ratio, t‐tau, and NfL, respectively. Blood glucose, HbA1c, and T2D diagnosis were not related to Aβ42/40 ratio and t‐tau but explained 3.7% of the variation in NfL (p<.001). Among non‐Hispanic Whites, blood glucose, HbA1c, and T2D diagnosis were negatively (b = ‐0.09, p<.01, β = ‐0.26), not (b = 0.34, p = .71, β = 0.04), and positively (b = 3.32, p<.01, β = 0.33) associated with NfL, respectively. In contrast, blood glucose and T2D diagnosis were not, while HbA1c was positively (b = 2.31, p<.001, β = 0.26), associated with NfL among Mexican Americans.

Conclusion

Blood glucose, HbA1c, and T2D may contribute to differences in NfL levels, but not Aβ42/40 ratio and t‐tau, in an ethnicity‐specific manner. Future studies are needed to corroborate our findings in longitudinal cohorts.
Investigating the role of Donepezil in promoting Oligodendrocyte precursor cell (OPC) differentiation and Therapeutic Potential in Alzheimer’s Disease (AD)
Authors: Ismail Youssef Ahmed , Walid Mohammad
Published: December 2023

Background

Statistical analysis of myelin basic protein (MBP) cells generated from Neural progenitor cell (NPC)‐derived Oligodendrocyte precursor cells (OPCs) treated with various AChEIs, including donepezil, huperzine A, rivastigmine and tacrine, revealed that only donepezil is capable of facilitating OPC‐to‐OL formation, indicating that donepezil’s effect in promoting OPC differentiation is not dependent on the inhibition of AChE. So, it can be possible that OPC‐to‐OL formation is why donepezil is considered leading in Alzheimer’s disease (AD) treatment.

Method

Trial will include transgenic rat line Tg6590 that expresses human APP with the Swedish mutation driven by the ubiquitin promoter that doesn’t develop extracellular beta‐amyloid pathology before 15 months at least. Controlling their genome influence, the cognitive characteristics of mice can be related to neurobiological characteristics only. Excluding a standard (S), group of control animals was subjected to a CPZ‐free diet; rat (+MBP) will be injected with OPCs, and rat (‐MBP) will be supplemented with 0.6% cuprizone (CPZ) for 2 weeks, which facilitates demyelination. This study enables us to observe the myelination effect on its behavioral impairment (n = 3). Luxol fast blue (LFB) test or MBP tracking will be held monthly to observe OPCs‐to‐OL process. It was reported that Tg6590 rats display learning and memory deficits in the Morris water maze at the age of 9 months and altered spontaneous behavior measured in open‐field. So, with continuous behavioral observations, by procedure for a redundant place/cued version of Morris water maze task, memory‐learning assessment (MLA) will depend upon duration it takes to observe obvious behavioral impairment.

Result

This clinical trial is now under process and it is set to start by late 2024.

Conclusion

OPCs implantation may lead to axonal adaptation to physical stress with less beta‐amyloid and may also maintain the myelination density in CNS, especially in hippocampal‐neocortical neural connections, which can be therapeutically efficient for memory‐learning deficits.
Contributors to sleep disturbances in caregivers and care recipients with dementia
Authors: Manning Carol A , Youngkin Anna E , Quigg Mark S
Published: December 2023

Background

Sleep disturbances in Alzheimer’s disease impact people with dementia (PWD) and caregivers (CGS) who have primary responsibility for care provision. However, it is unknown which aspects of dementia including cognitive decline and behavioral disturbance contribute most to sleep disturbances in patients and caregivers. This pilot study aims to discover what contributes most to sleep deficits, and whether these factors are consistent across both PWD and CGS.

Method

Patients: Six dyads with PWD and their primary CGS. Cognitive/behavioral variables: the Montreal Cognitive Assessment (MoCA) (PWD) and the Neuropsychiatric Inventory Questionnaire (NPI‐Q) completed by CGS. Polysomnography: recorded and scored for 1 night for each dyad member separately. Actigraphy: Wrist actigraphy recorded for 14 days in both members of the dyad divided into fixed rest (2200‐0600) and activity (0600‐2200) periods. Sleep variables: total sleep time (TST), sleep onset latency (SOL), nighttime activity as measured by actigraphy.

