bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hyperspectral analysis of amyloid beta (Aβ) evolutional changes in preclinical to late‐stage Alzheimer’s disease using matched brain and retinal tissue
Authors: Flanagan Margaret , Danner Benjamin , Zamudio Carlos , Spencer Callen , Lilek Jaclyn N , Matos Arleen , Morris Meghan , Ajroud Kaouther , Xie Wei , Bornbaum Catherine C , Westreich Jared , More Swati S 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is a progressive, degenerative brain disorder that leads to cognitive impairment and eventually death. It is marked by buildup of abnormal amyloid aggregates (Aβ) in the brain. This study aimed to elucidate the neuropathologic sequence and corresponding [RetiSpec] hyperspectral signals of Aβ evolutional changes in preclinical to late‐stage AD using retinal and brain samples.MethodWe used brain‐ and retina‐matched human tissue samples from the NIH Brain Bank at Johns Hopkins. Study groups included: No AD neuropathologic change with negative AD neuropathology (n = 15); Low‐level AD neuropathologic change with positive AD neuropathology (n = 15); High level AD neuropathologic change with positive AD neuropathology (n = 15). To validate retinal hyperspectral imaging (rHSI) detection of Aβ in these retinal samples, we quantified Aβ oligomers (AβOs) in human retinal tissue. Immunohistochemistry was performed. We used humanized, affinity‐matured, IgG2 mAβ selective biotinylated antibody (ACU‐193) to detect soluble AβOs in retinal and brain tissues followed by objective quantification of ACU193 retinal staining by performing annotations and data extraction using QuPath software. One‐way ANOVA and t‐tests were performed to compare between controls and AD stages.ResultWhen assessing ACU193 staining present from retinal tissue samples, we observed 29‐53% retinal tissue area positivity in controls and 15‐72% retinal tissue area positivity in the AD group. Level of AD pathology demonstrated an effect on the rHSI spectra (450‐600nm) in regions near the optic disc and the ventral periphery: intermediate AD pathology showed the strongest rHSI signature (decrease in optical transmittance) followed by high, then low AD pathology samples. Correlation of the Braak neurofibrillary tangle stage and ΔOD offered a Pearson r score of 0.79 (p = 0.004).ConclusionThis study was the first to assess and quantify AβOs in clinically, neuropathologically, and hyperspectrally characterized postmortem matched brain and retinal tissues. Progression of well‐established neuropathologically classified AD stages (e.g Braak) may correlate with retinal AβO levels measured using rHSI. Certain retina regions that share nervous tissue with the brain (optic disc, periphery) are likely more sensitive to rHSI‐mediated detection of AD pathology. Larger samples are needed to comprehensively assess and quantify retinal AβOs.
Incremental declines in independence associated with disease progression in early symptomatic Alzheimer’s disease (AD)
Authors: Chandler Julie , Ye Wenyu , Mi Xiaojuan , Dennehy Ellen B , Atkins Alexandra S , Wessels Alette M 
Published: December 2023

AbstractBackgroundAssociations between disease progression (DP) and health outcomes are poorly characterized in mild cognitive impairment (MCI) and mild AD (MILD). To address this, we examined the impact of DP on incremental changes in independent functioning over 18 months; baseline factors associated with DP were also explored.MethodsParticipants included amyloid‐positive participants assigned to placebo in EXPEDITION‐1/2/3 (solanezumab) and AMARANTH (lanabecestat) studies. DP defined as worsening ³5 (MCI1) or ³9 (MILD2) points on the Integrated Alzheimer’s Disease Rating Scale (iADRS). Endpoints included proportions of participants requiring home supervision (³1 hour) or unable to leave home independently (score <3) and change in total care partner time. Machine learning methods using penalized logistic regression and random forest identified factors associated with DP. Least squares mean change (LSMC) was estimated from mixed‐model repeated measures.ResultsOf 1884 participants (274 MCI, 1610 MILD), 56% of MCI and 63% of MILD participants met DP criteria over 18 months.Baseline AD medication use, greater care partner time, worse functional activities questionnaire (FAQ) score and CDR‐SB, higher iADRS, and lower BMI and MMSE increased odds of DP for MILD (Figure 1) but not for MCI.Proportion of participants with DP requiring home supervision (p<0.001; MILD only) and not leaving home independently (p<0.05; MCI&MILD) increased significantly at each post‐baseline visit over 18 months (Figure 2). DP in MILD only had significantly higher proportions of participants who could not be left home alone or travel outside of home independently vs no DP (p<0.05).In those with DP, total care partner time increased significantly from baseline to 18 months (LSMC: 46.0±12.5 hours/month for MCI and 73.2±5.5 for MILD) (Figure 3). For DP vs no DP, increased care partner time at 18 months was significantly higher for MILD (LSMC difference, 66.0±9.3 hours/month; p<0.001) but not for MCI.ConclusionsEarly symptomatic AD participants who progressed over 18 months had reduced independence and required more care partner time. Treatments that slow DP may preserve independence and reduce overall health care burden.References1. Wessels AM, et al. J Prev Alzheimers Dis. 2015;2:227‐2412. Wessels AM, et al. J Alzheimers Dis. 2022;88:577‐588.
