bluuebunny/crossref_metadata_2025_split huggingface dataset:
Visualizing Braak stages with deformation‐based morphometry in super‐sampled MRI
Authors: Shafiee Neda , Fonov Vladimir S , Collins D Louis 
Published: December 2023

AbstractBackgroundUnlike MRI data, histological data collected post‐mortem can’t be used to study the longitudinal formation of neurofibrillary tangles (NFT) and corresponding brain changes over time for individuals. Although structural MRI offers the possibility of non‐invasive longitudinal antemortem imaging, its resolution is a limiting factor. Using image processing and super‐sampling techniques, we examined the possibility of employing structural MRI to observe the NFT footprints in the brain.MethodData included baseline MRI scans of 1473 subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset including ADNI1, 2, and GO. Voxel size was super‐sampled to 0.5×0.5×0.5mm (Manjón et al. 2010) before non‐linear registration to an ADNI‐based unbiased symmetric MRI template. The resulting deformation fields were used to compute the Jacobian determinant map for each subject as a proxy for local volume. For each subject, the sex‐ and age‐corrected z‐scored Jacobian maps were then calculated and averaged for each diagnostic group: normal subjects(CN), early MCI, late MCI, and AD. The average map for CN group was subtracted from the other average maps to show the AD‐stage differences.ResultThe Braak tau staging pattern (Braak & Braak, 1995) is seen in average Jacobian maps as the disease progresses. Subjects in the MCI groups showed on average more pronounced neurodegeneration in the transentorhinal and entorhinal region (Braak Stages 1‐2), followed by degeneration in the hippocampus (Stages 3‐4). Later on, this neurodegeneration progresses toward the neocortex (Stages 5‐6). Figure 1 illustrates these results: A) the template, B)EMCI vs CN, C) LMCI vs EMCI, D) LMCI vs CN, E) AD vs CN. Red color shows an increase and blue indicates a decrease in local volume.ConclusionUsing novel image processing techniques, we were able to verify the staging of AD‐related neurofibrillary pathology progression in MRI data. This shows that structural MRI data, although limited in resolution, can still offer in‐depth insight into the brain antemortem which will in return allow the longitudinal and possible lifespan studies with an accuracy close to histological data.
Improving dementia prognostication in cognitively normal older adults: conventional versus novel approaches to modelling risk associated with neuropsychiatric symptoms
Authors: Ghahremani Maryam , Smith Eric E. , Ismail Zahinoor 
Published: December 2023

AbstractBackgroundIn persons with mild cognitive impairment (MCI) neuropsychiatric symptoms (NPS) are consistently associated with greater dementia incidence rates. However, in cognitively normal (NC) individuals, findings are inconsistent. Conventional approaches to NPS modeling are often cross‐sectional and silent on natural history of symptoms, introducing noise. Mild behavioral impairment (MBI) refines identification of risk by specifying that NPS must be later‐life emergent and persistent, increasing signal and reducing noise. Here, we explored associations of both MBI and conventionally‐measured NPS with incident dementia in persons with NC and subjective cognitive decline (SCD). We hypothesized greater dementia incidence in MBI, compared to NPS not meeting MBI criteria (NPS‐not‐MBI) and no NPS.MethodNational Alzheimer’s Coordinating Center (NACC) participant data were analyzed. MBI was operationalized as no history of psychiatric disorders (to satisfy the symptom emergence criterion) and NPS present at more than two‐thirds of pre‐dementia study visits (to satisfy the symptom persistence criterion). Kaplan‐Meier dementia‐free survival curves were generated for all three NPS groups. Cox proportional hazard models compared dementia incidence rates across groups, adjusted for age, sex, education, race, and APOE‐e4 status.ResultsThe NC sample comprised 1,408 MBI (age = 75.2±9.5; 54.3% female), 5621 NPS‐not‐MBI (age = 71.6±8.8; 65.5% female), and 5078 no‐NPS participants (age = 71.2±8.9; 67.6% female). Persons with MBI had lower dementia‐free survival (p<0.0001, Table 1) and a 3.17‐fold greater dementia incidence rate compared to no‐NPS (CI:2.62‐3.84, p<0.001, Figure 1); no significant differences were found for NPS‐not‐MBI (HR = 1.07, CI:0.91‐1.27, p = 0.420). Similarly, in the SCD subsample (n = 3,555), persons with MBI had a 1.99‐fold greater dementia incidence rate versus no‐NPS (CI:1.46‐2.70, p<0.001); NPS‐not‐MBI did not differ (HR = 0.89, CI:0.68‐1.16, p = 0.375).ConclusionsIn both NC and SCD, persons with MBI had greater incidence of dementia than no‐NPS, while NPS‐not‐MBI did not. Operationalizing NPS‐related risk in accordance with the MBI criteria of later‐life emergent and persistent symptoms improves the prognostic utility of NPS over conventional approaches. This method of MBI operationalization can be applied to legacy datasets and ongoing cohort studies to identify a high‐risk group. This group can be assessed for neurodegenerative disease biomarkers in advance of the objective cognitive decline that is usually used to identify risk.
Advanced measures of cortical microstructural change and associations with cognitive and blood‐based biomarkers in autosomal dominant Alzheimer’s disease
Authors: Veale Thomas , Malone Ian B , Abel Emily , Ocal Dilek , Ferguson Damien , O'Connor Antoinette , Zhang Hui , Fox Nick C , Cash David M , Weston Philip SJ 
Published: December 2023