Result

Preliminary results indicate that severity of cognitive dysfunction measured by the MoCA correlates with sleep time (CG r = 0.6224, PWD r = 0.5421). However, presence of neuropsychiatric symptoms and caregiver distress as measured by the NPIQ correlate with sleep onset latency (CG r = 0.9432*, PWD r = 0.7819) and nighttime activity in both CGs and PWD (CG r = 0.8467, PWD r = 0.8708). * = p<0.05.

Conclusion

This pilot study of six PWD/CGS dyads examines the relationship between cognition, behavioral disturbance, CGS response to the behavioral disturbance, and sleep. This data indicates that sleep disturbances in PWD and their CGs cannot be explained exclusively by worsening cognitive function and likely have stronger dependence on the neuropsychiatric well‐being of the PWD and CGS emotional response. This dyadic model is unique in that it looks at the interdependence of the PWD/CGS dyad using both objective measures of sleep, cognition, and behavioral disturbance as well as subjective CGS stress. Data from additional dyads is currently being collected to increase the sample size along with the inclusion of additional variables in order to increase understanding of the relationship between PWD characteristics, caregiver burden and sleep disturbances.
Disordered ganglioside localization in the Alzheimer’s disease brain
Authors: Ollen‐Bittle Nikita , Jiang Hanyu Y , Pejhan Shervin , Pasternak Stephen H , Whitehead Shawn N
Published: December 2023

Background

Alzheimer’s disease (AD) is a progressive dementia that impairs memory and cognition. Gangliosides are glycosphingolipids enriched within the central nervous system and known to alter the secondary structure of amyloid beta deposits, a hallmark of AD (Choo‐Smith et al., 1997). The ganglioside GM1 is known to exert neuroprotective properties and was proposed as a therapeutic for AD (Svennerholm, 1994). In support of this, intraventricular administration of GM1 decreased amyloid beta deposits and provided clinical benefit (Augustinsson et al., 1997). Pre‐clinical work has since demonstrated a shift from complex GM1 species to simple GM2 and GM3 is linked to neurodegenerative pathogenesis (Wang & Whitehead, 2020). However, the ganglioside GM1 also converts amyloid beta to a toxic form with beta sheet structure (Yamamoto et al., 2007), and acts as a seed for amyloid beta fibrillogenesis (Yanagisawa et al., 1995). It is possible that different GM1 subtypes may be responsible for varying affects. Understanding the profile of GM1 subtypes in the AD brain may be a key step in capitalizing on its therapeutic potential. We investigate the ratio between 18 and 20 carbon subtypes of GM1 and simple ganglioside species in post‐mortem human AD brain tissue and non‐AD controls. Brain regions interrogated include the entorhinal cortex, basal forebrain, anterior commissure and hippocampus.

Method

Neuroanatomical regions of interest (ROIs) were blocked from neuropathologically confirmed AD and non‐AD brains and stored in 10% formalin. Samples were prepared for matrix assisted laser desorption ionization imagining mass spectrometry (MALDI‐IMS) (Caughlin et al., 2017). MALDI‐IMS was performed in reflectron negative mode. Matching ROIs in AD and non‐AD samples (n = 5) were selected using TissueView software. Mass spectra were normalized by area under curve and peaks corresponding to gangliosides were statistically analyzed.

Result

Non‐AD brains demonstrated distinct d20:1/d18:1 ratios of both simple and complex gangliosides between different brain regions. This expression profile was lost in the AD brain samples. Additionally, a significant decrease in this ratio was observed in AD compared to non‐AD samples in several brain regions.

Conclusion

Ganglioside dysregulation and a decrease in the d20:1/d18:1 ratios in multiple brain regions are critical pathological biomarkers of AD.
Decline in everyday functioning in relation to cerebral tau burden across the clinical spectrum of Alzheimer’s disease
Authors: Dubbelman Mark A. , Mimmack Kayden J. , Sprague Emily H. , Amariglio Rebecca E. , Vannini Patrizia , Marshall Gad A
Published: December 2023

Background

Emerging difficulty performing cognitively complex everyday tasks, or ‘instrumental activities of daily living’ (IADL) may be an early clinical sign of Alzheimer’s disease (AD). We aimed to investigate how changes over time in everyday functioning relate to tau across the AD clinical spectrum.

