bluuebunny/crossref_metadata_2025 huggingface dataset:
Sex‐specific neuropsychiatric burden distinguished by APOE4 status and cortical thickness
Authors: Khoury Marc A , Valcic Mila , Churchill Nathan W , Fornazzari Luis R , Mortby Moyra E , Ismail Zahinoor , De Luca Vincenzo , Munoz David G. , Schweizer Tom A. , Fischer Corinne E.
Published: December 2023

Background

The APOE ε4 (APOE4) allele is a genetic risk factor for Alzheimer’s disease (AD). Prior work by our group found a significant association between the APOE4 allele and presence of psychosis as well as overall increased neuropsychiatric symptom (NPS) burden in female APOE4 homozygote AD patients, with no effect present in males. In this study, we sought to examine the relationship between APOE4 carrier status and sex on NPS burden from a neuroimaging perspective, with the aim to determine what brain regions may be driving this effect.

Method

A cohort of 752 AD patients were selected from the National Alzheimer’s Coordinating Center (NACC) database: 104 APOE4 homozygotes (40F|64M), 304 APOE4 heterozygotes (160F|144M) and 310 APOE4 non‐carriers (131F|179M). Presence of NPS was identified using the Neuropsychiatric Inventory (NPI). Structural T1‐weighted images were downloaded from the NACC imaging dataset and cortical thickness measures corresponding to frontal, cingulate, temporal and parietal regions were assessed. Statistical analysis included a Bayesian multilevel regression where cortical thickness was modeled as an outcome variable against an interaction between sex and APOE4 homozygote status (0|1), while controlling for heterozygote status, APOE4 non‐carrier status, age, sex and MMSE as predictor variables. Within‐ and between‐groups mean differences in thickness were measured as a probability density estimate (Highest Density interval), and partial correlation was used to examine NPI correlates to thickness.

Result

Female APOE4 homozygotes displayed a high probability (>90%HDI) of greater cortical thickness in the posterior cingulate and isthmus cingulate regions bilaterally and reduced cortical thickness in temporal regions (Figure 1). Cortical thickness in the fusiform cortex was positively correlated to greater NPI burden (p<0.05) among female homozygotes, and negatively correlated to NPI burden among female heterozygotes. Cortical thickness in males, regardless of carrier status, did not correlate to NPI burden in any region.

Conclusion

This study highlights an important relationship between the fusiform cortex and NPI burden in female APOE4 carriers, marking a female‐specific effect. Future work should further disentangle sex differences in APOE4 status and psychosis with a focus on the fusiform cortex as a potential region of interest.
The diagnostic and prognostic potential of plasma GFAP in older adults with subjective memory complaints at risk of Alzheimer’s disease
Authors: Chatterjee Pratishtha , Pedrini Steve , Doecke James D , Dore Vincent , Goozee Kathryn G , Taddei Kevin , Sohrabi Hamid R , Maruff Paul , Villemagne Victor L , Rowe Christopher C , Masters Colin L , Martins Ralph N
Published: December 2023

Background

The astrocyte cytoskeletal protein, Glial Fibrillary Acidic Protein (GFAP), is a potential blood‐based biomarker for diagnosis and prognosis of older adults in the Alzheimer’s Disease (AD) continuum, comprising cognitively unimpaired (CU) and cognitively impaired individuals with high brain amyloid‐beta load (Aβ+). However, specific attention to the potential of plasma GFAP in CU Aβ+ older adults with Subjective Memory Complaints (SMCs) is required, given that SMCs are a primary feature of Subjective Cognitive Decline (SCD) and individuals with SMCs are twice as likely to develop dementia compared to non‐memory complainers.

Method

Plasma GFAP was measured in older adults with SMCs from two independent cohorts, namely the Kerr Anglican Retirement Village Initiative in Ageing Health (KARVIAH; N = 76; 52 Aβ‐, 24 Aβ+) and the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL; N = 75; 50 Aβ‐, 25 Aβ+), using the Neurology‐4PlexA and Neurology‐4PlexE kits, respectively, on the Single Molecule Array (Simoa) platform (Quanterix). The Memory Assessment Clinic‐Q was used to assess participants with SMCs.

Result

Plasma GFAP was significantly elevated in Aβ+ SMCs compared with Aβ‐ SMCs in both cohorts before and after adjusting for age, sex and APOE ε4 carrier‐status (mean±SD in pg/mL; KARVIAH: Aβ‐ = 148±47, Aβ+ = 230±93, p<.0001; AIBL: Aβ‐ = 135±58, Aβ+ = 209±76, p<.0001). Plasma GFAP differentiated Aβ+ SMCs from Aβ‐ SMCs with an area under the receiver operating characteristic curve (AUC) of 80% (CI:68%‐92%) in KARVIAH and 77% (CI:66%‐89%) in AIBL. Based on the AUC, plasma GFAP performed equivalent to other putative plasma AD diagnostic markers such as plasma phosphorylated‐tau181 (p‐tau181) and plasma Aβ42/Aβ40 ratio but performed significantly better than plasma Neurofilament Light (NfL) in both cohorts (p<.05). A model comprising plasma GFAP, p‐tau181, Aβ42/Aβ40 ratio and the AD risk factors, age, sex and APOE ε4 carrier‐status significantly outperformed any of the biomarkers alone in differentiating brain Aβ‐/+ status in both cohorts (p<.05). Higher plasma GFAP in individuals with SMCs was associated with faster cognitive decline assessed by the Preclinical Alzheimer Cognitive Composite (PACC) score and with faster brain Aβ accumulation assessed by PET in AIBL.