AbstractBackgroundIn Alzheimer’s disease (AD), dysfunction and loss of cortical neurons occurs prior to symptom onset. Diffusion tensor imaging, measuring mean diffusivity (MD), provides a metric of microscopic change but lacks specificity for different underlying microstructural processes. We used Neurite Orientation Dispersion and Density Imaging (NODDI) to investigate specific cortical microstructural features across the disease course in autosomal dominant AD (ADAD).MethodSixty‐three ADAD family members (36 mutation carriers) (Table 1) underwent T1w and multi‐shell diffusion MRI (dMRI). Cortical thickness and cortical MD were estimated, with NODDI providing measures of tissue fraction (TF), neurite density index (NDI) and orientation dispersion index (ODI) (a proxy measure of dendritic complexity). Imaging metrics were sampled across six cortical regions of interest (ROIs) known to be particularly vulnerable to early neurodegeneration. Associations between dMRI measures and 1) disease stage as measured by estimated years to onset (EYO), 2) AD blood biomarkers, and 3) cognitive measures were assessed.ResultAcross mutation carriers, ODI (Figure 1) and TF (Figure 2) demonstrated negative associations (p<0.05) with EYO in most ROIs, while MD demonstrated positive correlations. Most associations remained after adjusting for cortical thickness. The association between ODI and EYO in the supramarginal gyrus also remained after adjustment for MD (p = 0.002). In presymptomatic carriers, EYO appeared most prominently associated with ODI (p<0.05 in 3/6 regions). ODI, TF and MD showed widespread associations with MMSE and CDR sum of boxes. TF was negatively, and MD positively, associated with serum NfL across ROIs, but for ODI this was only the case in the supramarginal gyrus. ptau181 demonstrated significant associations with ODI in the supramarginal (p = 0.0089) and inferior parietal (p = 0.033) cortices, and with MD in the entorhinal cortex (p = 0.015).ConclusionCortical dendritic complexity (modelled by ODI) and cortical tissue fraction decrease, while overall diffusivity increases as individuals approach symptom onset. ODI appears to be the metric most closely associated with presymptomatic disease stage, possibly reflecting early dendritic pruning, and is associated with ptau – a measure of early pathology – while MD and TF may be more sensitive to later larger scale changes, given their associations with serum NfL and cognitive measures.
Easing the burden: AD trials sharing data and samples through a national repository
Authors: Foroud Tatiana M. 
Published: December 2023