Method

We included 581 participants (73.9±7.6 years old; 52% female) from the Alzheimer’s Disease Neuroimaging Initiative who underwent tau positron emission tomography (PET) and completed at least two assessments of the Functional Activities Questionnaire (FAQ). FAQ total scores range 0‐30, with higher scores representing more functional impairment. Participants were classified as cognitively normal (n = 334) or symptomatic (n = 247), having either mild cognitive impairment or AD dementia. Using mixed‐effects models, we analyzed the association between longitudinal FAQ scores and baseline tau in six temporal, parietal, and frontal brain regions. The main effect of interest was the interaction term of tau by time. We covaried for age, sex, and baseline performance on tests for memory, executive function and premorbid cognition, and corrected for multiple testing. Models were run in the entire sample, as well as stratified by diagnostic group (cognitively normal or symptomatic). Baseline amyloid PET was additionally available for a subset (n = 363), and we investigated interactions between amyloid and tau in this subset.

Result

Greater tau burden in several frontal, temporal, and parietal regions was associated with steeper decline over time in everyday functioning (Table 1, Figure 1). These findings remained when adjusting for baseline global cortical amyloid; amyloid itself was only associated with change over time in FAQ scores when tau was not included (unstandardized b = 1.18, 95%CI = [0.39,1.97], t = 2.94, p = .01). When stratifying by diagnostic group, these effects were present only in the symptomatic group.

Conclusion

The rate of change in everyday functioning is related to baseline tau burden in various brain regions, more strongly so than global cortical amyloid. This aligns with previous findings that cognitive function relates more closely to tau pathology. Change in everyday functioning was only observed on the FAQ in symptomatic individuals. Longitudinal studies in incident dementia populations are needed to better understand functional changes in response to AD pathology across the disease spectrum.
Proteome Analysis in Plasma and Brain Reveals a Novel Plasma Biomarker Linked to Antemortem Cognitive Impairment and Postmortem Neuropathological Traits for Alzheimer Disease
Authors: Goldstein Daniel , Aytan Nurgul , Palmisano Joseph N , Tripodis Yorghos , Turk Katherine W , O'Connor Maureen K. , Goldstein Lee E , Budson Andrew E , Qiu Wei Qiao , Kowall Neil W , McKee Ann C. , Mez Jesse B. , Alosco Michael L , Farrer Lindsay A. , Stein Thor D. , Jun Gyungah R ,   Boston University Alzheimer’s Disease Research Center
Published: December 2023

Background

Identification of blood‐based biomarkers that are indicative of Alzheimer’s disease (AD) pathology may help with early detection.

Methods

We generated proteome data for ∼7,000 proteins in both antemortem plasma and postmortem brain tissue from 103 participants of the Boston University Alzheimer’s Disease Research Center. All participants completed comprehensive neuropsychological evaluations and dementia severity was measured by global cognitive dementia rating (CDR) scores. A pathological AD diagnosis was established using NIA Reagan criteria. We conducted association tests with dementia (i.e., CDR ≥1 for dementia, CDR <1 for control) and autopsy‐confirmed AD status as binary outcomes. Plasma proteins significantly associated with clinical or pathological AD (P<0.05) were tested for association with quantitative cognitive tests and AD‐related neuropathological traits in which outcomes were rank‐transformed after adjusting for sex and either age at last antemortem exam or death.

Results

Of the 103 brain donors, 43 were diagnosed with dementia and 55 had autopsy‐confirmed AD. Five proteins (ACES, AURKB, CBARP, G45IP, and MMP‐8) measured in plasma were significantly associated with both pathological AD and dementia, while 252 plasma proteins were associated with either diagnosis (P<0.05). MMP‐8 was the only protein that was significantly associated in both plasma and brain with autopsy‐confirmed AD (Pplasma = 0.005, Pbrain = 0.001) and dementia (Pplasma = 0.01, Pbrain = 9×10−5). ACES and AURKB levels in plasma and brain were significantly associated with dementia (P<0.05). Levels of these. Increased MMP‐8 level in plasma was associated with decreased animals (P = 0.03) and scores (P = 0.04), which both assess verbal fluency. Dementia and pathologically confirmed AD were associated with lower AURKB and elevated ACES levels in plasma. Decreased plasma ACES level was associated with executive function (TrailsB: P = 0.01) and language (Boston Naming Test: P = 0.02) impairment, and the reduced plasma AURKB level was associated with memory impairment (Logical Memory Immediate Recall score: P = 0.03).

