bluuebunny/crossref_metadata_2025 huggingface dataset:
Subjective vs. Objective Memory Predictors of AD Biomarkers and Future Cognitive, Clinical, and Functional Decline
Authors: Risacher Shannon L. , Deardorff Rachael , Saykin Andrew J.
Published: December 2022

Background

Subjective and objective memory have been previously linked to Alzheimer’s disease (AD) biomarkers and future clinical and cognitive decline. We the ability of two subjective memory assessments and two objective memory assessments to predict cross‐sectional amyloid, tau, and neurodegenerative (A/T/N) biomarkers, as well as future cognitive, clinical, and functional decline.

Methods

298 participants from ADNI were included, specifically 128 with normal cognition without memory concerns (CN), 123 with significant memory concerns (SMC; defined as a score of ≥20 on the first 12 items of the Cognitive Change Index (CCI)), and 47 with early mild cognitive impairment (EMCI). Objective memory was defined as immediate and delayed scores of Logical Memory and the Rey AVLT (RAVLT). Subjective memory measures included the memory sub‐scores of the ECog and CCI. Baseline Aβ and tau positivity were defined as positive on either neuroimaging and/or CSF biomarkers using standard cut‐offs. Neurodegeneration positive was defined as a hippocampal volume w‐score of 1.5 standard deviations below all CNs with 3T MRI in ADNI (adjusted for age, sex, and total intracranial volume). Cognitive decline was defined as a negative slope on the MMSE, while functional decline was defined as a longitudinal increase on the CDR‐sum of boxes and/or FAQ. For CN/SMC, conversion from normal cognition to MCI was also assessed. ROC curves were calculated for each objective and subjective measure for predicting conversion, functional decline, MMSE decline, and A/T/N positivity.

Results

Figure 1 shows ROC curves for the best predictor of each outcome. Baseline Aβ positivity, MCI conversion, and MMSE decline were best predicted by RAVLT immediate recall. However, functional decline and N positivity were best predicted by the CCI‐12. Tau positivity was also best predicted by subjective memory, the ECog memory sub‐score.

Conclusion

Objective memory provided the best prediction of Aβ positivity, MCI conversion, and cognitive decline, while subjective memory was the best predictor of T and N positivity and functional decline. These findings suggest that objective and subjective performance provide complementary information about prognosis in preclinical and very mild symptomatic individuals. Future evaluations of prognostication of these measures in a clinical setting will expand these findings.
Frailty and Alzheimer’s Disease Related Plasma Biomarkers in Men from Midlife to Early Old Age
Authors: Franz Carol E , Buchholz Erik , Kremen William S.
Published: December 2022

Background

About 7 million older American adults are affected by frailty (Bandeen‐Roche et al., 2015). Frailty places older adults at an increased risk of adverse physical and mental health outcomes, including Alzheimer’s Disease (AD). However, prior to old age, frailty or its relationship to AD biomarkers such as beta‐amyloid 40 and 42 (Aβ40, Aβ42), tau, and neurofilament light (NfL) are understudied.

Method

Participants in this prospective longitudinal observational study were community‐based men of predominantly European ancestry. Data were collected across 3 waves at average ages 56 (2002‐08), 62 (2009‐14), and 68 (2016‐19). We calculated frailty index (FI) scores using 37 out of 49 items from an index previously validated in the UK Biobank (Williams et al. 2019; Jiang et al. 2017) which assesses health deficits across multiple physiological systems. FI is calculated as a proportion of deficits out of the total, with scores ranging from 0 (no deficits) to 1 (all deficits present). AD‐related plasma biomarkers for Aβ40,and Aβ42, total tau, and NfL were assayed at average ages 56 and 68. Biomarker values were adjusted for study site and storage time.