Conclusion

These observations suggest that plasma GFAP has diagnostic and prognostic value for older adults at risk for AD.
Application of the mild behavioral impairment checklist in Chinese patients with the behavioral variant of frontotemporal dementia
Authors: Cui Yue , Liu Li , Chu Min , Xie Kexin , Chen Zhongyun , Wu Liyong
Published: December 2023

Background

The mild behavioral impairment checklist (MBI‐C) designed to capture neuropsychiatric symptoms in the whole spectrum of elder with or without dementia, have been verified in mild behavioral impairment, mild cognitive impairment and Alzheimer’s Disease, but never used in the behavioral variant of frontotemporal dementia (bvFTD).

Method

Fifty‐two patients with bvFTD (mild, n = 30; moderate‐severe, n = 22) and 82 community‐dwelling elderly individuals (HCs) were enrolled. All subjects were assessed with a full neuropsychological scale including the MBI‐C, Neuropsychiatric Inventory Questionnaire (NPI‐Q), and Frontal Behavioral Inventory (FBI). Receiver operating characteristic curves were drawn to analyze the sensitivity and specificity of the MBI‐C, NPI‐Q, and FBI, and cutoff points were determined using the Youden index.

Result

The MBI‐C and domain scores in all patients with bvFTD were significantly higher than those in HCs. The most common symptoms of bvFTD were apathy (82.7%) and impulse dyscontrol (80.8%). The MBI‐C score was positively correlated with the NPI‐Q, FBI, and Activities of Daily Living. For differentiating patients with both bvFTD and mild bvFTD from HCs, the optimal MBI‐C cutoff point was 5/6 with a sensitivity of 100% and specificity of 82%, and its sensitivity was higher than that of the NPI‐Q and FBI.

Conclusion

The MBI‐C is a sensitive tool for screening behavioral and psychological symptoms in patients with bvFTD, even in the early stages of the disease.
In vivo tau deposition in the brain stem nuclei and circadian rest‐activity rhythm change in non‐demented older adults
Authors: Jeon So Yeon , Yi Dahyun , Byun Min Soo , Jung Joon Hyung , Kong Nayeong , Chang Yoon Young , Keum Musung , Jung Gijung , Ahn Hyejin , Lee Jun‐Young , Lee Yun‐Sang , Kim Yu Kyeong , Kang Koung Mi , Sohn Chul‐Ho , Lee Dong Young ,   KBASE Research group
Published: December 2023

Background

Circadian rest‐activity rhythm (RAR) alterations are common in the early stage of Alzheimer’s disease (AD) disease. Given that the brainstem nuclei, the locus coeruleus (LC) and dorsal raphe nucleus (DRN) in particular, play key roles in modulating arousal and the sleep‐wake cycle, tau pathology in the brain stem nuclei, which occurs even before cortical tau progression, may relate to circadian RAR alteration in older individuals. Therefore, we aimed to test the hypothesis that in vivo tau deposition in the LC and DRN correlates with circadian RAR in non‐demented older adults.

Method

A total of 63 non‐demented older adults from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) were included. All participants underwent [11C] PiB PET and [18F] AV1451‐PET. Circadian RAR variables were measured using actigraphy for 8 consecutive days. Tau deposition of the LC and DRN (LC‐tau and DRN‐tau, respectively) was measured in the regions of interest (ROI) masks for each participant prepared in native space using the Harvard arousal network atlas for the LC and DRN. For the purpose of comparison, tau deposition in the substantia nigra (SN‐tau) was also measured in the neuromelanin sensitive MRI‐based ROI for the SN.

Result

Increased LC‐tau and DRN‐tau were significantly correlated with delayed acrophase (β = 0.303, p = 0.024 for LC‐tau and β = 0.398, p = 0.003 for DRN‐tau; Table 1 & Figure 1). In contrast, SN‐tau did not related with any RAR variables. Even after controlling for global tau deposition, the significance did not changed (β = 0.321, p = 0.021 for LC‐tau and β = 0.367, p = 0.008 for DRN‐tau, Table 1). In addition, Aβ positivity showed a significant moderation effect on the relationship between LC‐tau with acrophase. Subgroup analyses showed that increased LC‐tau significantly related with delayed acrophase in Aβ‐positivegroup (β = 0.427, p = 0.004), but did not in Aβ‐negative group (β = 0.099, p = 0.615)(Figure 2)

Conclusion

Our findings support the possibility that the tau pathology in the LC and DRN underlie circadian RAR alteration, more specifically delayed phase, in non‐demented older adults. In addition, such relationship appears to be more prominent in individuals with brain Aβ pathology.
The associations between handgrip strength asymmetry and future cognitive impairment in older adults
Authors: Chen Jen‐Hau
Published: December 2023

Background

The incidence and prevalence of dementia continue to increase exponentially as people age. Finding a pre‐clinical marker to detect dementia early is paramount in clinical practice. There are few prospective studies evaluating handgrip strength, handgrip strength asymmetry, and their combination on cognitive impairment. This study aimed to investigate the association of handgrip strength and handgrip strength asymmetry with future global and specific cognitive domain impairment.

Method

This is a seven‐year prospective cohort study (Fig 1). We used data from the ongoing Taiwan Initiative of Geriatric Epidemiological Research (TIGER), wave 3 (2015‐2017) to wave 5 (2019‐2022), with wave 3 as the baseline (n = 446). Low handgrip strength was defined as the lowest tertile of sex‐specific handgrip strength. Handgrip strength asymmetry was defined as a handgrip strength ratio <0.85 or >1.15 (i.e., a 15% difference). The cognitive assessment included global and specific cognitive domains. Generalized linear mixed models were used to assess the association of handgrip strength asymmetry and cognitive performance adjusted for age, years of education, cigarette smoking, alcohol drinking, hypertension, diabetes, hyperlipidemia, and physical activity.

