bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatially resolved transcriptomics in the APPSWE [Tg2576] mouse model of Alzheimer’s disease
Authors: Uytingco Cedric R , Chew Jennifer , Hartnett Andrej D , Weisenfeld Neil , Williams Stephen R , Ziraldo Solongo B , Meschi Francesca , Miller Kelly , Yin Yifeng
Published: December 2022

Background

Alzheimer's and other neurodegenerative diseases remain pervasive, impacting patients and their families as the disease progresses. Despite the continual expansion of our understanding of these conditions, the detailed molecular mechanisms and progression of pathology throughout the brain remain elusive and complex. Using genomic and RNA‐seq approaches, identification of individual cells and their genetic makeup provide an added perspective on their roles in how the central nervous system (CNS) function in both healthy and diseased states. Here we demonstrate the characterization of spatial transcriptomic patterns in the APPSWE [Tg2576] mouse model of familial Alzheimer’s Disease using the Visium Spatial Gene Expression Solution.

Method

Serial sections of fresh‐frozen transgenic APPSWE [Tg2576] and littermate control mouse brains were placed onto Visium Spatial Gene Expression slides. The slides consist of ∼5,000 spot arrays with uniquely barcoded probes allowing for the capture of native mRNA. The samples were H&E or immunostained and then permeabilized, allowing for the capture of transcripts and library generation. The resulting libraries were then sequenced on an Illumina NovaSeq. Then, using the 10x Genomics Space Ranger analysis pipeline and the Loupe Browser desktop software, the RNA‐seq data were merged with stained tissue images to align reads, perform clustering, and gene expression analysis.

Result

With the generated data, we demonstrated an improved version of the spotted oligo array technology that increases tissue coverage and spatial resolution with reduced spot size, and increased spot number and packing density. We captured spatial patterns of gene expression and mapped the information back to H&E and immunostained images with regional annotations. Performing differential analysis on the resulting spatial gene expression data, we observed elevated expression of the Pmch (pro‐melanin concentrating hormone) gene within the hypothalamic region of APPSWE [Tg2576] transgenic mice compared to the littermate controls. By immunofluorescence staining, we confirmed the gene expression patterns and utilized this approach to identify the cells and refine the gene expression characterization.

Conclusion

Together, this confluence of imaging and sequencing is a valuable tool for understanding the relationships between CNS cell types in healthy and diseased samples with an unbiased anatomical and gene expression‐driven method.
Deep plasma proteomics reveal age‐related molecular pathways modulated by GRF6019 treatment in Alzheimer’s disease patients
Authors: Nanasi Tibor , Feng Mia , Braithwaite Steven P , Lehallier Benoit
Published: December 2022

Background

Blood has been widely investigated to discover biomarkers and gain insights into the biology of aging and age‐related diseases. Its protein composition provides information about complex biological processes, as proteins are often direct regulators of cellular pathways. Using recent methodological developments allowing the measurement of thousands of proteins with very high sensitivity and specificity, we sought to understand comprehensive proteomic changes in two AD clinical trials.

Method

Phase 2 clinical trials (GRF6019‐201 n=40 and GRF6019‐202 n=26) testing the safety, tolerability, and feasibility of repeated infusions of the plasma fraction GRF6019 in Alzheimer's disease (AD) were used as the source to measure more than 7000 proteins in plasma using the SOMAscan and Olink assays. To evaluate the relevance of the proteomics changes induced by GRF6019, we compared these changes to those observed in a healthy aging cohort (∼5000 proteins measured in 370 subjects).

Result

Standard statistical analysis at the protein levels lacked power due to the small sample size in phase 2 clinical trials. By analyzing trajectories of groups of proteins, clinical proteomics revealed multiple clusters of proteins responding to GRF6019. Remarkably, several pathways modulated by GRF6019 were particularly relevant for the biology of aging and AD – including the complement/coagulation cascades and neuronal pathways (q<0.05).

Conclusion

Altogether, our results suggest that the treatment of AD patients with a complex plasma fraction modulates biological pathways that are relevant to aging and AD. Our results establish deep proteomics as a powerful tool to study human response to treatment in clinical trials.
Role of ABCA7 in Neural Lipid Metabolism and Its Association with Alzheimer's Disease Neuropathology
Authors: Garliyev Viktor , Wiener Joel P. , Pratico Domenico , Lyssenko Nicholas N.
Published: December 2022

Background

Strong genetic evidence supports involvement of adenosine triphosphate binding‐cassette transporter subfamily A member 7 (ABCA7) in Alzheimer’s disease (AD) pathogenesis. ABCA7 closely resembles ABCA1, a cholesterol transporter, in structure. However, molecular specificity of ABCA7‐mediated lipid transport and the role of this protein in AD pathophysiology are understood incompletely. We advance the hypothesis that ABCA7 protects against AD development by removing neurodegenerative lipid from the brain.

Method

A validated monoclonal antibody was used to measure ABCA7 protein in a cohort of 104 individuals represented by the hippocampus and a different cohort of 119 individuals represented by the parietal cortex. Both cohorts included individuals with Braak stages 0‐V. Changes in ABCA7 level in response to treatment with lipid metabolism modulators were investigated in human microglial C20 and HMC3 and human astrocytic A172 cell lines.