Result

Average FI score at age 56 was .2, equivalent to having about 7 health deficits. Frailty was significantly correlated (rs=.67‐.74) over time. Higher frailty at both age 56 and 62 doubled the risk for mortality across the 12 years of the study. Age 56 frailty was significantly associated with age 56 tau. Age 68 frailty was significantly associated with age 68 NfL, tau, Aβ40 and Aβ42. In models adjusted for age, education, and ethnicity, age 56 frailty predicted age 68 NfL (B=0.64, t=2.72, p=0.007); associations with age 68 Aβ40 (B=0.39, t=1.96, p=0.0513) and Aβ42 were attenuated (B=0.27, t=1.79, p=0.0743). Age 62 frailty mediated associations between age 56 tau and age 68 tau and NfL, but not other biomarkers.

Conclusion

The results are striking given the relatively young age of the sample. Even as early as one’s 50s, links between frailty and increased risk for AD emerged. Public health groups have recommended routine frailty screening in adults over 65, but it may be important to start screenings earlier.
Interrogating the role of APOE4 in Alzheimer’s disease and Down syndrome using human induced pluripotent stem cells (hiPSC)‐derived cerebral organoids
Authors: Dooling Breanna , Johnson Noah R , Joshi Molishree , Vielle Anne , Vergara M. Natalia , Potter Huntington
Published: December 2022

Background

Nearly all adults with Down syndrome (DS) will develop Alzheimer’s disease (AD) brain pathology by their 40s, and most will become demented by age 50‐60. The inheritance of the apolipoprotein E (apoE) ε4 allele (APOE4) is the strongest risk factor for AD other than age, whereas the ε3 allele (APOE3) does not change AD risk. ApoE is a cholesterol carrier protein, and APOE4‐positive astrocytes have been demonstrated to exhibit impaired cholesterol transport. ApoE4 has also been shown to catalyze amyloid‐beta (Aβ) polymerization. As such, the APOE4 genotype is associated with earlier and more rapid cognitive decline in individuals with DS. Understanding the molecular changes in AD neuropathology resulting from APOE4 in DS would aid in the development of therapies to alleviate dementia risk, especially in individuals with DS.

Method

We used CRISPR‐Cas9 editing to modify DS hiPSCs, or isogenic control hiPSCs disomic for chromosome 21, from an APOE3/3 genotype to APOE4/4, or to knock out the APOE gene. We developed cerebral organoids (COs) to test the effects of APOE4 on a three‐dimensional in vitro model system of AD pathology in DS. As a preliminary investigation, we also exogenously treated COs with each apoE isoform for 90 days in the culture medium to examine their effects on AD‐related pathologies.

Result

Our preliminary investigation of exogenous apoE exposure of DS and control COs revealed a significant increase in apoE expression/accumulation in DS organoids, but not in control organoids, at 90 days in vitro. Amyloid‐beta production/deposition were also differentially regulated in DS and control organoids, as evaluated by immunoblotting and immunohistochemical analyses. There were also significant size differences between DS and HC organoids. These initial findings support continued investigation of APOE genotype and AD pathology in DS and control COs.

Conclusion

Interrogation of APOE4‐driven AD pathologies will enable the development of more targeted and proactive therapies to improve the quality of life for individuals who harbor this risk allele. Understanding differences in AD pathology in individuals with DS could enable the prevention of dementia in individuals with DS, and further elucidate the pathways by which APOE acts in conferring AD risk.
Physical Activity, Stress and Cognitive Concerns During the COVID‐19 Pandemic Among Older Adults in the United States
Authors: Guzman‐Velez Edmarie , Torres Valeria L. , Martinez Jairo E. , Vila‐Castelar Clara , Fox‐Fuller Joshua T. , Pardilla‐Delgado Enmanuelle , Pluim Celina F. , Babulal Ganesh M , Ramirez‐Gomez Liliana A. , Munera Diana , Quiroz Yakeel T.
Published: December 2022

Background

The COVID‐19 pandemic has increased psychological distress. Research shows that physical activity can reduce emotional distress and improve cognitive functioning. Yet, the pandemic has limited opportunities to engage in physical activity. In this study, we examined whether older adults who maintained physical activity during the pandemic perceived less subjective cognitive concerns and better emotional distress management compared to those who reduced or did not engage in activity. 8

Method

80 adults (ages 55‐94 years) from the community completed an online survey. Subjective cognitive concerns were measured using the Everyday Cognition Scale. Physical activity was measured with the question, “Have you maintained your physical activities during social isolation?” and answers were grouped into yes, no, or partially. Emotional distress was measured with the question, “How well you think you have been able to manage your emotions, worries and stress, and answers were grouped into good/very good, regular, or bad/very bad.