Result

The mean age of participants was 75.7 years, and 55% were female. Participants with handgrip strength asymmetry were mostly female, never smokers, and more likely to have lower handgrip strength. Handgrip strength asymmetry was associated with poor global cognition [ = ‐2.14, 95% confidence interval (CI): ‐3.60, ‐0.68] and digit span‐forward ( = ‐0.69, 95% CI: ‐1.25 to ‐0.14) over time in men. Low handgrip strength was associated with cognitive impairment (global cognition: = ‐1.13, 95% CI: ‐2.07 to ‐0.19; immediate free recall: = ‐0.48, 95%CI: ‐0.87 to ‐0.09; delayed free recall: = ‐0.45, 95% CI: ‐0.85 to ‐0.08); Trail Making Test‐ A: = ‐0.43, 95% CI: ‐0.75 to ‐0.12), and digit span‐forward ( = ‐0.67 to 95% CI: ‐1.02 to ‐0.31) over time in men. Concomitant weakness and handgrip strength asymmetry had greater impairment in cognitive function in men.

Conclusion

In this community‐dwelling older population, those with low handgrip strength and handgrip strength asymmetry had an increased risk of cognitive impairment. This relationship seems more prominent in men than women.
Individual bioenergetic capacity as a potential source of resilience to Alzheimer’s disease
Authors: Arnold Matthias , Buyukozkan Mustafa , Doraiswamy P. Murali , Wu Tong , Nho Kwangsik , Gudnason Vilmundur , Launer Lenore J J. , Wang‐Sattler Rui , Adamski Jerzy , De Jager Philip L , Ertekin‐Taner Nilufer , Bennett David A. A , Saykin Andrew J. , Peters Annette , Suhre Karsten , Kaddurah‐Daouk Rima F. , Kastenmuller Gabi , Krumsiek Jan ,   the Alzheimer’s Disease Neuroimaging Initiative and the Alzheimer’s Disease Metabolomics Consortium
Published: December 2023

Background

Brain glucose hypometabolism is among the earliest pathogenic changes in Alzheimer’s disease (AD). This metabolic dysfunction points to the personal bioenergetic capacity, defined as the ability to maintain energy homeostasis under all circumstances including deregulated glucose uptake, as a potential source of resilience to the disease. Fasting blood acylcarnitine profiles are a central readout for this capacity in the absence of dietary glucose and capture the activity and efficiency of glucose‐independent routes of mitochondrial energy metabolism.

Method

We used fasting serum acylcarnitine profiles of 1,531 participants (465 with normal cognition, 762 with mild cognitive impairment, and 304 with clinical AD) from the AD Neuroimaging Initiative to perform unsupervised subgroup identification using hierarchical clustering. Identified subgroups were investigated for differences in A/T/N biomarker profiles and cognitive status. The contributions of genetic and potentially modifiable factors defining the subgroups were quantified using analysis of explained variance. The influence of the strongest determining factors on longitudinal cognitive trajectories was estimated using linear mixed‐effects models and gene‐by‐environment interaction analysis.

Result

We found several bioenergetically distinct subgroups with significant differences in AD biomarker profiles and cognitive function. The strongest genetic contribution to this bioenergetic endophenotype seems to be specifically linked to succinylcarnitine metabolism and significantly modulates the rate of future cognitive decline. In contrast, potentially modifiable sustainment of beta‐oxidation efficiency seems to decelerate bioenergetic aging, thus creating a bioenergetic reserve that delays progression of cognitive decline. Using gene‐by‐environment interaction analysis, we demonstrate that this molecular framework identifies a subgroup of individuals that is likely to benefit significantly from personalized therapeutic, dietary or lifestyle interventions tailored to increase resilience against bioenergetic disturbances in AD.

Conclusion

Our study reports on a set of genetic and metabolic markers that define bioenergetically distinct subgroups with significant differences on the AD biomarker and cognitive level. Longitudinal data suggest that targeting the modifiable fraction of this endophenotype might be a promising strategy to slow down disease progression in individuals with specific allelic configurations.
ABHD6 inhibition alleviates memory deficits in an Alzheimer’s disease mouse model
Authors: Zhu Xiaolei , Xu Yun
Published: December 2023

Background

Synaptic dysfunction plays a crucial role in the pathogenesis of Alzheimer’s disease (AD). α/β‐hydrolase domain‐containing 6 (ABHD6) inhibition has shown potential therapeutic values in several neurological disorders. However, the role of ABHD6 in AD has not been fully defined.

Method

Adeno‐associated virus (AAV) mediated shRNA targeting ABHD6 (AAV‐sh‐ABHD6) was slowly injected into bilateral hippocampus of APPswPS1dE9 (APP/PS1) mice, or ABHD6 inhibitor wwl70 was intraperitoneally injected into APP/PS1 mice for 30 days. The behavioral tests including Open field, New object recognition, Y maze, Morris water maze and Fear condition were performed. Synaptic transmission, dendritic spine density and synaptic proteins levels were investigated by electrophysiological tests, Golgi staining and western blot respectively. The protein levels of amyloid β peptide (Aβ), GFAP and Iba1 were determined by Immunostaining.