Conclusion

MMP‐8, a neutrophil collagenase and member of the matrix metalloproteinase family, is a potential blood‐based biomarker for dementia and underlying AD pathology and is associated predominantly with impaired verbal fluency.
Change on the Repeatable Battery for the Assessment of Neuropsychological Status and its relationship to brain amyloid
Authors: Duff Kevin , Dixon Ava , Embree Lindsay , Hoffman John M.
Published: December 2023

Background

The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) has been associated with commonly used biomarkers of Alzheimer’s disease (AD), including brain amyloid plaque density. However, less is known about if changes in the RBANS across time are also related to brain amyloid deposition. The current study sought to expand on prior work by examining the relationship between changes over time on the RBANS and amyloid deposition via positron emission tomography (PET).

Method

One‐hundred twenty‐six older adults with intact or impaired cognition and daily functioning underwent repeat assessment with the RBANS across nearly 16 months, as well as had a baseline amyloid PET scan.

Result

In the entire sample, amyloid deposition was significantly related to change on all five Indexes and the Total Scale score of the RBANS (rs = ‐0.28 – ‐0.61), with greater amyloid deposition being associated with worsening cognition. This pattern was also observed in 11 of 12 subtests. In the intact individuals, this pattern was only observed on change in the Immediate Memory Index (r = ‐0.32). In the subjects with MCI, this pattern was only observed on change in the Delayed Memory Index (r = ‐0.35). There was no association between change on the RBANS and brain amyloid deposition in those with AD.

Conclusion

Whereas prior studies have identified a relationship between baseline RBANS and amyloid status, the current findings support that changes in the RBANS are also indicative of AD brain pathology. Although replication in a more diverse sample is needed, these results continue to support the use of the RBANS in AD clinical trials.
Investigating the role of structural variants in Alzheimer’s Disease and AD‐Related traits
Authors: Vialle Ricardo A , Lopes Katia de Paiva , Tasaki Shinya , Schneider Julie A , De Jager Philip L , Bennett David A. A
Published: December 2023

Background

Although recent advances have led to a greater understanding of the genetics of Alzheimer’s Disease (AD), there remains a discrepancy between the predicted and observed genetic heritability estimates when using single nucleotide polymorphisms (SNPs) and small indel data. Large genomic rearrangements, known as structural variants (SVs), have the potential to account for this missing genetic heritability.

Method

Here, we investigate the role of SVs in AD and AD‐related dementias (ADRD) by leveraging data from two ongoing cohort studies of aging and dementia, the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP). We analyzed over 25,000 SVs discovered using whole genome sequencing (WGS) data of 1,106 participants and tested for association with multiple indices for AD/ADRD, including measurements of cognitive decline, amyloid beta, neuronal neurofibrillary tangles, TDP‐43, cerebral amyloid angiopathy, and resilience.

Result

Our findings revealed five associations reaching genome‐wide significance. These included a 106 bp insertion (chr21:17,134,448; MAF = 0.01), located in the intronic region of the gene USP25, associated with a higher TDP‐43 burden (P‐value = 1.83×10−6). An 82 bp insertion at chr19:45,444,699 (MAF = 0.25), previously mapped as eQTL for APOC1 and sQTL for APOC2 in brain tissues, was linked to greater cerebral amyloid angiopathy (P‐value = 1.02×10−6). An 820 bp deletion chr15:26,003,040 (MAF = 0.031) overlapping a CTCF site near ATP10A was associated with greater odds of Lewy Body disease (P‐value = 1.03×10−6). A 55 bp insertion (chr12:131,797,376; MAF = 0.21) in an intergenic region was found to be associated with reduced vascular disease burden (P‐value = 2.96×10−7); and a 53 bp insertion (chr4:99,901,557; MAF = 0.014) mapped as protein QTL for ADH5 was linked to lower cognitive resilience (P‐value = 8.51×10−7).

Conclusion

These findings provide evidence that common genetic variation, particularly SVs, can play a significant role in AD/ADRD traits. We are now investigating the functional impact of these SVs by integrating multi‐omics assays available from brain tissues of the same individuals. Our goal is to connect genetics to phenotype and gain a deeper understanding of the role of SVs in AD/ADRD.
Machine learning composite of remote cognitive tests for screening of preclinical AD cohorts
Authors: Liu Shu , Fedyashov Victor , Zisis Georgios , Masters Colin L , Maruff Paul , Goudey Benjamin
Published: December 2023

Background

Computerized cognitive tests are critical in the screening of preclinical Alzheimer’s Disease (AD) given their ability to be conducted remotely at low cost. Here, we explore whether machine‐learning derived composites of remote cognitive tests can improve sensitivity when detecting brain amyloid (Aβ) accumulation in cognitively normal (CN) cohorts than traditional pen‐and‐paper alternatives.