Result

To match for age, the cohorts were subdivided into 63‐78 and 79‐94 age‐at‐death brackets. There was no significant correlation between ABCA7 protein levels and Braak stages. However, individuals with Braak stages II‐V as a group had significantly lower ABCA7 levels than individuals with Braak stages 0/I as a group in the 63‐78 age bracket of both cohorts (Mann‐Whitney p<0.0001 and p=0.003, respectively) and in the 79‐94 bracket of the parietal cortex cohort (p=0.037) but not in the hippocampus cohort (p=0.33). One of the reasons for this difference between the hippocampus and parietal cortex was that ABCA7 levels decreased significantly with age in the Braak stage 0/I group in the hippocampus but not the parietal cortex (p=0.02 vs p=0.77 for ABCA7 levels in the 63‐78 vs 79‐94 age bracket, respectively). An analysis of lipid metabolism using pharmacological modulators revealed that ABCA7 expression in microglial and astrocytic cells does not respond to the intracellular cholesterol level or regulators of intracellular cholesterol metabolism.

Conclusion

These results are in line with the hypothesis that ABCA7 prevents AD neuropathogenesis, i.e., loss of ABCA7 protein occurs sharply and early between Braak stages I and II. There also appear to be brain region‐specific changes in ABCA7 expression with age. The neurodegenerative lipid that ABCA7 removes from the brain remains to be identified.
Hippocampal grading is sensitive to changes in cognition in early MCI
Authors: Morrison Cassandra , Dadar Mahsa , Shafiee Neda , Collins Louis D
Published: December 2022

Background

Increased age and cognitive decline are both associated with changes in the hippocampus. These associations are often measured using hippocampal volume measurements and changes in episodic memory. Some studies have also observed a relationship between hippocampal volume and global cognition. However, these studies often only find associations in progressed stages of cognitive decline. This study examined (1) if hippocampal grading is associated with global cognition in cognitively normal controls (NC), early MCI (eMCI), late (lMCI), and Alzheimer’s disease (AD), and (2) whether these associations differ across diagnostic cohorts.

Methods

Participants for this study were selected from the Alzheimer’s Disease Neuroimaging Initiative. They were included if they completed baseline MRI scans and the Alzheimer’s disease Assessment Scale (ADAS‐13) and Clinical Dementia Rating – Sum of Boxes (CDR‐SB) cognitive tests. A total of 1620 older adults met the inclusion criteria and were included (495 CN, 262 eMCI, 545 lMCI, and 318 AD). Linear regressions examined the association between hippocampal grading and cognitive scores.

Results

Lower global cognition (measured by increased ADAS‐13 scores) was associated with hippocampal grading scores in in NC, eMCI, lMCI and AD cohorts. Lower global cognition (measured by increased CDR‐SB scores) was associated with hippocampal grading scores in lMCI and AD, but not in eMCI or NC groups.

Conclusion

Hippocampal grading was associated with changes in global cognition in healthy controls and in disease cohorts when there is sufficient dynamic range in the cognitive test. No correlation between CDR‐SB and NC was found because the NC group only had CDR‐SB scores of 0 and 1. Hippocampal grading may, thus, be a useful measure that is sensitive to progressive changes early in the disease course. Future research should determine if this method is associated with longitudinal changes in cognition.
Association of life‐course traumatic brain injury with the risk of dementia: a nationwide twin study
Authors: Zhang Lulu , Yang Wenzhe , Li Xuerui , Dove Abigail , Qi Xiuying , Pan Kuan‐Yu , Xu Weili
Published: December 2022

Background

Traumatic brain injury (TBI) in late‐life has been related to dementia, but the impact of life‐course TBI on dementia remains unclear.We aimed to examine the association between TBI occurring at different ages and dementia, and to explore the role of cardiometabolic diseases (CMDs) and genetic and early‐life environmental factors in this association.

Method

Within the Swedish Twin Registry,35,312 dementia‐free twin individuals (mean age = 62.78±9.74 years, 53.95% female) were followed for up to 18 years.Life‐course TBI was ascertained from records in the SwedishNational Patient Registry (NPR) and divided into five age groups (≤39, 40‐49, 50‐59, 60‐69, and ≥70 years) according to age at TBI occurrence.Diagnoses of dementia and CMDs (including type 2 diabetes mellitus, heart disease, and stroke) were identified through the NPR and the Swedish Cause of Death Register.Generalized estimating equation (GEE) models were applied for the unmatched case‐control analysis among all individuals, and conditional logistic regression models were used for the co‐twin matched case‐control analysis in dementia‐discordant twin pairs.

Result

Of all participants, 1,086 (3.1%) had TBI at baseline and 3,292 (9.3%)developed incident dementiaduring thefollow‐up.In multi‐adjustedGEE models, the odds ratio (OR, 95% confidence interval [CI]) of dementia was 1.27 (1.03–1.57) for TBI at any age, 0.86 (0.43–1.72)for TBI at ≤39 years, 1.33 (0.81‐2.19) for TBIat 40‐49 years,1.55 (1.04–2.31) for TBI at 50‐59 years, 1.68 (1.13–2.50) for TBI at 60‐69 years, and 0.91 (0.59–1.41) for TBI at ≥70 years. In joint effect analysis, the multi‐adjusted OR (95% CI) of dementia was 2.51 (1.60‐3.93) for those who had TBI between ages 50‐69 yearsand CMDscompared to those with neitherTBI nor CMDs. There was a statistically significant interaction between TBI occurring between ages50 and 69 years and CMDs on dementia (P<0.05). In multi‐adjusted conditional logistic regression, the TBI‐dementia association remained significant. The difference in ORs from the unmatched and co‐twin matched analyses was not statistically significant (P = 0.36).