An ultra‐fast MRI protocol in dementia enabled by Wave‐CAIPI
Authors: Grilo Miguel A Rosa , Chughtai Haroon R , Thomas David L , Cash David M , Beament Millie , Coath William , Prosser Lloyd , Malone Ian B , Lim Emma , Jäger H Rolf , Alexander Daniel C , Fox Nick C , Mummery Catherine J , Parker Geoff JM , Barkhof Frederik 
Published: December 2023

AbstractBackgroundStructural brain imaging is essential for the diagnostic workup in dementia and for safety monitoring of disease modifying therapies. MRI has several advantages over other imaging techniques, but its use is limited by cost and availability. Reducing acquisition time holds the potential for its democratisation. We developed a prototype ultra‐fast MRI protocol based on an optimised 3D parallel imaging approach. Here we present the finalised version, developed using a qualitative and quantitative approach to optimisation.MethodIn this ongoing real‐world study, participants are sequentially recruited from the cognitive disorders' clinics of a tertiary centre. Patients due to have a standard 3T MRI scan as part of their diagnostic pathway are eligible. The standard‐of‐care protocol includes T1w, T2w, FLAIR and T2*/SWI sequences [scan time ∼18mins]. The prototype rapid protocol utilises Siemens work‐in‐progress 3D Wave‐CAIPI (Controlled Aliasing in Parallel Imaging) sequences, enabling a reduction in scan time of more than 60% (table 1). For qualitative analysis, scans (of 9 individuals) were reviewed by six raters and assessed side‐by‐side against the gold‐standard scan for diagnostic utility. For a quantitative analysis, volumes were calculated from T1w scans using the default cortical reconstruction and volumetric segmentation pipeline in FreeSurfer 7.3.2. Key volumes (e.g., deep grey matter, cortical grey matter, white matter) for each participant were compared between the two protocols. Independent visual QC was performed on T1w datasets by an experienced clinical trials team.ResultSide‐by‐side visual assessment results of 9 participants is shown in figure 1. For all sequences bar FLAIR, raters scored the ultra‐fast sequences of comparable image quality in at least 67% of cases. For quantitative analysis, 10 T1w sequence pairs were reviewed, with 1 clinical scan failing QC due to motion. Bland‐Altman analyses (figure 2.) comparing volumes between the clinical and ultra‐fast sequences show little bias.ConclusionOur preliminary results demonstrate that for most contrasts the ultra‐fast sequences are diagnostically non‐inferior and quantitatively equivalent to the clinical protocol both for diagnosis and for safety monitoring.