Method

Based on the CogState Brief Battery tests in CN individuals from the A4 dataset (n = 4230, Aβ‐ = 3094), we construct a data‐driven composite, denoted the Remote Empirical Cognitive composite for Alzheimer’s Disease (RECAD), designed to be sensitive to Aβ‐PET positivity. Specifically, the composite uses a random feature elimination logistic regression to identify a subset of predictive tests. We construct and evaluate the model using 10 repeat, 5‐fold cross‐validation in the A4 baseline data. We conduct temporal validation with the A4 second visit and external validation using CN participants from the ADNI (n = 389, Aβ‐ = 143), comparing against the pen‐and‐paper‐based PACC composite and previous computerized composites CBB and C3.

Result

RECAD includes three accuracy scores (Identification, One‐Back and One‐card) and one reaction time (Detection). In cross‐validation in the A4 baseline, RECAD show a significantly higher ability to discriminate Aβ status [mean Cohen’s d = 0.26] than PACC [mean d = 0.25, t‐test p<0.001] and computerized composites CBB [median d = 0.13, p<0.001] and C3 [mean d = 0.18, p<0.001]. RECAD significantly improves beyond C3 in the A4 second visit (z‐test p<0.001). Moreover, these trends are replicated in the ADNI at baseline (RECAD d = 0.215, PACC d = 0.061) and 24 months (RECAD d = 0.295, PACC d = ‐0.026) but the small sample and effect size limits our ability to demonstrate statistical significance.

Conclusion

RECAD, as a machine‐learning derived composite of remotely conducted cognitive tests, shows a comparable or better sensitivity to the established pen‐and‐paper composite test when screening for Aβ+ among CN cohorts. While effect sizes are small, conducting such remote tests repeatedly may be a useful pre‐screening for downstream biofluid evaluation.
Correlation between longitudinal changes of clinical symptoms and striatal DAT uptake in DLB
Authors: Shimizu Soichiro , Takenoshita Naoto , Yamamoto Ryo , Inagawa Yuta , Inagawa Shoya , Sato Tomohiko
Published: December 2023

Background

It is widely known that there is low striatal 123I‐FP‐CIT dopamine transporter single photon emission tomography (DaT‐SPECT) uptake in patients with dementia with Lewy bodies (DLB). There are no study about the association between longitudinal changes of clinical sign and DaT‐uptake in Parkinson syndrome, especially in DLB. The aim of this study is to investigate the association between the longitudinal changes of DaT uptake and severity of parkinsonism and cognitive funtion in DLB.

Method

A total of 35 outpatients with probable DLB who underwent DaT‐SPECT twice (initial and follow up period) from the Memory Disorder Clinic at the Department of Geriatric Medicine, Tokyo Medical University, were enrolled in this study from April 2014 until September 2020. We examined the correlation between annual changes of DaT uptake and symptoms (cognitive function decline, parkinsonism) in the patients with DLB.

Result

There was significant correlation between annual changes of severity of parkinsonism and DAT uptake in left posterior putamen (r = ‐0.39, p = 0.03), MMSE scores and DaT uptake in the entire regions except right posterior putamen (P< 0.05) in patients with DLB.

Conclusion

These results may suggest clarifying the mechanism of dysfunction of nigrostriatal projection pathway in DLB.
Leptin Bioavailability and Markers of Brain Aging and Vascular Damage in Middle Age. The Framingham Heart Study
Authors: Charisis Sokratis , Short Meghan I , Aslam Asra , Himali Jayandra Jung , Habes Mohamad , Shipp Eric L. , Beiser Alexa S. , Decarli Charles , Vasan Ramachandran S , Seshadri Sudha , Maillard Pauline , Satizabal Claudia L.
Published: December 2023

Background

Leptin perturbations have been associated with dementia and cognitive decline in older adults. However, given the long preclinical stages that characterize these disorders, previous findings might be confounded by reverse causality. To gain further insights into the potential role of leptin in neurodegeneration and vascular brain injury, we investigated the associations of leptin markers with cognitive function, and MRI markers of brain aging and vascular damage in cognitively‐healthy middle‐aged adults living in the community.