Conclusion

TBI, especially occurring between ages 50‐69 years, is associated with an increased risk of dementia, and this risk is exacerbated among people with CMDs.Genetic and early‐life environmental factors may not account for the TBI‐dementia association.
Simulated communication skills training program effects using augmented reality with real‐time feedback: A randomized control study
Authors: Kobayashi Masaki , Iwamoto Miyuki , Une Saki , Kurazume Ryo , Nakazawa Atsushi , Honda Miwako
Published: December 2022

Background

While communication with dementia patients is challenging, known educational methods to improve communication skill for medical professionals are lacking. Our study aimed to assess the efficacy of simulated communication skills training for nursing students using augmented reality (AR) with real‐time feedback.

Methods

This is a randomized control study. Twenty‐five nursing students enrolled and learned standardized multimodal comprehensive care communication skills through a self‐learning material, which includes pathophysiology and clinical manifestations of dementia. Subsequently, participants were randomly assigned to one of the two learning systems—AR training or conventional nursing mannequin training. Each group had the training intervention to change the clothes of mannequins for one hour. The mannequin of the AR group was a superimposed computer graphic of an elderly woman’s face which reacted to participants' communication. Further, the communication skills of gaze and voice were evaluated by artificial intelligence (AI) and feedbacked to the participants’ head‐mounted display in real‐time. The conventional training group had the self‐training with nursing mannequins. All participants performed basic nursing care, including changing clothes and bed bath, to simulated patients before and after the training intervention, which were video‐recorded by an eye‐tracking camera and a fixed camera, then the videos were analyzed the communication skills by AI. Additionally, participants' empathy to patients was evaluated by the Jefferson Scale of Empathy‐Health Professions Students Version (JSPE‐HSP). The primary outcome was the proportion of time spent in eye contact during the care to simulated patients. The secondary outcome was the empathy score of JSPE‐HSP.

Results

After the training intervention, the proportion of time spent in eye contact in the AR training group significantly increased than the conventional training group (eye contact 13.6% versus 4.4%, P<0.05). Moreover, the JSPE‐HSP score increased from pre‐training to post‐training in the AR training group, whereas it decreased in the conventional training group [Mean (SD): 9.1 (6.6) versus ‐1.3 (3.8), P<0.01].

Conclusions

The simulated communication skills training for nursing students using augmented reality with real‐time feedback was associated with increased interactive communication skills to simulated patients and the empathy to patients.
Optimizing cCOG, a web‐based tool, to detect dementia with Lewy Bodies.
Authors: van Gils Aniek M. , van de Beek Marleen , van Unnik Annemartijn , Tolonen Antti , Handgraaf Dédé , van Leeuwenstijn Mardou , Lötjönen Jyrki , van der Flier Wiesje M. , Lemstra Afina W. , Meester Hanneke F.M. Rhodius‐
Published: December 2022

Background

Diagnosing dementia with Lewy bodies (DLB) is challenging due to overlapping clinical and cognitive presentation with Alzheimer’s disease (AD). Web‐based cognitive and clinical assessments could aid by providing remote and easily accessible diagnostic tools. In this study, we adapted a web‐based cognitive test tool, cCOG, by adding a visuospatial test and a brief clinical survey and assessed its ability to differentiate between DLB and AD.

Method

We included 110 patients (67±7 years, 44% female, MMSE 26±4; n = 30 DLB, n = 32 AD dementia and n = 48 controls with subjective cognitive decline (SCD)). All completed cCOG, comprising six cognitive subtasks assessing memory functioning, reaction time, executive functioning, a visuospatial task, and a brief survey addressing seven self‐reported DLB core features and suggestive autonomic features. First, we compared cCOG cognitive tasks to traditional neuropsychological tasks for all diagnostic groups and clinical questions to validated assessments of clinical features in DLB only. Then, we studied the performance of cCOG cognitive tasks and clinical questions, separately and combined, in differentiating diagnostic groups.

Result

cCOG cognitive tasks and clinical survey had moderate to strong correlations to standard neuropsychological testing (.61≤ rs
≤ .77) and to validated assessments of clinical features (.41≤ rs ≤ .65), except for fluctuations and REM‐sleep behavior disorder (RBD) (rs= .32 and rs= .10). cCOG cognitive tasks only, resulted in a diagnostic accuracy of 0.70 [95% CI 0.61‐0.78]. Full cCOG, including both cognitive tasks and brief survey had a diagnostic accuracy of 0.82 [95% CI 0.73‐0.89], with good discrimination of DLB versus AD/controls (acc 0.90 [0.83‐0.95]) and DLB versus AD (acc 0.87 [0.76‐0.95]).

Conclusion

We illustrated that cCOG aids in distinguishing DLB and AD patients by using remote assessment of cognition and clinical features. Our findings pave the way to a funneled, harmonized diagnostic process among memory clinics and eventually to a more timely and accurate diagnosis of DLB and AD.
Polygenic determinants of White Matter Hyperintensities and sex‐specific genetic profiles in the Alzheimer’s continuum
Authors: Genius Patricia , Rodríguez‐Fernández Blanca , Operto Grégory , Falcon Carles , Minguillón Carolina , Fauria Karine , Molinuevo Jose Luis , Esteller Manel , Guigó Roderic , Zetterberg Henrik , Blennow Kaj , Sudre Carole H , Suárez‐Calvet Marc , Navarro Arcadi , Gispert Juan Domingo , Vilor‐Tejedor Natalia
Published: December 2022

Background

Recent genetic association studies suggested the polygenic contribution to white matter hyperintensities (WMH). The aim of this study was to provide a genetic characterization of WMH in middle‐aged cognitively unimpaired individuals at higher risk of Alzheimer’s disease (AD) by investigating whether the genetic predisposition to specific complex diseases is associated with WMH and whether these effects are sex‐specific and dependent on core AD CSF biomarker levels.