AbstractThe availability of biological samples accompanied by detailed clinical data have been essential to support research to understand the biology and underpinnings of Alzheimer’s disease and related dementias (ADRD). These samples have been fundamental to the identification of ADRD genetic risk factors, the pathways implicated in ADRD pathology, and the development of biomarkers of ADRD onset and progression. The broad sharing of samples as well as the data generated from these samples has accelerated the rate of discovery and in turn the development of effective therapeutics. Importantly, to share samples with researchers outside the study, participants must be appropriately consented.Samples and data collected as part of clinical trials are important resources for further research discovery. However, trial participants are often not consented to allow their samples to be utilized for broader research goals. As a result, the samples from these well characterized research participants are not available to support additional, often collaborative, research.NIA has developed infrastructure, including the National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD), to make the banking, sharing and distribution of samples easier. Uniform protocols and standard sample handling procedures has made it seamless to utilize samples collected across different studies. NIA has also developed infrastructure including the National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS), the National Alzheimer’s Coordinating Center (NACC) and other data repositories to make the data generated from biological samples available to the research community.During this presentation, we will discuss the importance of sample and data sharing and the advantages that can be gained from the ability to work across studies and trials. In addition, we will discuss challenges and important considerations when planning for future sharing with the research community.
One Form of tDCS Does Not Fit All: The intersectionality of severity level and expected tDCS benefit
Authors: Roncero Carlos Tyler , Chertkow Howard 
Published: December 2023

AbstractBackgroundWe investigated if a mixed group of people living with dementia (Alzheimer’s Disease (n = 16) or Frontotemporal dementia (n = 8)) would have faster response times on an N‐Back task (1‐back), a measure of working memory, after practicing the task with 20 minutes of tDCS, versus an analogous placebo condition. Crucially, half of these participants were slower than normal on the task at baseline, while the other half has normal response times. Our primary outcome measure was improvement on the MMSE task.MethodEach participant practiced the n‐back in three separate nine‐session rounds, two months apart, with a different form of stimulation in each round: (1) 4mA unilateral stimulation, with one anode electrode over the left dorsolateral prefrontal cortex area and a cathode electrode over the occipital lobe area; (2) 4mA bilateral stimulation, using the same configuration, but with an extra active anode electrode over the right dorsolateral prefrontal cortex, and (3) SHAM stimulation.ResultWe found the condition x time x severity variable was significant (F (12, 264) = 2.17, p < .05), which suggests the results founds were dependent both of the tDCS montage received and the initial severity level of the participants. More specifically, as supported by post‐hoc tests, participants initially impaired on the N‐Back task improved on the MMSE when they received the bilateral tDCS montage, but those participants with normal response times improved on the MMSE when they received the unilateral tDCS montage.ConclusionConsistent with past studies, results suggest tDCS can be used to improve cognition in people living with dementia. Optimization, however, may depend both on the montage applied and the indiosyncratic nature of the participant. A bilateral montage, for example, that theoretically impacts a wider range of brain areas, may be superior to a unilateral one when people with dementia exhibit a greater degree of impairment.
Toxoplasma gondii‐induced amyloid reduction and neuroimmune responses in Alzheimer’s disease
Authors: Yanes Katherine Olivia , Tomasello Julia , Guanzon Nathaniel , Azevedo Ricardo , Wheeler Damian G. , Gandhi Sunil , Lodoen Melissa 
Published: December 2023