Care practices respecting the autonomy of older people with dementia
Authors: Shimada Chiho , Hirayama Ryo , Ito Mio , Wakui Tomoko 
Published: December 2023

AbstractBackgroundHow people with dementia perceive the world has been recently described in better detail, making it easier to understand their unique situations and needs. In caregiving situations, it is desirable to understand the subjective world of people with dementia and to consider the impact of the caregiver’s approach. This study aimed to explore how care providers identify cues to understand the needs and subjective world of people with dementia.MethodsOverall, 4,000 sites (24.3% sampling rate) were selected from all small facilities (with less than 30 residents) providing dementia care in Japan. A questionnaire was mailed to caregiver leaders, and data was collected online. A two‐case vignette depicted a situation in which care staff experienced significant difficulty caring for residents with dementia; one described a resident who refused to bathe and the other a resident who walked around the facility in the middle of the night. In each situation, respondents were asked to speculate on how they would act to understand the thoughts of the person with dementia. The analysis consisted of 1) segmenting and coding the behavioural and verbal descriptions of each scene, and 2) interpreting and categorising the caregivers’ intentions.ResultsThere were 599 respondents (response rate 15.0%); of these, 566 and 558 were for the bathing and night‐time situations, respectively. The descripted responses were categorised into the following five groups. 1) Before providing specific care, it is necessary to ‘build a secure relationship’ by spending time together doing activities and talking about unrelated topics, regardless of the care. 2) To understand the resident’s thoughts and feelings, care workers ‘explore the subjective world’ by asking residents directly about their reasons. 3) Care workers also 'infer from objective information' such as care records and other sources. 4) Caregivers should ‘keep trying acceptable methods until the resident agrees to receive care’. 5) Caregivers should ‘allow things to not work out as intended’.DiscussionThe study showed that care providers use a variety of strategies to build rapport and respect the autonomy of the residents, such as exploring, speculating, suggesting, and waiting for the residents to express their intentions.
Designing Homes for Healthy Cognitive Ageing: Passive Sensing of Environmental Quality in the Homes of Older People Living in Scotland
Authors: Quirke Martin , Davison Lisa , Rutherford Alasdair , Bowes Alison 
Published: December 2023

AbstractBackgroundCharacteristics of the indoor home environment such as temperature, humidity, and air quality are associated with risk of injury, illness, and cognitive decline.Method68 passive environment monitoring sensors were installed in the homes of (n = 10) people aged 55 or older, experiencing age related cognitive change, and living in Scotland. The size of the homes ranged from 4‐12 rooms and data collection periods ranged from 2‐7 months. Environment data along with infra‐red based space occupancy data was collected every 60 seconds for the duration of each installation. Analysis included evaluation of sensor based environmental data against participants’ experiential account of their habits and activities whilst living in their homes.ResultAnalyses of average usage patterns, showing typical weekday and weekend activity within the homes over the data collection period were used to identify potential influences on the health supporting qualities of indoor home environments. These include regional weather conditions, occupant activity patterns, ventilation, and heating, as well as the influence of fuel poverty.ConclusionHigh fuel costs in combination with regional climatic conditions may be increasing the risk of indoor home environments contributing to poor health outcomes, including cognitive decline, amongst older people living in Scotland.
Risk of COVID‐19 infection, hospitalization, and mortality in older adults with versus without dementia during the first wave of COVID‐19 pandemic: A Swedish nationwide study
Authors: Hoang Minh Tuan , Wastesson Jonas , Szilcz Máté , Maura Géric , Blotière Pierre‐Olivier , Johnell Kristina 
Published: December 2023

AbstractBackgroundThe difference in the risk of COVID‐19 infection, hospitalization, and mortality between older adults with and without dementia is understudied. This study aimed to compare the risk of COVID‐19 infection, hospitalization, and mortality between dementia patients aged 65 years and above with non‐dementia counterparts, during the first wave of COVID‐19 in Sweden.MethodThis observational study included data from 2,031,069 older adults in Sweden (2015‐2020), based on the linkage of various Swedish nationwide registries. Outcomes included COVID‐19 infection, hospitalization, and mortality during the first wave of COVID‐19 in Sweden (from 01 March to 31 August 2020). We performed flexible parametric survival models to investigate the association between outcomes and having dementia, adjusted by age at the start of the first COVID‐19 wave in Sweden, sex, Charlson Comorbidity Index, hospital frailty risk score, and other sociodemographic covariates. Subgroup analyses were conducted on age groups, sex and living arrangement (nursing homes versus community dwelling).ResultCompared to the non‐dementia group (n = 1,965,194), the dementia patients (n = 65,875) were older (median 82.0 years, IQR 77.0‐87.0 versus 74.0 years, IQR 69.0‐79.0), had higher proportions of women (59.1% versus 53.2%), living alone (60.0% vs 47.5%), living in nursing homes (39.0% vs. 2.2%) and having lower socioeconomic positions. Comorbidities were more common among the dementia group, as shown by their higher Charlson Comorbidity Index or hospital frailty risk score. Our main analyses showed the dementia group was at higher risks of COVID‐19 infection (hazard ratio (HR) 3.13, 95% confidence interval (95% CI) 3.00‐3.27), COVID‐19 hospitalization (HR 1.32, 95% CI 1.23‐1.42) and COVID‐19 death (HR 4.01, 95% CI 3.75‐4.29), compared to the non‐dementia group. The dementia group living in nursing homes had higher risks of COVID‐19 infection and death, but a lower likelihood of COVID‐19 hospitalization (HR 0.79, 95% CI 0.68‐0.92), compared to the non‐dementia group.ConclusionWe confirmed that the older adults with dementia had higher risks of COVID‐19 infection, hospitalization, and mortality, than those without dementia during the first wave of COVID‐19 in Sweden. However, dementia patients living in nursing homes were at a lower risk of COVID‐19 hospitalization, compared to older adults without dementia.