Method

The concentrations of leptin, soluble leptin receptor (sOB‐R), and their ratio (free leptin index [FLI]), indicating leptin bioavailability, were measured in 2,262 cognitively‐healthy participants (mean age 40.4, standard deviation [SD] = 8.6 years; 47.6% men) from the Third Generation Cohort of the Framingham Heart Study (Table 1), that had undergone neuropsychological evaluation; of these, 2,129 also underwent brain MRI. Cognitive function was assessed using the Wechsler Adult Intelligence Scale similarities test, Trail Making Test (TMT) part A, TMT part B, logical memory delayed task, and the Hooper Visual Organization Test. The MRI protocol included T1w, FLAIR, and DTI MRI sequences. Relationships of leptin markers with cognitive and MRI measures of interest were assessed using linear regression models. The false discovery rate (FDR) was used to account for multiple testing at p<0.05.

Result

Higher sOB‐R concentrations were associated with lower fractional anisotropy (FA, Beta = ‐0.11±0.02, p<0.0001), and higher free water (FW, Beta = 0.09±0.02, p<0.0001) and peak‐width skeletonized mean diffusivity (PSMD, Beta = 0.08±0.02, p<0.001), indicating an overall worse white matter (WM) microstructural integrity (Table 2). Similarly, higher FLI, reflecting an increase in leptin bioavailability, was associated with higher FA (Beta = 0.12±0.03, p<0.0001), and lower FW (Beta = ‐0.10±0.03, p = 0.001) and PSMD (Beta = ‐0.09 ±0.03, p = 0.002), indicating an overall better WM microstructural integrity. Relationships between leptin markers and cognitive measures or structural MRI markers were not significant after FDR correction (Table 3).

Conclusion

Higher leptin bioavailability was associated with better WM integrity in middle‐aged cognitively‐healthy adults. Considering that alterations in WM microstructure represent an early event in asymptomatic individuals who may later develop cognitive decline due to Alzheimer’s disease and/or vascular pathology, these findings support the putative role of leptin perturbations in late‐life dementia risk.
Altered Gut Microbiota in Dementia and Mild Cognitive Impairment in Community‐Dwelling Older Adults in Taiwan
Authors: Fang Chuang Yi‐
Published: December 2023

Background

The microbiota‐gut‐brain axis has been implicated in the pathogenesis of dementia. However, research about gut microbiota changes in cognitive impairment remains scarce, and results vary with methodological differences. This study examines biodiversity and the differential abundance of gut flora associated with cognitive impairment in a community‐based cohort of older adults.

Method

The study sample of 298 older adults was derived from a community‐based prospective cohort study, the Epidemiology of Mild Cognitive Impairment in Taiwan (EMCIT). Among them, 82 were ascertained as MCI or dementia. Fecal samples were analyzed by Illumina shotgun metagenomic sequencing. The Metagenomic Phylogenetic Analysis (MetaPhlAn2) pipeline was applied to generate a relative abundance of gut microbiota.

Result

Individuals with dementia or MCI were older (76.6 ± 7.2 years vs. 67.8 ± 6.6 years) and had less education (9.3 ± 4.5 years vs.12.0 ± 3.9 years). There is no significant difference in alpha‐diversity between MCI/dementia and cognitively normal adults after adjusting for age, gender, education, and BMI. However, the PERMANOVA test revealed significant differences in beta‐diversity. The results of linear discriminant analysis (LDA) effect size (LEfSe) showed a differential abundance of taxonomy between the two groups. Increased abundance of several species, including Bacteroides thetaiotaomicron and Ruminococcus torques, and reduced abundance of Prevotella, Eubacterium, and Bifidobacterium were associated with MCI/dementia (Figure 1).

Conclusion

The gut microbiota of older adults with MCI/dementia significantly altered in overall diversity and compositions. The mechanism of how altered gut microbiota contributes to the development of dementia needs to be further investigated.
Thymoquinone protects against lipopolysaccharides‐induced neurodegeneration and Alzheimer‐like model in mice.
Authors: Adeoluwa Olusegun Adebayo , Adeoluwa Gladys Onyinye , Akinluyi Elizabeth Toyin
Published: December 2023

Background

Chronic neuroinflammation has become a cornerstone in the study of neurodegeneration and Alzheimer’s diseases. Thymoquinone is a known anti‐inflammatory agent with a strong antioxidant activity. This study aimed at evaluating its mechanisms of neuroprotective effect against neurodegeneration, cognitive and synaptic dysfunctions in lipopolysaccharides‐induced Alzheimer‐like model in in mice.