Result

54% of participants reported having maintained or increased their physical activity levels, 33% partially maintained their usual levels, and 13% reduced or did not engage in activity. 64% reported that they were managing their emotions, worry and stress good/very good, 30% regular, and 6% bad/very bad. Participants who maintained or increased their physical activity levels reported less cognitive concerns and greater ability to manage their emotions, worry and stress, compared to those who reduced, partially or did not engage in physical activity.

Conclusion

Encouraging individuals and providing resources for increasing physical activity may help mitigate some of the pandemic’s adverse effects on psychological well‐being.
Functional Outcomes of a Comprehensive, Individualized, Person‐Centered Management Program in Advanced Alzheimer’s Disease(AD): Results from a 52‐Week Randomized Controlled Trial
Authors: Kenowsky Sunnie , Shao Yongzhao , Zhang Qiao , Dafflisio Gianna , Vedvyas Alok , Vedvyas Gaurav , Golomb James B. , Torossian Carol , Marsh Karyn , Heller Sloane , Sadowski Martin J. , Reisberg Barry
Published: December 2022

Background

We conducted a 28‐week, single‐blind, randomized, controlled trial of the efficacy of Comprehensive, Individualized, Person‐Centered Management (CI‐PCM) and memantine treatment (Reisberg et al., Dement Geriatr Cogn Disord, 2017) in advanced AD persons. CI‐PCM and memantine was approximately 7.5 times more beneficial to AD persons on the Functional Assessment Staging Tool (FAST) (Kenowsky et. al., Alzheimer’s and Dementia, 2017) than to AD persons who received memantine alone in the memantine FDA approval pivotal trial conducted by Reisberg et. al., (NEJM 2003). We also conducted a 24‐week extension study. Herein, we report the difference in functional outcomes between the CI‐PCM and Usual Community Care (UCC+FC) groups at 52‐weeks on the FAST and the ADCS‐ADLSev‐Abv. See Figures 1 and 2.

Method

After screening, 20 eligible subject‐carepartner dyads were randomized equally to the CI‐PCM and UCC+FC groups. All 20 dyads completed the 28‐week study and entered the 24‐week extension study. One subject in the UCC+FC group died during the extension study. The FAST and ADCS‐ADLsev‐abv were conducted at baseline, and weeks 4, 12, 28, and 52. P values were calculated using the Wilcoxon Mann Whitney test.

Result

The mean FAST total score from baseline (6.6±0.1SE) to week 52 (6.5±0.01SE) showed an improvement of functional limitations in the CI‐PCM group. The mean FAST total score for the UCC+FC group showed a functional decline from baseline (6.6±0.1SE) to week 52 (6.8±0.1SE), displaying a robustly significant difference between the two groups (p<0.0014). The mean ADCS‐ADL‐sev‐abv total score for the CI‐PCM group demonstrated a 20.9% improvement in functioning from baseline (15.3±2.0SE) to week 52 (18.5±2.5SE). The mean ADCS‐ADL‐sev‐abv total score for the UCC+FC group showed a decline of 48.6% from baseline (14.8±2.1SE) to week 52 (7.6±2.3SE), indicating a significant difference between the two groups (p<0.009).

Conclusion

The CI‐PCM program is the only evidenced‐based treatment to date that can significantly improve and reverse functional deterioration in advanced AD persons. The functional success of the CI‐PCM program may primarily be attributed to care partners learning to memory coach AD persons to perform daily activities such as bathing, dressing, feeding and toileting themselves, and to become/maintain urinary and fecal continence.
Optogenetic model of tau aggregation for tauopathies
Authors: Hurtle Bryan , Donnelly Christopher , Zhang Xin , Thathiah Amantha
Published: December 2022