Method

A total of 497 cognitively unimpaired middle‐aged participants at risk of AD were included (63.2% of women). A subgroup of 288 individuals also had available information on CSF biomarkers measured using the Elecsys ® and the exploratory Roche NeuroToolKit immunoassays. We classified individuals in groups defined by their biomarker profile (A/T framework). Genetic predisposition was calculated through polygenic risk scores (PRS), estimated from the most recent genome‐wide association meta‐analyses for cerebrovascular/vascular, neurodegenerative, and AD‐related biomarkers. WMH volumes were quantified through fluid‐attenuated inversion recovery (FLAIR) images obtained from magnetic resonance scans. We used non‐parametric Spearman’s rank tests to assess the association between global WMH volumes and PRSs (nominal p‐value < 0.05). Models stratified by sex and A/T group were assessed to discern WMH sex‐specific genetic differences and to discriminate genetic profiles associated with WMH in the earliest stages of the Alzheimer’s continuum.

Result

Genetic predisposition to small vessel disease was positively correlated with volumes of WMH only in women [Figure 1]. Furthermore, only for A+T‐ individuals, we found that genetic predisposition to higher CSF interleukin 6 levels and cerebral infarction was positively correlated with WMH volumes. Moreover, genetic predisposition to abnormal CSF p‐tau levels and AD was negatively correlated with volumes of WMH. We did not find significant results neither in A+T+ nor in A‐T‐ individuals.

Conclusion

Sex differences were found suggesting better genetic predictability of cerebrovascular‐PRSs to assess WMH in women. Results by A/T group suggested that asymptomatic individuals that are amyloid‐β‐positive but tau‐negative (A+T‐) have several differential genetic patterns associated with WMH that were not significant in the other groups. Overall, these findings may lead to sex differences and different biological mechanisms affecting WMH in the Alzheimer's continuum.
The assessment of ubiquitin C‐terminal hydrolase‐1 (UCH‐L1) in patients with Alzheimer’s disease
Authors: Kulczynska‐Przybik Agnieszka , Dulewicz Maciej , Mroczko Piotr , Borawska Renata , Doroszkiewicz Julia , Litman‐Zawadzka Ala , Arslan Daria , Slowik Agnieszka
Published: December 2022

Background

Alzheimer's disease is a debilitating disease that leads to a disability of the patient and it is therefore interesting not only from a medical but also from a legal point of view. Despite progress in studies on pathological mechanisms underlying the Alzheimer's disease (AD) still remains incurable. One of the mechanisms responsible for the oligomerization / aggregation of misfolded or damaged proteins in AD may be dysfunction of the ubiquitin‐proteasome system (UPS), including the highly abundant neuronal enzyme ubiquitin carboxyl‐terminal hydrolase L1 (UCHL‐1). UCHL‐1 is involved in the regulation of proteasomal degradation of damaged proteins. The presence of UCH‐L1 was found in neurofibrillary tangles in the AD brain. The aim of the present study was to measure UCHL1 levels in the cerebrospinal fluid (CSF) patients with AD and evaluate a relationship between concentrations of UCHL1 and classical neurochemical dementia biomarkers.

Method

The concentrations of UCHL‐1 and classical AD biomarkers were measured in 30 subjects, including AD patients and individuals from control group by means of multiplexing assay.

Result

The CSF concentration of UCHL‐1 was significantly higher in AD group in comparison with cognitively normal individuals. Additionally, in the whole study group levels of UCHL‐1 correlated negatively with decreased concentration of Aβ 1‐42, MMSE. Furthermore, the significant relationship between UCHL‐1 and tau proteins was also revealed.

Conclusion

The study suggest a potential role of UCHL‐1 protein in the pathology of AD and its potential usefulness as a candidate biomarker of AD, but these investigations need to be further confirmed.
Sex modifies the association between hippocampal blood flow and episodic memory in cognitively unimpaired individuals
Authors: Brugulat‐Serrat Anna , Cobigo Yann , Fonseca Corrina S. , Tsuei Torie , Goldberger Lauren , Rosen Howard J. , Kramer Joel H. , Elahi Fanny M , Staffaroni Adam M. , Casaletto Kaitlin B
Published: December 2022

Background

Cerebral blood flow (CBF) is disrupted in Alzheimer’s disease (AD) and associated with worse cognition, including episodic memory performance. Sex differences have been noted in both CBF and memory performance in AD; women demonstrate higher global CBF and memory performance than men. However, the effect of sex on the association between CBF and memory performance has not been explored. This study examined whether there were sex differences in the association between memory performance and CBF in AD‐related regions in typically aging older adults.

Method

The study included 119 functionally intact (CDR=0) older adults from the UCSF Hillblom Aging Network (mean age 74.9 (5.7), 51.2% females) who completed a cognitive assessment with brain MRI including T1‐weighted and arterial spin labeling (ASL) in hippocampal and precentral gyrus (as control) regions. Episodic memory was assessed by the California Verbal Learning Test and Benson figure delayed recall. Mean Z‐scores estimated a memory composite score. Memory composites were the dependent variable in regression models testing the interaction between regional ASL and sex as predictors, and age, education, APOE‐ε4, hippocampal volume, and vascular burden composite as covariates.