Result

The expression of ABHD6 was significantly increased in the hippocampus of APP/PS1 mice. AAV‐sh‐ABHD6 treatment attenuated synaptic dysfunction and memory impairment of APP/PS1 mice, while it didn’t affect the Aβ levels and neuroinflammation in the brains. In addition, intraperitoneal injection of wwl70 improved the synaptic plasticity and memory function in APP/PS1 mice. Furthermore, wwl70 significantly decreased the Aβ levels and neuroinflammtion in the hippocampus of AD mice, which indicated that wwl70 might exert the neuropreotctive effects not only by neuronal ABHD6 inhibition.

Conclusion

We demonstrate firstly that ABHD6 contributes to the memory impairment in AD, and ABHD6 inhibition enhances synaptic plasticity and memory functions in APP/PS1 mice, indicating that ABHD6 inhibition is a promising therapeutic strategy for AD treatment.
Multiple patterns of structural brain change trajectories in AD: MRI deep learning verification with enhanced sequential pattern analysis
Authors: Pan Dan , Zeng An , Song Xiaowei
Published: December 2023

Background

Our recently proposed interpretable Ensemble 3DCNN deep learning (DL) technique has allowed the derivation of a P‐score based on brain structural magnetic resonance imaging (sMRI) modelling to predict patterned neurodegeneration in AD (https://doi.org/10.1002/advs.202204717). Sequential association rules with a support rate greater than 18% have been used to define a neurodegenerative progression pattern. To more prudently test the meaningfulness of the patterns found, we further calculated the lift values of the various sequential patterns underlying the suggested longitudinal sMRI changes.

Method

The lift value of an association rule is defined as the rule’s confidence rate divided by the support rate of the rule consequent, i.e., the support rate of the rule divided by the product of the support values of the rule consequent and the rule antecedent. For example, with {L.NAC}→{L.NAC, R.NAC} (https://doi.org/10.1002/advs.202204717), among the 167 AD subjects employed for analyzing neurodegenerative progression patterns, the number (N) of the subjects with at least an sMRI image containing both L.NAC and R.NAC as neurodegenerative regions at all time points examined was firstly calculated. Secondly, among the above‐mentioned 167 AD subjects, the number (M) of the subjects with at least an sMRI image containing only L.NAC as neurodegenerative regions at all time points examined was counted and the time point (P) corresponding to the selected (earlier/earliest) sMRI image was saved. Thirdly, among the above selected M subjects, the number (K) of the subjects with at least an sMRI image containing both L.NAC and R.NAC as neurodegenerative regions at all time points latter than the P was computed. Thus, lift value = (K/M)/(N/167).

Result

The lift values of the fifty sequential association rules reported in the recent paper (https://doi.org/10.1002/advs.202204717) ranged between 1.27 and 2.59(i.e., all > 1; Table 1), further confirming the longitudinal sMRI change patterns in AD.

Conclusion

This study analyzing the lift values of the sequential association rules further verified the multiple patterns of longitudinal sMRI trajectories in AD brains, as reported recently. The research demonstrated featured and heterogeneous whole‐brain structural degeneration with AD progression.
Reduced visual associative learning is linked to Alzheimer’s disease pathology
Authors: Dubbelman Mark A. , Tomassen Jori , van der Landen Sophie M. , Bakker Els D. , Kamps Suzie , van Unnik Annemartijn A. J. M. , Glind Marie‐Christine M.A.B.J. , van der Vlies Annelies , Koene Teddy , Barkhof Frederik , van Harten Argonde C. , Teunissen Charlotte E. , Giessen Elsmarieke , van der Flier Wiesje M. , Sikkes Sietske A.M.
Published: December 2023

Background

Reduced learning is an early sign of memory impairment and relevant in the context of Alzheimer’s disease. The Visual Association Test (VAT) is a brief visual associative memory task comprising two sets (A and B) of six interactive pictures (e.g., a monkey holding an umbrella). We hypothesized that the VAT may be able to elicit learning deficits on set B when administered directly following set A, particularly in patients with Alzheimer’s disease‐related episodic memory deficits. We related learning on the VAT to medial temporal lobe atrophy (MTA) and amyloid‐β positivity.

Method

We selected 3,599 patients (63.9±8.9 years, 41% female) who completed two VAT sets. Patients had subjective cognitive decline (n = 1,369, 38%), mild cognitive impairment (n = 756, 21%), Alzheimer’s disease dementia (n = 856, 24%), or other types of dementia (n = 618, 17%). Average MTA scores of both hemispheres from magnetic resonance imaging were available for all; amyloid‐β status was obtained from cerebrospinal fluid or positron emission tomography for n = 2,769 (77%). We modeled learning curves on both VAT sets using linear mixed models, including an interaction with amyloid‐β status. Using logistic regressions, we analyzed the relationship between learning of associations on both sets (either all associations on both sets, or all associations on the first, but not the second set) and MTA, as well as amyloid‐β status.

Result

Most patients learned all associations on both sets (n = 2,442, 68%). Patients who learned all associations on the first, but not the second set (n = 640, 18%) were more likely to have higher MTA scores and to be amyloid‐β positive than those who learned all associations (Table 1). Figure 1 shows learning curves on both sets of the VAT, stratified by amyloid‐β status. Less steep learning curves seem to suggest that amyloid‐β positive patients benefited less from completing a first set than amyloid‐β negative patients.