Methods

Following one‐week acclimatization, thirty‐five Swiss mice were distributed randomly into five groups (n = 7). Group I received vehicle (10mL/kg, p.o.), Group II (LPS) received vehicle (10mL/kg), Group III received TQ (15mg/kg), Group IV received TQ (30mg/kg, p.o) and Group V received donepezil (5mg/kg, p.o.) for seven days. Starting from day 8, sixty‐minutes after treatment with vehicle or TQ or donepezil, animals in groups II‐IV were daily injected with LPS (0.5mg/kg, i.p.) consecutively for seven days. Twenty‐four hours after the treatment on day fourteen of the study, Novel Object Recognition, (NORT), Y‐maze, were used to assess cognitive functions. Tumor necrosis factor‐α (TNF‐α), interlukin‐1β (IL‐1β), acetylcholinesterase (AChE) were assessed using ELISA techniques, microglia, amyloid‐beta, choline acetyltransferase (ChaT), synaptophysin, were quantified using immunohistochemistry, while, gene expression of interlukin‐10 and β‐secretase were measured with quantitative Polymerase Chain Reaction. Cox Golgi staining procedure was performed to evaluate morphology of the pyramidal dendrites.

Results

LPS significantly impaired performance in the Y‐maze and NORT and induced behavioural abnormalities, compared to control. These were all ameliorated by treatment with TQ (15‐30mg/kg). The TQ also significantly (P<0.05) reduced the concentration of LPS‐induced TNF‐α, IL‐1β, AChE and expressions of amyloid‐beta, microglia and β‐secretase/mRNA in hippocampus and prefrontal cortex. The TQ increased IL‐10/mRNA, ChaT, synaptophysin in hippocampus and PFC. TQ significantly (P<0.05) prevented neurodegeneration of dendrite and neuronal cells in the hippocampus of LPS‐treated mice.

Conclusion

Our study shows that thymoquinone possesses neuroprotective effect against LPS‐induced neurodegeneration and cognitive impairment by suppressing chronic neuroinflammation, cholinergic disruption, depleted synaptic protein and Aβ accumulation.
Better living with non‐memory led dementia: results from a pilot randomised clinical trial of an online training programme for carers of people with PCA, PPA and bvFTD
Authors: Gonzalez Aida , John Amber , Brotherhood Emilie V , Camic Paul , McKee‐Jackson Roberta , Melville Mel , Sullivan Mary Pat , Tudor‐Edwards Rhiannon , Windle Gill , Crutch Sebastian J , Hoare Zoe , Stott Joshua , Impact Rare Dementia Support
Published: December 2023

Background

Dementias starting with symptoms other than memory are low prevalent. Educational and training resources for caregivers of people living with these conditions are scarce and difficult to access. The aim of this trial is to test the feasibility of an online training program for carers of people with three non‐memory led dementias: Posterior Cortical Atrophy (PCA), Primary Progressive Aphasia (PPA) and behavioural variant FTD (bvFTD). The trial design is a randomised feasibility study.

Method

Setting: Community. Participants were recruited from the organisation Rare Dementia Support (RDS). Participants: Carers of people with PCA, PPA and bvFTD

Intervention: The experimental group was given access to an eight‐week online program consisting of 6 digital manuals addressing practical strategies to better support people living with PCA, PPA or bvFTD (depending on diagnosis of the care recipient). The control group was directed to RDS’s existing website (TAU).

Outcome measures: Feasibility of recruitment, measurement tools (clinical outcomes, see Table 1) and acceptability. Measures were collected at baseline, immediate post intervention (8 weeks post‐randomisation) and 3 months post‐randomisation.

Randomization: Allocation ratio was 2:1 (intervention: control) stratified by diagnosis carried out by a central computer system. Participants were unblinded to intervention. All measures were self‐reported online by the participants.

Result

Numbers randomized: 31 participants were recruited. 30 participants were randomized (1/31 did not complete baseline) (21 to intervention, 9 to control group). Trial status: closed.

Numbers analysed: 30 participants for intention to treat analysis (3 dropped out).