Result

There were no significant sex differences in levels of hippocampal CBF, but females performed better on the memory composite (p<0.001) than males after adjustment for age and education. We found that sex modified the association between hippocampal CBF and memory performance (figure 1) (p=0.04). Specifically, the positive association between hippocampal CBF and memory performances was stronger in men compared to women. This interaction remained significant after further adjusting for APOE‐ε4, hippocampal volume, and vascular burden. There was no significant sex by CBF interaction on memory performance when examining precentral CBF (p=0.79).

Conclusion

Our result suggests that sex modifies the association between memory performance and perfusion in brain regions vulnerable to pathological changes in preclinical AD. Specifically, greater hippocampal CBF is positively associated with memory performance in men but not women. Men may benefit more from increased blood flow, possibly reflecting vascular integrity, in hippocampal regions in memory performance than women. This work highlights mechanisms that may be differentially vulnerable by sex differences and inform risk for neurodegenerative diseases.
Sildenafil (Viagra) is a candidate drug for Alzheimer’s disease
Authors: Cheng Feixiong , Fang Jiansong , Zhang Pengyue , Zhou Yadi , Chiang Chien‐Wei , Tan Juan , Hou Yuan , Cummings Jeffrey
Published: December 2022

Background

The hypothesis that accumulation of amyloid‐beta protein and consequent tau pathology represents the main cause of Alzheimer’s disease (AD) has dominated the field for more than 2 decades; yet, anti‐tau or anti‐amyloid selective drug discovery approaches have lack of clinical benefits for AD patients. We posited that systematic identification of underlying AD‐related endophenotype modules shared by amyloid and tau may provide a foundation for generating predictive models to characterize pathogenesis and therapeutic development for AD.

Method

In this study, we developed an endophenotype network‐based methodology for in silico drug repurposing in AD. Specifically, we proposed an integrated network‐based framework by incorporating systems pharmacology and network medicine strategies to identify candidate drugs for AD. We further evaluated the drug‐AD outcomes by analyzing 7.23 million U.S. commercially insured individuals and investigated the drug’s mechanism‐of‐action using AD patient‐induced pluripotent stem cells (iPSC)‐derived neuron models.

Result

Using an endophenotype disease module‐based methodology for Alzheimer’s disease (AD) drug repurposing, we identified sildenafil as a potential disease risk modifier. Based on retrospective case‐control pharmacoepidemiologic analyses of insurance claims data for 7.23 million individuals, we found that sildenafil usage was significantly associated with a 69% reduced risk of AD (hazard ratio = 0.31, 95% confidence interval 0.25‐0.39, P<1.0´10−8). Propensity score stratified analyses confirmed that sildenafil is significantly associated with a decreased risk of AD across all four drug cohorts we tested (diltiazem, glimepiride, losartan and metformin) after adjusting age, sex, race, and disease comorbidities. We also found that sildenafil increases neurite growth and decreases phospho‐tau expression in AD patient iPSC‐derived neurons, supporting mechanistically its potential beneficial effect in Alzheimer’s disease.

Conclusion

We identified sildenafil (Viagra) as potential treatment of AD; yet, the association between sildenafil use and decreased incidence of AD does not establish causality or its direction, which requires a randomized clinical trial approach.
CSF proteins involved in neuroplasticity are associated with altered whole brain connectivity in prodromal AD
Authors: de Leeuw Diederick Martijn , Dicks Ellen , Barkhof Frederik , Visser Pieter Jelle , Tijms Betty M.
Published: December 2022

Background

Individuals with prodromal Alzheimer’s Disease (AD) and higher gray matter connectivity measures show slower decline, suggesting resilience to AD. However, the precise biological processes underlying preserved brain connections remains unclear. Here, we studied this question using cerebrospinal fluid (CSF) proteomics.

Method

From the ADNI we selected 78 individuals with MCI and abnormal CSF amyloid (i.e., prodromal AD) and 34 with normal cognition and normal CSF amyloid levels for whom MRI and CSF proteomic data was available. For each T1 MRI scan we constructed gray matter networks using an automated pipeline (Tijms, Series et al. 2012) and calculated degree, connectivity density, clustering, path length and small‐world measures (i.e. gamma, lambda and small world coefficient). Linear models were used to test associations between each connectivity measure and CSF protein levels while correcting for age and gender. Proteins showing associations of p < 0.1 were selected to find groups of proteins that are associated with biological processes according to Gene Ontology (GO). Proteomic profiles for each connectivity measure were compared to investigate overlap. Finally, we tested for enrichment of potential upstream drivers with the Enrichr tool.

Result

In total, 115 proteins were associated with altered connectivity in prodromal AD subjects (figure 1). The majority of proteins (n = 93, 80%) showed higher levels with stronger (i.e., resilient) brain networks characterized by increased degree, connectivity density, clustering, path length, gamma, lambda or small world coefficient values. In controls, 80 of these 93 proteins showed an opposite relationship, with lower levels relating to higher values for these connectivity measures, which suggests that increased levels in prodromal AD may indicate a compensatory mechanism to maintain strong brain connectivity. According to a pathway analysis in GO, these proteins associated with stronger brain networks were mainly involved in neuroplasticity pathways. A subsequent Enrichr analysis suggested involvement of upstream divers SUZ12 and REST, which are known to regulate neuroplasticity processes.