Conclusion

We observed reduced learning on the second set, with those who did not learn all associations on both sets having more medial temporal lobe atrophy and more often being amyloid‐β positive. The VAT may be a useful, simple tool to assess early episodic memory deficits in the presence of Alzheimer’s disease pathology.
Dynamical irreversibility, high‐order interactions, and whole‐brain modeling of gamma oscillations in neurodegeneration
Authors: Cruzat Josefina A , Herzog Ruben A , Coronel‐Oliveros Carlos , Prado Pavel , Gonzalez‐Gomez Raul , Moguilner Sebastian , Medel Vicente , Rosas Fernando E. , Taglizucchi Enzo , Ibanez Agustin
Published: December 2023

Background

Abnormal gamma oscillations (γ) have been systematically reported in preclinical animal models of Alzheimer’s disease (AD) and human AD patients. However, little is known about the underlying mechanisms, non‐linear dynamics, and high‐order interactions of γ in dementia.

Method

To bridge this gap, we combined EEG and fMRI with three novel approaches to offer a comprehensive pathophysiological characterization of γ oscillations: We assessed the irreversibility of large‐scale brain dynamics to provide a precise signature capable of distinguishing AD at the global, local and network levels and at different oscillatory regimes (study 1). A high‐order functional connectivity (HOFC) multivariate information theory approach capturing interactions between 3 or more regions across spatiotemporal scales was compared with standard connectivity metrics for dementia characterization (study 2). A whole‐brain semi‐empirical model with a perturbational approach combined EEG, structural connectivity, and atrophy to explain the disrupted high‐order interactions observed in AD (study 3).

Results

Study 1: AD was associated with a breakdown of temporal irreversibility at the global, local, and network levels at γ and other oscillations. The irreversibility of brain dynamics provided higher accuracy and more distinctive information than classical neurocognitive measures when differentiating AD from controls. Study 2: EEG‐HOFC revealed hypoconnectivity in γ between frontal, limbic, and sensory regions in AD, and large effect sizes, compared to standard pairwise metrics, proving a more accurate and parsimonious characterization of AD and frontotemporal dementia (FTD) patients. Study 3: whole‐brain modeling showed that a combined mechanism involving reduced structural integration (DTI) and hypo‐excitability (altered excitation/inhibition balance) triggered the altered high‐order interaction γ dynamics observed in AD and FTD. A perturbational approach identified physiopathological regions (SFG, MTG, precuneus) deviating the trajectories from disease to a healthy brain state.

Conclusion

The present results offer new evidence regarding the pathophysiological link, mechanistic processes, and non‐linear whole‐brain dynamics between altered resting‐state γ rhythms and the characterization of AD and FTD, opening new avenues for dementia research at different levels.
Alabama Brief Cognitive Screener scores correlate proportionally with MoCA and DRS‐2 scores and vary appropriately by diagnosis
Authors: Pilonieta Giovanna , Murchison Charles F , Love Marissa C. Natelson
Published: December 2023

Background

The Alabama Brief Cognitive Screener (ABCs) was developed as a nonproprietary replacement for the MMSE (Mini‐Mental State Examination) in order to screen for cognitive deficits. It requires 5‐10 minutes to complete and participants can score up to 30 points.

Method

To assess the clinical correspondence of Alabama Brief Cognitive Screener (ABCs) scores relative to both the Montreal Cognitive Assessment (MoCA) and Dementia Rating Scale (DRS‐2) and also compare score differences by education attainment and the subject’s clinical diagnosis‐ of either Normal Cognition (NC), Mild Cognitive Impairment (MCI), or Dementia. Participants from the UAB Alzheimer’s Disease Center (ADC) from 2018 to 2022 were analyzed retrospectively. The ABCs, MoCA, and DRS‐2 were administered at the initial visit to subjects (n = 116) and their scores were compared to each other using Spearman’s rank correlation along with their clinical diagnosis which included NC (n = 47), MCI (n = 41) and Dementia (n = 28) and their previous education using the Kruskal‐Wallis test.

Result

Median scores for all three assessments were found to be associated with clinical diagnosis (MoCA: χ2 = 62.3, p = <.0001; ABCs: χ2 = 51.3, p = <.0001; DRS‐2: χ2 = 56.5, p = <.0001) and education level (MoCA: χ2 = 24.8 p = <.0001; ABCs: χ2 = 18.1, p = 0.0001; DRS‐2: χ2 = 11.15, p = 0.0038). Cognitive differences observed higher scores in the cognitively unimpaired relative to either MCI or subjects with dementia and in subjects with college or graduate degrees compared to those with only a high school education. Strong correspondence was observed between all assessments with significant correlations for all pairwise comparisons (MoCA v ABCs: ρ = 0.73; MoCA v DRS‐2: ρ = 0.72; ABCs v DRS‐2: ρ = 0.61, p = <.0001). When comparing sub‐types of the ABCs and DRS‐2, significant correlations were observed in the domains of memory (ρ = 0.61, p<0.001), attention (ρ = 0.26, p = 0.0054), construction (ρ = 0.37, p<0.001), and conceptualization (ρ = 0.30, p = 0.011).

Conclusion

ABCs correlates proportionally with MoCA and DRS‐2 scores while also varying appropriately by diagnosis. ABCs shows promise as a non‐proprietary alternative to the MMSE for use as a screening instrument to identify and assess severity of cognitive deficits in medical practice, as well as measure progression of those deficits in patients with neurodegenerative disease.
Computerized Games versus Crosswords Training in Mild Cognitive Impairment: The COG‐IT trial
Authors: Devanand Davangere P.
Published: December 2023

Background

Mild cognitive impairment (MCI) increases the risk of dementia. The efficacy of cognitive training in MCI is unclear.