AbstractBackgroundToxoplasma gondii is a foodborne parasite that induces monocyte recruitment and microglial activation during infection of the brain. Similarly, in Alzheimer’s disease (AD), activated immune cells are often found in the brain and these localize near amyloid beta plaques. However, after infection with T. gondii in AD mouse models, there are fewer amyloid beta plaques in the brain, increased microglial activation, and decreased severity of AD symptoms. We hypothesize that T. gondii infection activates and enhances the phagocytic ability of microglia to clear amyloid beta.MethodFemale 5xFAD mice were infected with T. gondii or PBS treated, and their brains harvested after 6 weeks of infection. Brain tissue from these animals was analyzed for amyloid (Amyloglo) and immune cell markers for microglia, monocytes, and T cells (IBA1, CD68, CD11c, CD11b, CD45, CD3) by light sheet imaging, confocal microscopy, or flow cytometry. Mice were also fitted with headplates and cranial windows and injected with methoxy‐X04 (10 mg/kg) to enable longitudinal imaging of amyloid over the span of infection.ResultConfocal microscopy of brain sections and light sheet imaging of intact brains from infected and uninfected 5xFAD mice have shown increased microglial activation markers (IBA1 and CD68) and decreased amyloid surface area and volume throughout infected brains in infected animals. Infected mouse brains also have increased co‐localization of amyloid and CD68 compared to uninfected mouse brains. Two‐photon imaging reveals that amyloid plaque area in vivo no longer increases in infected mouse brains as early as three weeks post‐infection and lasts as long as thirteen weeks post‐infection. Additionally, after six weeks of infection, we see an increase in Disease Associate Microglia (DAM) by flow cytometry, as well as an influx of other immune cells in the brain of infected mice as compared to PBS treated control mice.ConclusionOur data show that infection with T. gondii increases microglial markers associated with the DAM profile and these cells likely increase phagocytosis of amyloid beta. Infection with T. gondii appears to modulate the neuroimmune environment, including responding microglial cells, resulting in a neuroprotective phenotype.
Relationships between sleep apnea and insomnia with cognition among Latinos in the National Alzheimer’s Coordinating Center (NACC)
Authors: McKinnon Andrew C , Stickel Ariana M 
Published: December 2023

AbstractBackgroundSleep difficulties (e.g., sleep apnea, insomnia) have been associated with worse late life cognitive health and increased risk for dementia. However, the role of sleep, a potentially modifiable factor, in cognitive aging is understudied among Hispanics/Latinos/Latinxs (henceforth Latinos)—a group that faces dementia disparities. Therefore, we examined the relationships between sleep difficulties and cognition in this population using data from the National Alzheimer’s Coordinating Center (NACC).MethodParticipants included 1,633 Latinos (64% females) ages 21 to 98 years old from the NACC (funded by NIA/NIH Grant U24 AG072122). This analysis used data collected at 35 ADRCs from 2015‐2022. Exposures included history of self‐reported and/or clinically assessed sleep apnea (n = 261) and hyposomnia/insomnia (n = 384). Outcomes were concurrent cognitive scores from tests of learning, memory, semantic fluency, processing speed, confrontation naming, and executive functioning. Covariates included age, sex, education, heritage (e.g., Cuban), cognitive status, and body mass index. General linear models separately tested the associations between sleep difficulties with cognition in crude and fully‐adjusted models. Additionally, we examined whether sex, age, or heritage modified these associations.ResultsSleep apnea was associated with faster processing speed, and insomnia was associated with worse confrontation naming in crude but not fully‐adjusted models. In fully adjusted models, sex modified the associations of both sleep apnea and insomnia with semantic fluency. Specifically, men without sleep apnea had worse semantic fluency than all other groups; no other group differences emerged. Females in either insomnia group had better semantic fluency than men in either insomnia group, and women without insomnia had marginally better semantic fluency than women with insomnia. Older age (continuous) was associated with worse executive functioning, specifically working memory, among individuals with insomnia to a greater extent than those without insomnia. Heritage did not modify associations between sleep difficulties with cognition.ConclusionConsistent with previous, we found that sleep measures were associated with cognition in this group of Latinos from a wide age‐range. Our findings were specific to semantic fluency and varied based on demographic factors (e.g., sex). Future studies should examine the relationships between sleep with longitudinal change in cognition in this underserved community.
The contribution of vascular risk to amyloid and tau PET deposition in middle‐aged adults from the community
Authors: Satizabal Claudia L. , Koijs Daniel , O’Donnell Adrienne , Ghosh Saptaparni , Johnson Keith A. , Beiser Alexa S. , Seshadri Sudha 
Published: December 2023