Conclusion

We observed that higher CSF levels of neuroplasticity associated proteins were associated with higher brain connectivity values in prodromal AD, suggesting that plasticity mechanisms may play a role in resilience to AD pathology.
Identification of preclinical dementia according to ATN classification for stratified trial recruitment: A machine learning approach
Authors: Koychev Ivan G , Marinov Evgeniy , Young Simon , Lazarova Sophia , Grigorova Denitsa , Palejev Dean
Published: December 2022

Background

There is a strong case for de‐risking neurodegenerative agent development through highly informative experimental medicine studies early in the disease process. These types of studies are dependent on a research infrastructure that includes volunteer registries holding highly granular phenotypic and genotypic data to allow stratified study selection. Examples of such registries include the Brain Health Registry, Great Minds and PROTECT cohorts which rely on remote cognitive, self‐reported medical history and genetic data. This requires the development of effective algorithms to predict the presence of preclinical dementia pathology. In this study we sought to address this need by building a machine learning (ML) ATN risk prediction algorithm which incorporates data typically collected in such registries.

Methods

To build a ML algorithm that is validated against an existing regression‐based model (Calvin et al. 2020), we used the EPAD LCS cohort (V1500.0). We excluded participants with 1) known diagnosis of dementia or Mild Cognitive Impairment or Clinical Dementia Rating scale ≥ 0.5 and 2) no cerebrospinal fluid biomarkers. Participants were categorised into 5 ATN categories: (i) Normal AD biomarkers: A−T−(N)−; (ii) Alzheimer’s pathologic change: A+T−(N)−; (iii) Alzheimer’s disease: A+T+(N)±; (iv)

Alzheimer’s and concomitant non‐Alzheimer’s pathologic change: A+T−(N)+; (v)

Non‐AD pathologic change: A−T ± (N)+; A−T+(N)−. Using a Weight of Evidence and Information Value method we identified 13 significant features for testing differences between each of the four neurodegeneration‐related groups vs. controls (A‐T‐N‐). Random Forest and XGBoost with 5‐fold cross validations were used to optimise the Area Under the Curve (AUC) metric.

Result

The study dataset included 927 individuals. Our optimal results outperformed the regression models in the Calvin et al. 2020 paper by between 2 and 12%. The optimal feature sets were not consistent across the 4 models with the A+T−(N)+ vs A−T−(N)− differing the most from the rest.

Conclusion

Our study demonstrates the gains offered by ML in generating ATN risk prediction over logistic regression models among pre‐dementia individuals. The reliance of the model on variables that can be collected remotely demonstrates its utility for research registers. An openly available version of the ML algorithm for use by research registries is under development.
The Brain Health Registry: Lessons learned and next steps for remote, online AD and aging clinical research
Authors: Weiner Mike W. , Truran‐Sacrey Diana , Flenniken Derek , Fockler Juliet , Camacho Monica R , Ashford Miriam T. , Howell Taylor , Kwang Winnie , Aaronson Anna , Eichenbaum Joseph , Nosheny Rachel L ,   The Brain Health Registry
Published: December 2022

Background

Remote, internet‐based methods for recruitment, screening, and longitudinally assessing older adults have the potential to greatly facilitate Alzheimer’s disease and related research, including clinical trials and observational studies.

Methods

The Brain Health Registry (BHR) is an online website and registry that includes a comprehensive battery of self‐ and study partner‐report questionnaires and online neuropsychological tests. Participants are asked to return at 6‐month intervals for longitudinal follow‐up. Recently, new online infrastructure for managing remote biomarker (saliva, blood) collection and for linking in‐clinic and online data were added. Multiple current initiatives aim to increase recruitment and engagement of underrepresented populations using digital, community engaged research strategies to improve generalizability of results. These include the recent launch of a Spanish‐language website, and projects focused on increasing enrollment and task completion of Black/African American and Hispanic/Latinx individuals.

Results

BHR includes >95,000 participants, >9000 of whom have enrolled study partners, 40% return for longitudinal follow up, 64% are age 55+, 80% are female, 80% identify as Non‐Latinx White, and 10% identify as Hispanic/Latinx. Participants have an average of 16.2 years of education. BHR has made >86,000 referrals to other studies, resulting in >5000 BHR participants enrolled in 25 different aging and AD observational studies and treatment trials. Over 2400 participants are co‐enrolled in BHR and collaborator studies, with online data linked to in‐clinic data. 573 participants have undergone APOE genotyping using remote saliva collection, and 629 have had blood collected using local phlebotomy for AD plasma biomarker analysis. Accumulating evidence supports the feasibility and validity of the approach, including associations with in‐clinic assessments, the ability to accurately detect MCI and enrichment for amyloid positivity.

Conclusions

Major advantages of the BHR approach are scalability and accessibility. Challenges include compliance, retention, and cohort diversity. Lessons learned from BHR, and components of the existing infrastructure, can be used to inform future remote clinical trial design. One such future effort is ADNI4. To facilitate enrollment of new participants, ADNI4 will establish an online recruitment and screening portal, with a remote phlebotomy component, to efficiently identify those from underrepresented populations, and those likely to have preclinical and prodromal AD.
Patient’s reaction to smartwatch based interventions in a controlled environment: preliminary results from the SAMi intervention study
Authors: Goerss Doreen , Köhler Stefanie , Rong Eleonora , Bieber Gerald , Teipel Stefan
Published: December 2022

Background

Assistive technologies show promising features to support people with cognitive impairment in daily life, e.g. mobile sensors for falls detection or getting lost. On the other hand, smartwatches bear potential to not only monitor but also interact with the user. While sensor based monitoring in dementia care is already part of many projects, direct interaction of people with cognitive impairment with smartwatches is little investigated.