Method

In a two‐site, single‐blinded, 78‐week trial, participants with MCI — stratified by age, severity (early/late MCI), and site — were randomly assigned to 12 weeks of intensive, home‐based, computerized training with Web‐based cognitive games or Web‐based crossword puzzles, followed by six booster sessions. In mixed‐model analyses, the primary outcome was change from baseline in the 11‐item Alzheimer’s Disease Assessment Scale‐Cognitive (ADAS‐Cog) score, adjusted for baseline. Secondary outcomes included change from baseline in neuropsychological composite score and Functional Activities Questionnaire score at 78 weeks, adjusted for baseline. Changes in hippocampal volume and cortical thickness on magnetic resonance imaging were assessed.

Result

Among 107 participants (n = 51 [games]; n = 56 [crosswords]), ADAS‐Cog11 score worsened slightly for games and improved for crosswords at week 78 (least squares [LS] means difference, 21.44; 95% CI 22.83 to 20.06; P = 0.04). From baseline to week 78, mean ADAS‐Cog score worsened for games (9.53 to 9.93) and improved for crosswords (9.59 to 8.61). The late MCI subgroup showed similar results (LS means difference, 22.45; SE, 0.89; 95% CI 24.21 to 20.70). Among secondary outcomes, the Functional Activities Questionnaire score worsened more with games than with crosswords at week 78 (LS means difference, 21.08; 95% CI 21.97 to 20.18, p = 0.02). Other secondary outcomes showed no differences. Decreases in hippocampal volume and cortical thickness were greater for games than for crosswords (LS means difference, 34.07; SE, 17.12; 95% CI 0.51 to 67.63, p < .05 [hippocampal volume]; LS means difference, 0.02; SE, 0.01; 95% CI, 0.00 to 0.04, p = .02 [cortical thickness]).

Conclusion

Home‐based computerized training with crosswords demonstrated superior efficacy to games at 78 weeks. Common directionality was observed in the primary outcome of ADAS‐Cog (cognition) and the secondary outcomes of FAQ (function) score and changes in MRI hippocampal volume and cortical thickness (neurodegeneration). If these effects are replicated and expanded in future trials with the inclusion of a control group that does not receive cognitive training, crossword puzzles training could become a home‐based, scalable, cognitive enhancement tool for individuals with MCI.
Challenges when monitoring and providing care to loved ones,Perspectives of Dementia caregivers in Canada
Authors: Chowdhury Fariha , Dauphinee Dale , Luy Luis , Macaulay Susan , Masoud Sara , Mayo Nancy , Na Eunjung , Rhayel Ashwak , White Carole L , Kuspinar Ayse
Published: December 2023

Background

Family caregivers see firsthand the progression of their care recipient’s dementia and know every aspect of their lives and needs. They make important decisions on interventions and care. Currently, there are no measures that account for caregivers’ perspectives when evaluating the impact of dementia or interventions. The aim of this study was to explore the perspectives of caregivers’ of people living with dementia across Canada to generate domains for a new caregiver‐reported measure.

Method

Participants were recruited across Canada. Listening sessions were conducted virtually over three months, using open‐ended questions to encourage participants to share their perspectives. A semi‐structured interview guide was developed to facilitate the sessions. The interviewer asked questions to encourage caregivers to share their experiences on providing care, dementia monitoring, treatment impact and seeking alternative care. The data were coded and analyzed using NVivo. A thematic analysis approach was applied by two reviewers to analyze the data.

Result

Seven listening sessions were conducted with 34 caregivers who were providing care to their loved ones with dementia. Seventy‐four percent of the participants were women and 59% had 6 or more years of caregiving experience. Each listening session included three to six caregivers and was approximately one hour long. Example of codes included gait limitations, distance walked, difficulties with memory, and changes in behaviour. Overall, data were organized into three broad themes (i) psychosocial impact of dementia, (ii) physical and emotional changes for dementia monitoring and treatment, (iii) symptomalogy changes for dementia monitoring and treatment.

Conclusion

This study explored the perspective of caregivers across Canada, the activities and symptoms that are important to assess when evaluating dementia progression. It also questioned caregivers on how best to evaluate treatment effects. These findings may help identify strategies to better support caregivers and improve the quality of life of individuals living with dementia. Furthermore, the findings of this study can be a resource to help healthcare professionals, communities, and policymakers to provide better support for caregivers and the lives of individuals with dementia.
Detection of Brain‐derived Neurotrophic Factor Expression in Insulin‐Resistant SH‐SY5Y Neuroblastoma Cells
Authors: Nelson Mackayla
Published: December 2023

Background

More researchers are coining Alzheimer’s disease (AD) “type 3 diabetes” due to its significant comorbidity and shared pathology with type 2 diabetes mellitus (T2DM). A bi‐directional relationship between T2DM and AD exists, by which 50‐75% of individuals with T2DM have a greater risk of developing AD compared to non‐diabetes and that AD symptoms progress with impaired glucose utilization. Interestingly, brain‐derived neurotrophic factor (BDNF), a small protein that maintains neuron health and glucose homeostasis, has been implicated in both AD and IR. As such, this experiment investigates if insulin resistance (IR) alters BDNF expression in SH‐SY5Y neuroblastoma cells.

Method

Objective 1: create a model of insulin resistance at 24, 48, 72 and 96 hours (hr) and determine expression of pAkt (S473), tAkt, insulin receptor b (INSRB) and pINSR (T1362) on Western blots. (n = 5)

Objective 2: Detect mRNA and protein BDNF via Rt‐PCR and Western blotting. (n = 5)

Objectives 3: Determine alterations to BDNF expression via Western blotting and qPCR. (n = 5)

Result

Levels of pAkt expression were significantly decreased in insulin‐pretreated and activated samples at each timepoint of 24, 48, 72 and 96 hr; although, with each timepoint, pAkt does appear to steadily increase. pro‐BDNF and mature BDNF were detected at their respective sizes, 27kDa and 19kDa, on a Western blot and BDNF mRNA was detected on an agarose gel after PCR.