AbstractBackgroundVascular risk factors during midlife are associated with an increased risk of Alzheimer’s disease (AD). However, it is unclear how exposure to vascular risk factors decades before disease onset contributes to the accumulation of AD neuropathological hallmarks. We aimed to investigate the association of vascular burden with amyloid and tau PET deposition in middle‐aged participants from the Framingham Heart Study (FHS).MethodWe included 376 participants from the FHS Third‐generation cohort (mean age 55.3 ±8.8 years, 53% men) with vascular risk factors and PET imaging (Table 1). Vascular predictors included BMI, HDL cholesterol, systolic blood pressure, use of antihypertensive medication, elevated blood pressure, smoking, and history of diabetes, all derived from the study examination closest to PET. Participants underwent brain PET imaging with Pittsburgh Compound B and Flortaucipir to quantify amyloid and tau, respectively. Our analyses focused on global amyloid (i.e., fronto‐lateral‐retrosplenial composite, FLR) and regional tau (i.e., rhinal and inferotemporal cortices) uptake. Linear regression models were used to assess the association between vascular risk factors and PET outcomes, adjusting for age, age‐squared, sex, PET camera, time between vascular and PET data collection, APOE4 status, and education. We additionally explored interactions with APOE4 status.ResultHigher HDL cholesterol was related to a lower FLR amyloid deposition (Beta±SE, ‐0.40±0.18, p‐value = 0.026), whereas higher BMI was related to higher inferotemporal tau (0.65±0.31, p‐value = 0.035). Intriguingly, current smoking was associated with lower tau deposition, both in rhinal (‐0.88±0.25, p‐value = 0.001) and inferotemporal (‐0.80±0.23, p‐value = 0.001) cortices (Table 2). We further observed interactions between APOE4 status and smoking on rhinal tau (p‐value = 0.029 for interaction), with significant associations only among non‐e4 carriers (‐0.08±0.53, p = 0.88 in e4 carriers; ‐1.35±0.28, p‐value<0.0001 in non‐carriers).ConclusionOur findings suggest vascular risk factors may have an impact on global amyloid and tau deposition in midlife. If confirmed, these results have important implications for early prevention or intervention strategies in AD. Given the reported protective effect of smoking on the incidence of Parkinson’s disease, further analyses are needed to unravel the role of smoking in the accumulation of tau during midlife and the implications in the development of AD.
Helping Carers to Care: feasibility of the 10/66 Dementia Research Group caregiver intervention in rural Benin
Authors: Guerchet Maëlenn , Kouanou Marlène O.G. , Yoro‐Zohoun Inès , Boumédiène Farid , Houinato Dismand S , Preux Pierre‐Marie 
Published: December 2023

AbstractBackgroundIn sub‐Saharan Africa, the number of people living with dementia is expected to double every 20 years, from 2.7 to 7.6 million. The shortage of trained health professionals leads family members of older people living with dementia to provide informal care. However, lack of knowledge and understanding about dementia leads to difficulties. There is therefore an urgent need to develop interventions to improve the lives of people with dementia and their families in this region. The objective of this study was to determine the feasibility of the Helping Carers to Care (HC2C) caregiver intervention in rural Benin.MethodThis was a before‐and‐after quasi‐experimental study conducted from January to December 2022 in Djidja‐Abomey‐Agbangnizoun, Benin. Two groups of 30 dyad (caregiver / person with dementia) were to receive the intervention in the beginning of the trial or six months later. The intervention consisted of three modules: 1) assessment; 2) basic education about dementia; and 3) training regarding specific problem behaviors. Main outcome measures for caregivers and patients with dementia were assessed at baseline, at 3‐month and at 6‐month. For caregivers, measures included strain (Zarit Burden Interview), psychological distress (SRQ‐20), and quality of life (WHOQOL‐BREF). Dementia participants completed scales assessing behavioral and psychological symptoms (NPI‐Q) and quality of life (DEMQOL).ResultThe study population consisted of 22 elderly people living with dementia and their primary caregiver divided into two groups ‐ control and intervention ‐ of 11 dyads. Both groups were similar with regards to sex, education, marital status, occupation, dementia severity but people in the control group were older. Participation rate was 100% and most of them found the intervention beneficial and advisable to others in the same situation. Full description of the outcomes and group differences at different times will be presented in details.ConclusionThe need for such intervention among the families of people living with dementia in Benin is obvious. Preliminary results show that implementation is challenging in rural Benin, where dementia awareness is low and care structures are lacking. These results will add to the scarce evidence on feasibility and benefits of caregiver interventions in low‐and middle‐income countries.