Method

Based on qualitative studies, we designed interventions for a usual consumer smartwatch. We conceptualized two different tasks: A) drinking water and B) circling bells on a worksheet. Moreover, we implemented two different modes of intervention‐intensity affecting vibration patterns, alarm sounds, text sizes, display times or appearance of images and animations. We observed patients’ reactions to interventions A and B remotely via cameras. In case of failure, interventions were repeated up to three times. Here we present data of the interim analysis after completion of n = 20 patients that were equally assigned either to mode 1 (regular interventions) or mode 2 (intensive interventions). In addition to observations, participants feedback was obtained with questionnaires. Patients were diagnosed with MCI (n = 7) or dementia (n = 13) in the local memory clinic.

Result

We found it feasible to study patient‐smartwatch‐interactions with a mixed methods approach. The majority of participants (n = 18) were able to successfully complete at least one of two tasks, see Fig. 1. Circling bells (B) was completed only by 11 participants, while drinking water (A) was solved by 16 participants. The regular interventions were successful in 24%, the intensive interventions in 65%. Repetitions did not lead to an improvement of outcome in 13 cases, but in two cases. Reasons for insufficient task completion varied, e.g. patients showed unexpected reactions such as circling the picture on the smartwatch or doing arm circles. One patient fell asleep and did not react at all.

Conclusion

Remote observation of patients’ reaction to smartwatch based interventions is technically challenging but offers intriguing insights into human‐computer interaction. User‐centered design for patients with MCI or dementia differs from the approach for usual smartwatch users and needs to respect special needs and requirements.
The association between long‐term PM2.5 exposure and late‐life amyloid burden in the Atherosclerosis Risk in Communities (ARIC) study cohort
Authors: Bennett Erin E , Xu Xiaohui , Lynch Katie M , Park Eun Sug , Ying Qi , Smith Richard L , Stewart James D , Whitsel Eric A , Mosley Thomas H , Yanosky Jeff D , Wong Dean F , Liao Duanping , Gottesman Rebecca F , Power Melinda C
Published: December 2022

Background

A number of studies show an association between long‐term exposure to ambient particulate matter ≤ 2.5 um (PM2.5) and late‐life cognitive impairment. Mechanistic models suggest that PM2.5 may influence cognitive health through promotion of Alzheimer’s disease, which is characterized by brain amyloid accumulation. However, the association between long‐term PM2.5 exposure and brain amyloid deposition remains poorly characterized in epidemiological studies.

Method

We used data from the Atherosclerosis Risk in Communities (ARIC) study cohort. We used a chemical transport model with data fusion to estimate mean PM2.5 concentrations (ug/m3) in 36‐, 12‐, 4‐, and 1‐km grid cells in ARIC study areas. We linked the concentrations to geocoded participant addresses and calculated mean PM2.5 concentrations from 2000 to 2007. We estimated amyloid deposition using florbetapir amyloid positron emission tomography (PET) scans in 346 ARIC‐PET participants with normal cognition or mild cognitive impairment in 2011‐2014. We defined amyloid positivity as a global cortical standardized uptake value ratio (SUVR) ≥ the sample median of 1.2. We used logistic regression models to quantify the association between amyloid positivity and mean 2000‐2007 PM2.5 concentration after adjusting for potential confounders. We additionally explored effect measure modification by APOE e4 allele status and tested whether effect estimates were consistent using alternate PM2.5 exposure methods.

Result

After restricting to participants with non‐missing exposure and confounder data and excluding one participant with dementia, the analytic sample included 279 participants. At the time of amyloid‐PET scans, their mean age was 78 years, 56% were female, 42% were Black, and 26% had mild cognitive impairment. After adjusting for age, sex, education, and race‐study center, we found no significant association between brain amyloid positivity and long‐term mean PM2.5 exposure. We also found no evidence of effect measure modification by APOE e4 allele status. Results were consistent when we used alternate PM2.5 estimation methods.

Conclusion

Our findings suggest that ambient PM2.5 may induce neurotoxic effects through non‐amyloid, potentially vascular pathways, though we note the small sample size may have made us underpowered to detect a significant association.
The Experiences of Son’s caring for a parent with Alzheimer’s Disease
Authors: DiLeone Christine , Maruca Annette T.
Published: December 2022

Background

Among primary caregivers (individuals who indicate having the most responsibility for helping their relatives) of people with dementia, over half take care of their parents. Most caregivers (66 percent) live with the care recipient in the community (Fisher, et al., 2011). The responsibilities of caring for someone with dementia often fall to women (Kasper et al., 2015). Men are underrepresented in the literature pertaining to family caregiving in dementia. Yet, they play an important role in providing care for cognitively impaired older adults in the community (Houde, 2001). While there is extensive literature on caregiving in dementia, only a few studies have emphasized the caregiving role of men (Coe & Neufeld, 1999; Kramer, 2000; Russell, 2007a, 2007b).

Method

We employed the meta‐ethnography methodology. Five electronic bibliographic databases were used to retrieve studies published from 1997‐2021 that explored son caregivers' experiences of caring for a parent with Alzheimer’s Disease. Five qualitative studies were finally included for the synthesis, based on the eligibility criteria.

Result

Common themes that emerged in the son’s experiences include a sense of loss, stress, and enduring the caregiving journey. Son’s caregiver roles included case manager, disease educator to in home paid help, and coping with sibling conflicts. Two studies showed positive outcomes.