Conclusion

It appears that insulin resistance is occurring at 24, 48, 72 and 96 hr solely based off Akt expression. This result will be further confirmed with the the completion of INSR‐B and p‐INSR blots. Ongoing experiments include western blots and qPCRs of BDNF to determine if there is any alteration to expression.
The relevance of tract‐specific white matter hyperintensity burden to clinical impairment in groups at risk of Alzheimer’s disease
Authors: Heyman Cameron C , Morgan Catherine A , Stones Richard , Dell'Acqua Flavio , Manson Tabitha , Roberts Reece P , Kirk Ian J , Melzer Tracy R , Heron Campbell J Le , Dalrymple‐Alford John C , Anderson Tim J , Cutfield Nick J , Tippett Lynette J ,   the NZ‐DPRC
Published: December 2023

Background

White matter hyperintensities (WMHs) are common in normally functioning older adults. While greater WMH volume may be associated with an increased risk of cognitive dysfunction and dementia, the impact of the location of WMHs is less well understood. We investigated whether WMH burden in specific white matter (WM) tracts is associated with clinical classification and global cognitive scores in at‐risk groups for Alzheimer’s disease (AD).

Method

Participants from Dementia Prevention Research Clinics, New Zealand, were classified as control, subjective cognitive decline, single‐domain amnestic mild cognitive impairment (MCI), multiple‐domain amnestic MCI, or early AD by a multidisciplinary team (Table 1). Several tract‐WMH “overlap scores” (the percentage of total tract voxels containing WMHs) were calculated for each participant’s binarised WMH map (Lesion Segmentation Toolbox, SPM) using seven tract probability templates from a 140‐subject tract atlas (www.megatrackatlas.org). Tract templates were of the superior longitudinal fasciculus (SLF), inferior longitudinal fasciculus (ILF), inferior fronto‐occipital fasciculus (IFOF), uncinate fasciculus (UF), cingulum (CB), fornix, and corpus callosum (CC). Between‐group differences in overlap scores were tested with ANOVAs. Pearson’s correlations examined associations between tract‐WMH overlap and global cognitive scores.

Result

Figure 1 shows WMH overlap with one tract, the IFOF, in a representative participant. Considering the whole sample, the highest tract‐WMH overlap scores can be seen in the IFOF and CC. Significant between‐group differences were found for the SLF, ILF, IFOF, UF, and CC (p < .05), but not the CB or fornix (Fig. 2), with significant linear trends describing the relationship between overlap scores and clinical classification. Post‐hoc tests confirmed significant pairwise comparisons for overlap scores in all aforementioned tracts except the SLF (Fig. 2). We found Addenbrooke’s Cognitive Examination‐III scores negatively correlated with overlap scores in the ILF (r = ‐0.19), IFOF(r = ‐0.22), UF(r = ‐0.22), and CC(r = ‐0.19) (all p < .01), but not the SLF, CB, or fornix (p > .05).

Conclusion

Our findings highlight that WMH burden within specific WM tracts is associated with degree of clinical impairment in groups at‐risk of AD. Future research will investigate relationships between overlap scores in specific WM tracts and executive functioning, episodic memory, and processing speed performance.
“By Any Means Necessary”: Understanding the willingness of African‐American and American Indian/Alaska Native communities to engage in genetic and biomarker research: The UBIGR Study
Authors: Gooding Diane C. , Umucu Emre , Van Hulle Carol A. , Zuelsdorff Megan , Carter Fabu P. , Lewis Jordan P. , Bouges Shenikqua , James Taryn T. , Salazar Hector , Floyd Lytonia , Bester James , Gleason Carey E.
Published: December 2023

Background

Research investigating underrepresented groups’ willingness to engage in research has largely relied on qualitative research and/or specialized samples (e.g., patients’ first‐degree relatives). Moreover, extant quantitative studies include disproportionately small numbers of these participants. This investigation is from an ongoing project whose overall goal is to understand biomarker and genetic Alzheimer’s disease (AD) and schizophrenia research participation in underrepresented groups (UBIGR Study), to facilitate greater diversity in future biomarker research and clinical trials. We extended knowledge by including community‐based participants, more racialized participants, and utilizing quantitative methods.

Method

We administered an online questionnaire to 1444 adults. Focusing exclusively on data pertaining to AD detection, we assessed demographic characteristics as well as participants’ views on dementia, research, and genetic and biomarker testing. We tested our conceptual model (Figure 1) with structural equation modeling (SEM; SPSS AMOS). Our model consisted of demographic covariates (gender, education, family history of AD dementia), racial‐ethnic identity group, knowledge about AD, stigma, willingness to undergo any type of AD biomarker testing (outcome variable). Not implying white to be the standard, we created a BIPOC variable (Black, Indigenous, Person of Color) to examine differences based on Black/African American and American Indian/Alaska Native vs. White identity. A stigma score was derived from 5 questions. The knowledge score was based on 2 questions. The specific survey item used as the outcome measure asked for agreement with the statement: “I would be willing to undergo any type of testing necessary if it was the only way to find out if I was at risk for AD before there were any symptoms,” answered on a Likert scale (1 = strongly disagree – 7 = strongly agree)

Result

Participants were mostly male and middle‐aged (Table 1). Path analysis revealed an excellent model fit, χ2(6, N = 1444) = 14.203. See Figure 2 for paths and factor loadings.