Outcomes: Feasibility of recruitment (see Figure 1 Flowchart) is 40% (31 people consented/78 approached). Retention rate is 87%. The proportion of eligible participants who agree to participate is 97% (30/31).Assessment of feasibility of measurement tools (proposed clinical outcomes) shows 96% response rates at 8 weeks (29/30) and 90% (27/30) at 3 months. Acceptability: 100% of participants agreed to be randomised. Intervention coherence: 28% (6/21) participants interacted with facilitator during the intervention. Follow‐up qualitative interviews were conducted to gain a better understanding of how to improve intervention coherence.

Conclusion

The trialled intervention shows excellent feasibility of recruitment, retention and measurement tools. Enhancement of intervention coherence is required.
What matters in everyday life for people living with dementia: a qualitative inquiry
Authors: Huizenga Jacoba , Scheffelaar Aukelien , Bleijenberg Nienke , Wilken Jean Pierre , Van Regenmortel Martine R.F. , Keady John
Published: December 2023

Background

Research on what matters to people with dementia in their everyday lives is crucial to develop tailored interventions and programs. However, they are rarely asked. A scoping review of studies with the perspective of people with dementia revealed that no study has explicitly examined everyday life as a whole (Huizenga et al., 2022). A conceptualization of everyday life is lacking. This qualitative study uses the lens of everyday sociology, which focuses on the ordinary mundane aspects of life that are often unseen and unnoticed. The aim of this study was to explore how people with dementia experience their everyday lives and what matters to them. This will provide insight into the essential ingredients for support to ensure the quality of everyday life.

Method

Using a phenomenological approach, open interviews were conducted with 15 people with dementia living at home. The topic list compromised the following topics: experience of activities, relationships, places, the condition of dementia, and health and social care. Respondents participated in 1‐3 interviews. The interviews were supplemented with home tours (Pink, 2009) and walking interviews. The analysis was performed in Atlas.Ti using a descriptive content analysis. The analysis followed the phases of open, axial and selective coding. During the analysis, an advisory board of people living with dementia was consulted to ensure the content validity of the findings.

Result

Preliminary findings show that everyday life for people living with dementia is a continuing struggle to maintain balance in managing progressive disruptions. Helpful are meaningful activities, especially in meeting centers, feeling connected in relationships and a sense of feeling at home related to the house and the neighborhood. Everyday life is described as living in the present but is also influenced by life history. Furthermore, other conditions, such as financial problems and physical conditions hinder everyday life.

Conclusion

A preliminary conclusion is that this study gives insight in what matters to the daily life of people living with dementia at home. These insights help to gain a better understanding and better connect to needs.
Validation and comparisons of the Amnesia Light and Brief Assessment (ALBA), the door Picture Naming and Immediate Recall (PICNIR) and the Addenbrooke’s Cognitive Examination III (ACE‐III) for detecting cognitive impairment
Authors: Bartos Ales , Polanská Hana
Published: December 2023

Background

Two unique very brief tests are easily administered and cognitively demanding. The Amnesia Light and Brief Assessment (abbreviated from the initial letters as ALBA) lasting 3 minutes and the door PICture Naming and Immediate Recall (PICNIR) lasting 4 minutes were validated and compared with the seven times longer Addenbrooke’s Cognitive Examination III (ACE‐III) (20‐30 minutes).

Methods

The ALBA, PICNIR and ACE‐III were administered to 155 elderly individuals in 2 groups comprising 40 patients with neurocognitive disorders according to DSM‐5 criteria and 116 normal elderly adults. The ALBA was evaluated using the memory ALBA score (MAS). The PICNIR was assessed using numbers of naming errors (NE) and correctly recalled picture names (PICR).

Results

All the tests were significantly different between the two age‐ and education matched groups (ACE‐III: 73±11 vs. 96±4 points) and showed excellent accuracy as assessed by the area under the ROC Curve (AUC): 0.89 for MAS, 0.81 for NE, 0.96 for PICR and 0.98 for the ACE‐III. The AUCs of PICR and ACE‐III were comparable and larger than those of MAS and NE. The ACE‐III strongly correlated with MAS and PICR (0.8, R2 = 60% each) and NE (‐0.7, R2 = 48%) in the whole sample.

Conclusions

The innovative and efficient ALBA and PICNIR tests have high discriminant validity for cognitive impairment and high convergent validity with the ACE‐III. Moreover, they can reliably predict total ACE‐III scores. Brevity and simple administration and evaluation are major advantages of the ALBA and the PICNIR over much longer ACE‐III for busy clinical practice.

Supported by grant COOPERATIO Neuroscience, Charles University, GAUK 268321 a SVV 260599 and grant NU20‐07‐00100.