Conclusion

This review provides a deeper understanding of son’s caregivers' experiences of caring for a parent with Alzheimer’s Disease. The findings can help healthcare providers in the development and implementation of tailored interventions specific to son’s caregiver needs.
First results of the AMYPAD Prognostic and Natural History Study: amyloid‐PET centiloids predicts cognitive functioning in a pre‐dementia population
Authors: García David Vállez , Collij Lyduine E. , Mastenbroek Sophie E , Alves Isadora Lopes , Gispert Juan Domingo , Ritchie Craig W. , Boada Mercè , Marquié Marta , Grau‐Rivera Oriol , Fauria Karine , Scheltens Philip , Vandenberghe Rik , Hanseeuw Bernard J , Schöll Michael , Frisoni Giovanni B , Boecker Henning , Jessen Frank , Wolz Robin , Grootoonk Sylke , Stephens Andrew W , Buckley Christopher , Ford Lisa , Visser Pieter Jelle , Farrar Gill , Barkhof Frederik
Published: December 2022

Background

The AMYPAD Prognostic and Natural History Study aims to evaluate the value of (semi‐)quantitative amyloid PET imaging for predicting progression within an Alzheimer’s disease risk probability spectrum. The project is actively recruiting non‐demented participants from 17 sites across Europe, with a particular interest in those with emerging amyloid pathology.

Method

As of 17th January 2022, a total of 1,460 participants had been included. Of those, clinical data of 1,015 were processed, with 688 (68%) having at least a quantified amyloid PET at baseline, with [18F]flutemetamol or [18F]florbetaben. The primary metric used to assess amyloid burden was the Centiloid (CL), measured from the ratio of the GAAIN cortical target and whole cerebellum. Scans were categorized as negative (CL≤12), gray‐zone (1250). The distribution of these groups was assessed using a Gaussian mixture model. Independent linear mixed‐effect models were used to explore the predictive value of CL, and its interaction with time, for several cognitive outcomes: mini‐mental state examination (MMSE), memory (immediate recall, IR), attention (digit‐span forward, DSF), language, visuospatial, and executive functions. In addition, years from baseline, parent cohort, age, sex, education, APOE‐ε4, and the Clinical Dementia Rating (CDR) score were used as independent variables.

Result

Demographics are shown in Table 1. At baseline, 88% of the subjects were classified as cognitively unimpaired (CDR=0). A majority of 384 (56%) was categorized as negative (1±7CL), 210 (30%) as grey‐zone (14±11CL), and 94 (14%) as positive (58±31CL) [Figure 1]. Baseline CL (‐0.007 [‐0.010; ‐0.004]) and its interaction with time (‐0.002 [‐0.003; ‐0.001]) were predictive of IR. Baseline CL, but not its interaction with time, predicted MMSE (‐0.007, 95%CI [‐0.010; ‐0.003]) and DSF (‐0.003 [‐0.005; ‐0.001]) [Figure 2]. No significant relationships were observed for executive, language, or visuospatial function.

Conclusion

Higher baseline CL were associated with lower global cognitive function and attention scores. Whereas, higher CL were associated with a steeper memory decline over time.

Current results suggest that cerebral amyloid accumulation is predictive of future overall cognitive function, attention, and memory decline. Further analysis is assured, including more participants, longitudinal PET outcomes, and other biomarkers of the disease.
What subtypes are driving the association between hypertensive disorders of pregnancy and dementia? Findings from an 80‐year retrospective cohort study
Authors: Schliep Karen Cecilia , Shaaban C. Elizabeth , Baradaran Hediyeh , Fraser Alison , Meeks Huong , Varner Michael
Published: December 2022

Background

We recently found that women with, versus without, a history of HDP had a higher hazard of all‐cause dementia, vascular dementia (VaD), and other/unspecified dementia, but not Alzheimer’s disease (AD). Here, we assess associations of HDP subtypes with later life dementias.

Methods

We performed a retrospective cohort study among women with at least 1 singleton pregnancy (1939–2019) in Utah. Classification of HDP was done via birth certificates (text string, 1939–1977; ICD9 codes, 1978–1988; and check boxes with additional text, 1989–2013) with death certificates and inpatient records used for validation. Classification of dementia was assessed using ICD 9/10 codes via death, inpatient, and Medicare records. HDP exposed women (n=19,989) were one‐to‐two matched with unexposed women (n=39,679) by 5‐year age groups, year of childbirth, and parity at the time of pregnancy (Figure 1). Cox regression models were used to estimate adjusted Hazard Ratios (aHR) and 95% CI for HDP subtypes with all‐cause and specific dementias.

Results

HDP pregnancies were comprised of preeclampsia/eclampsia (65.9%) and gestational hypertension (33.5%). The remaining HDP cases were due to HELLP syndrome (0.6%), which we did not evaluate here due to small case count. Incidence of dementia over follow‐up (1979–2019) was 4.1%; of these, 70% were other/unspecified, 24% were AD, and 6% were VaD. Women with a history of preeclampsia/eclampsia, compared to unexposed, had a 1.38 higher hazard of all‐cause dementia, while women with gestational hypertension had a 1.36 higher hazard (Table 1). Breaking down by dementia subtypes, women with a history of preeclampsia/eclampsia had a 1.51 higher hazard of other/unspecified dementia, while women with gestational hypertension had a 1.31 higher hazard. The strength of association of gestational hypertension with VaD was 2.75, nearly double that for preeclampsia/eclampsia, which was 1.58. HDP subtypes were not associated with AD.

Conclusion

Our results are in line with the largest study to date conducted in Denmark that found preeclampsia to be most strongly associated with VaD compared to other dementia subtypes. Our results further suggest that risk of VaD may be just as high for women with a history of gestational hypertension as for preeclampsia.