Conclusion

1. BIPOC participants in our nonpatient, non‐research sample were less willing to undergo testing than White participants. 2. Stigma and knowledge regarding AD are influential and modifiable factors underlying research willingness. Findings indicate need for outreach and engagement programs to occur before attempting research recruitment, particularly with BIPOC populations.
Could differential under‐reporting of loneliness between men and women bias the gender‐specific association between loneliness and memory aging? A quantitative probabilistic bias analysis
Authors: Yu Xuexin , Zahodne Laura B. , Gross Alden L. , Needham Belinda L , Langa Kenneth M , Cho Tsai‐Chin , Kobayashi Lindsay C
Published: December 2023

Background

Loneliness is associated with later‐life dementia risk, with conflicting findings on gender as an effect modifier. The causality of this effect modification is difficult to assess, as men may have a lower propensity than women to admit loneliness potentially due to self‐perceived “masculinity”, leading to distorted gender‐specific estimates. We aimed to estimate the potential magnitude of information bias due to differential loneliness under‐reporting by gender in the gender‐specific associations between loneliness duration and memory aging.

Method

Data were from respondents aged ≥50 in the US Health and Retirement Study from 1996‐2016 (N = 9,032). We conducted quantitative probabilistic bias analyses to simulate various bias‐parameter selections and reclassify loneliness status (yes; no) at the record level as measured biennially from 1996‐2004. We used sensitivity values of loneliness self‐reports of 0.20‐0.45 among men and 0.30‐0.55 among women, and specificity values of 0.90‐1.00, as informed by a validation analysis. We ran mixed‐effects linear regression models on the corrected data with a three‐way interaction between loneliness duration (0, 1, 2, or ≥3 time points), years of follow‐up (0‐12), and gender (men; women) to test gender differences in the association between loneliness duration and memory decline (100 replications).

Result

Compared to the uncorrected estimate (‐0.008), mean estimates of the three‐way interaction attenuated in magnitude, ranging from ‐0.006 (sensitivity 0.40‐0.45 for men and 0.50‐0.55 for women) to ‐0.001 (sensitivity 0.20‐0.25 for men and 0.30‐0.35 for women; see Figure 1). Approximately 64%, 84%, 96%, and 100% of simulation estimates remained negative while holding sensitivity distribution at 0.20‐0.25, 0.25‐0.30, 0.30‐0.35, and >0.35 among men, respectively.

Conclusion

The likelihood of observing gender‐specific loneliness‐memory relationship reduces as sensitivity values of loneliness self‐reports declines.
Development of a neuroimaging biomarker of the pro‐coagulant state in Alzheimer’s disease: The BioClotAD Project
Authors: Casquero‐Veiga Marta , Cerón Carlos , Herreros‐Pérez Desiré , Fernandez‐Nueda Irene , Kossatz Susanne , Sehlin Dag , Desco Manuel , Salinas Beatriz , Cortes‐Canteli Marta
Published: December 2023

Background

Alzheimer’s disease (AD) is the most common form of dementia1. Its multifactorial profile includes a strong vascular factor, partially driven by an early haemostatic dysregulation. Accordingly, fibrin, the main protein component of blood clots, is significantly increased in AD‐patients’ brains2. Furthermore, amyloid‐β contributes to this process by interacting with fibrin and producing degradation‐resistant clots3. Consequently, this pro‐thrombotic milieu intensifies hypoperfusion, neurodegeneration and blood‐brain barrier (BBB) disruption4, but it does not affect all patients. Therefore, early detection of these phenomena would be invaluable to identify patients likely to benefit from anticoagulant therapies5. Therefore, the BioClotAD Project aims to develop an imaging biomarker based on a fibrin binding probe (FBP)6 to non‐invasively identify AD’s pro‐coagulant state.

Method

BioClotAD involves four partners in three European countries with complementary expertise. To optimize and test FBP we use extensive in vitro, ex vivo and in vivo assays, including AD animal models and human AD samples. Our project is comprised of three blocks: 1) Testing the FBP to in vivo detect the cerebral occlusions by nuclear imaging. 2) Detecting fibrin deposits inside the brain parenchyma with FBP coupled to a transferrin receptor antibody (FBP‐TfR) to facilitate BBB crossing7. FBP‐TfR will be labelled for optical and nuclear imaging. 3) Validating the most promising FBP probes in frozen brain samples of AD patients by autoradiography or fluorescence microscopy.

Result

BioClotAD provides feasible neuroimaging strategies to in vivo detect the fibrin cerebral accumulation of AD models and identify the specific regional distribution in the brain. Our project will set the basis for future clinical trials on neuroimaging of the cerebral fibrin accumulation in AD.

Conclusion

BioClotAD neuroimaging biomarkers will allow the early detection of the pro‐thrombotic state in AD, opening a window of opportunity to delay the disease progression by personalized anticoagulant therapies.

Funding: EU Joint Programme – Neurodegenerative Disease Research (JPND)

References

1. Alzheimer’s Association. 2021. https://www.alz.org/media/documents/alzheimers‐facts‐and‐figures.pdf.

2. Cortes‐Canteli, et al. 2015. https://doi.org/10.1016/j.neurobiolaging.2014.10.030

3. Petersen, et al. 2018. https://doi.org/10.1038/nrn.2018.13

4. Cortes‐Canteli, et al. 2012. https://doi.org/10.3233/JAD‐2012‐120820

5. Cortes‐Canteli, et al. 2019. https://doi.org/10.1016/j.jacc.2019.07.081

6. Oliveira, Caravan. 2017. https://doi.org/10.1039/c7dt02634j

7. Sehlin, et al. 2019. https://doi.org/10.1007/s00259‐019‐04426‐0