Novel Tip60 HAT activators as neuroepigenetic therapeutic modulators for Alzheimer’s Disease
Authors: Elefant Felice , Bhatnagar Akanksha , Dasari Rohan , Chnogtham Neha , Kortagere Sandhya 
Published: December 2023

AbstractBackgroundAlzheimer’s Disease (AD) etiology involves a complex interplay of genetics, age, and environmental factors that influence neuroepigenetic mediated neural gene control. Reduced histone acetylation in the AD brain is a widespread hallmark underlying neural gene repression and cognitive impairment in AD etiology. As histone acetylation is dynamically regulated by antagonistic histone deacetylases (HDACs) and histone acetyltransferases (HATs), pharmacological treatments aiming to restore histone acetylation via HDAC inhibition are a research hotspot for developing AD cognitive enhancing drugs. Although promising, HDAC inhibitor treatments in the AD animal models are rarely translated into clinical trials due to non‐specific global hyperacetylation. Alternatively, enhancing activity of specific HATs with non‐redundant functions serves as an exciting new therapeutic strategy that remains unexplored. To this end, our lab has identified and published a neuroprotective role for HAT Tip60 in multiple neural circuits impaired in AD pathology. Human and Drosophila AD brains exhibit reduced Tip60 and enhanced repressor HDAC2 that triggers histone deacetylation with concomitant repression of cognition genes. All these deficits are prevented by genetically increasing Tip60 in the Drosophila AD brain. Here, we test that pharmacologically enhancing Tip60’s HAT function replicates this AD neuroprotective function.MethodWe used in silico structural modeling and a novel pharmacophore based virtual screening approach to design and synthesize novel small molecule compounds strongly predicted to target and enhance Tip60’s HAT activity.ResultOur screen produced 19,000 hits that we individually docked on Tip60’s HAT domain using GOLD docking software. 13 compounds were identified that exhibited significantly high Tip60 docking scores, and optimal ease of synthesis, drug like properties and blood brain barrier peneteration. These compounds were custom synthesized. We show that several of these compounds fully rescue locomotor neural based deficits and cognition gene expression alterations in both Tip60 knockdown and AD Drosophila in vivo models with no observable side effects, underscoring their therapeutic effectiveness. These compounds will ultimately be assessed for further specificity and for their therapeutic effectiveness in AD animal models in vivo.ConclusionWe propose our first‐in‐class small molecule Tip60 HAT activators will serve as powerful novel chemical entities for development of specific acetylation‐based cognition enhancing drugs for AD.
High VEGF‐A and low PlGF in plasma are associated with reduced longitudinal tau PET burden and slower cognitive decline in preclinical Alzheimer’s disease
Authors: Yau Wai‐Ying Wendy , Yang Hyun‐Sik , Carlyle Becky C. , Trombetta Bianca A. , Zhang Can , Schultz Aaron P. , Pruzin Jeremy J. , Fitzpatrick Colleen D , Kirn Dylan , Rabin Jennifer S. , Buckley Rachel F. , Hohman Timothy J. , Rentz Dorene M. , Tanzi Rudolph E. , Johnson Keith A. , Sperling Reisa A. , Arnold Steven E. , Chhatwal Jasmeer P. 