Background

Alzheimer’s disease (AD) and >20 other dementias, termed tauopathies, are pathologically defined by insoluble aggregates of the microtubule‐associated protein tau (MAPT). A predictive relationship between the onset and progression of clinical AD symptoms correlates with post‐translational modifications of tau in cerebrospinal fluid and tau aggregation in the brains of AD patients. However, the biological basis for the transition of tau from a microtubule‐associated protein to an insoluble aggregate and the precise relationship between tau aggregation and neuronal dysfunction remains unknown. Recent studies have reported the development of photo‐inducible systems to control protein aggregation using photo‐oligomerizable proteins that self‐associate upon exposure to blue light. We hypothesized that the development of a photo‐inducible system, which permits temporal control of tau aggregation, would provide a novel tool to study the cause and consequence of tau aggregation.

Methods

We fused Vivid (VVD), a photoreceptor that self‐associates upon exposure to blue light, to full‐length (2N4R) tau, termed optoTAU. In addition, we generated optoTAU plasmids that contain other MAPT isoforms (e.g., 0N4R, 1N4R) and pro‐ and anti‐aggregation mutations in MAPT. We investigated the effect of blue stimulation on the soluble and insoluble aggregation of optoTAU in a cellular and neuronal model by immunoblot and immunocytochemical analysis.

Results

OptoTAU permits temporal control of tau aggregation that faithfully reproduces the isoform‐specific and dementia‐associated aggregation properties of tau. OptoTAU provides a platform to visualize the transition of tau from a soluble to an insoluble aggregate in a cellular model of tau aggregation.

Conclusions

OptoTAU is a biologically‐relevant model to investigate modifiers of tau pathobiology in AD and other tauopathies and is a drug discovery platform to identify pharmacological modifiers of tau aggregation.
Cerebrospinal Fluid Markers of Neurodegeneration Associated with Postoperative Delirium in an Older Elective Arthroplasty Population
Authors: Sweeney Aoife , Passmore Anthony Peter , Beverland David , McGuinness Bernadette , McAuley Daniel F , Mawhinney Tim , Schott Jonathan M , Heslegrave Amanda , Zetterberg Henrik , Cunningham Emma L
Published: December 2022

Background

Postoperative delirium (POD) is associated with subsequent cognitive decline. It is not yet clear to what extent that is because delirium indicates underlying neurodegeneration.

Method

An observational cohort study of POD in an elective arthroplasty population recruited 315 individuals. All participants were community‐dwelling adults aged over 65, without a diagnosis of dementia, undergoing hip or knee replacements. Cerebrospinal fluid (CSF) was sampled pre‐operatively at the time of spinal anaesthesia and delirium was assessed daily on days 1‐3 postoperatively. Stored CSF samples (n = 270) were analysed for markers of inflammation and neurodegeneration. Statistical analysis was carried out to determine associations of these CSF markers with POD.

Result

Those who developed POD (n = 44) had significantly higher levels of CSF glial fibrillary acidic protein (GFAP; p=0.04), a marker of inflammation; CSF neurofilament light (NFL; p=0.04), a marker of axonal degeneration; and CSF triggering receptor expressed on myeloid cells 2 (sTREM2; p=0.02), a marker of age‐related neuroinflammation and tau‐related neurodegeneration and significantly lower levels of CSF amyloid‐beta 1‐42 (Aβ42; p=0.01) and CSF Aβ42/40 ratio (p=0.01) compared to participants who did not develop POD.

Conclusion

Significantly higher levels of preoperative neurodegenerative CSF markers associated with dementia were found in those who developed POD following elective arthroplasty surgery. This suggests that people, without a pre‐existing diagnosis of dementia, who develop POD after elective arthroplasty surgery are more likely to have underlying neurodegeneration.
Extent ‐ A Global Spatial Distribution Measure to Estimate Progression and Demonstrate Treatment Effect in Flortaucipir Scans
Authors: Kotari Vikas , Southekal Sudeepti , Kennedy Ian Andrew , Morris Amanda , Pontecorvo Michael J.
Published: December 2022

Background

We previously reported that donanemab slows global and regional increase in flortaucipir standardized uptake value ratios (SUVRs)1. In addition to SUVR, a method to estimate spatial distribution of flortaucipir (FTP) uptake might provide valuable and complementary information. Here, we apply the previously developed Extent method to estimate the spread of FTP uptake in PET images and present comparisons against neocortical SUVR for the measurement of treatment effect in the TRAILBLAZER‐ALZ trial. We performed vertex‐wise statistical comparisons.