Published: December 2023

AbstractBackgroundVascular dysfunction is increasingly recognized as an important partner in the pathogenesis of Alzheimer’s disease (AD). Alterations in vascular endothelial‐derived growth factor (VEGF) pathways have been implicated as potential mechanisms. However, the specific impact of VEGF proteins in preclinical AD and their relationships with other AD and vascular pathologies during this critical early period remain to be elucidated.MethodWe examined 316 cognitively unimpaired at baseline older adults from the Harvard Aging Brain Study (Table 1). VEGF family proteins (VEGF‐A, VEGF‐C, VEGF‐D, PlGF, VEGFR‐1) were measured in baseline fasting plasma using MSD V‐PLEX Angiogenesis Panel. Using linear mixed effects models, we examined the interactive effects of baseline plasma VEGF proteins and amyloid PET burden (Pittsburgh Compound‐B) on longitudinal cognitive decline (Preclinical Alzheimer Cognitive Composite‐5). We further investigated if effects on cognition may be mediated by longitudinal inferior temporal tau PET burden (Flortaucipir; subset n = 186) or hippocampal atrophy (subset n = 206). Lastly, we examined the impact of adjusting for baseline cardiovascular risk score or white matter hyperintensity volume (WMH).ResultHigh plasma VEGF‐A (β = 0.06, t = 3.23, p = 0.001) and low PlGF (β = ‐0.08, t = ‐3.88, p<0.001) each interacted with elevated baseline amyloid burden to slow prospective cognitive decline (Figure 1A). Concordantly, high VEGF‐A (β = ‐0.12, t = ‐4.56, p<0.001) and low PlGF (β = 0.09, t = 3.63, p<0.001) were associated with reduced longitudinal tau accumulation in those with elevated amyloid (Figure 1B). Moderated mediation analyses revealed that, under elevated amyloid, reduced tau accumulation fully mediated the effects of high VEGF‐A and partially mediated the effects of low PlGF (30%) on slower cognitive decline (Figure 2). There were no significant associations with hippocampal atrophy. The interactive effects of VEGF‐A and PlGF on tau and cognition remained significant after adjusting for cardiovascular risk score or WMH (p<0.003).ConclusionHigh plasma VEGF‐A and low PlGF were associated with slower prospective cognitive decline in preclinical AD, which was fully (VEGF‐A) and partially (PlGF) mediated by reduced tau accumulation. These effects were distinct from conventional vascular risk and injury measures, highlighting VEGF‐A and PlGF as potential molecular targets in preclinical AD to modify the vascular‐AD synergy in combination with anti‐amyloid and traditional vascular risk reduction therapies.
Herpes zoster vaccination prevents or delays dementia: causal evidence from a country‐wide natural experiment in Wales
Authors: Eyting Markus , Xie Min , Hess Simon , Geldsetzer Pascal 
Published: December 2023

AbstractBackgroundThere is growing recognition that infectious agents, particularly herpesviruses, could play a role in the development of some types of dementia.MethodIn Wales, eligibility for the herpes zoster vaccine (Zostavax) for shingles prevention was determined based on an individual’s exact date of birth. Those born before September‐2‐1933 were ineligible (and remained ineligible for life), while those born on or after September‐2‐1933 were eligible. This natural experiment provides causal, as opposed to correlational, evidence because there is no plausible reason why adults born just one week apart should differ systematically from each other. We used a regression discontinuity design in Welsh country‐wide data on primary and secondary care encounters, and death certificates. The outcome was a new dementia diagnosis as recorded in any of these data sources.ResultWe included 282,541 individuals born between September‐1‐1925 and August‐31‐1941. The percentage who received the zoster vaccine increased from 0.01% among those one week too old to be eligible, to 47.2% among those one week younger. Receiving the vaccine reduced the probability of a new dementia diagnosis over a follow‐up period of seven years by 3.5 percentage points (95% CI: 0.6‐7.1, p = 0.019), corresponding to a 22.4% relative decrease. There were significant protective effects from the vaccine for Alzheimer’s disease but not vascular dementia. Effects were far stronger among women than men. To demonstrate that our approach is causal, we show that i) there were no differences in pre‐existing conditions or uptake of other preventive interventions across the date‐of‐birth eligibility cutoff; ii) the zoster vaccine had no effects on any other common causes of morbidity and mortality; and iii) no other interventions used the same date‐of‐birth eligibility cutoff.ConclusionIn addition to identifying a readily available preventive intervention for dementia, our findings strongly suggest an important role of the varicella zoster virus in the etiology of dementia, particularly among women. Unlike existing studies in this field, this analysis provides causal evidence because individuals who differ in age by just one week are exchangeable with each other on both observed and unobserved characteristics, except for a large difference in the probability of receiving the zoster vaccine.