Method

Subjects in the phase 2 TRAILBLAZER‐ALZ study completed FTP and florbetapir PET scans and MRIs at baseline and 18‐months. Flortaucipir images were processed using standard techniques2 and normalized to the cerebellum crustaneous reference region3. Each FTP image was converted to a z‐score image relative to sixteen young cognitively normal (YCN) subjects. Clusters with z‐scores smaller than a false discovery rate corrected p‐value of 0.01 were retained within a predefined neocortical mask. The neocortical mask and thresholds were selected based on previous data to maximize signal to noise ratio in 18‐month change of mild AD subjects. Extent is the ratio of voxels in this predefined mask that have abnormally elevated tau, defined as at least 2.32*SD above the mean of YCNs (values range between 0‐1). The primary outcome was 18‐month change in Extent and MUBADA2 SUVR between placebos and donanemab treated subjects. We performed vertex‐wise group comparisons to capture the differences in tau burden.

Result

Both Extent and MUBADA showed significant difference between treated and placebo subjects (Figure 1). The 18‐month change (SUVR and Extent) surface maps of the treated and placebo groups show larger spread of FTP in the superior, middle and medial orbito‐frontal regions (Figure 2 & 3). The difference and p‐value maps show clusters of vertices in the inferior temporal, parahippocampal, supramarginal, middle, medial and superior frontal regions as being significantly different.

Conclusion

Subjects treated with donanemab have significantly lesser flortaucipir distribution by Extent compared to placebo, and differences in surface maps of intensity and spread of FTP. Clusters in temporal, parietal, and frontal regions were significantly different. In addition to intensity differences, spatial distribution was different between treatment groups.
A novel machine learning technique using resting‐state EEG to assess and monitor cognitive impairment
Authors: Wu Yunan "Charles" , Quirk Colin , Brookshire Geoffrey , Gerrol Spencer , Merrill David A. , Caselli Richard J. , Lucero Ché
Published: December 2022

Background

Monitoring changes in cognitive impairment is an important aspect of care for aging patients. Traditionally, this is done with pen‐and‐paper assessments such as the Mini‐Mental State Exam (MMSE). EEG is a low‐cost and widely available neurophysiology tool that provides a data‐rich measure of brain health, but signal complexity has limited its impact. Advances in machine learning bring new possibilities to decode those complex signals and leverage EEG in patient care. Here, we engineer novel EEG features for assessing brain health with the [Banded Fractal Variability] (BFV) technique. We use [BFV] and other EEG metrics to assess patients’ cognitive function via a continuous score (a [Cognitive Impairment Index], or [CII]). We validate the diagnostic value of the EEG features by comparing our model against reduced models lacking the EEG features.

Method

The patient sample (N=97, mean (sd) age = 69.1 (11.0), 52.6% female) was collected at the Pacific Brain Health Center. Diagnostic categories included subjective cognitive impairment (n=44), mild cognitive impairment (n=26), and dementia (n=27). Mixed disease (AD, DLB, FTD, vascular, diabetes) was common in the impaired sample, and 39.6% were diagnosed with AD. We developed a continuous [CII] model trained on patients’ MMSE scores (range = 11 to 30, mean = 26.6) using a gradient boosting model with [Banded Fractal Variability] and other EEG features computed from clinical wake EEGs. Model development and testing took place within a rigorous nested cross‐validation (NCV) procedure to prevent overfitting. Performance was compared to reduced (no‐EEG features) models using the non‐parametric Wilcoxon sign‐rank test.

Result

The approach showed a Mean Absolute Error of 1.98 (sd = 0.28) across 5 test folds in the NCV outer loops, significantly outperforming both the baseline intercept‐only model (p = 0.031) and the demographics (age and years of education) model (p = 0.031).

Conclusion

These preliminary results suggest that our [CII] derived from machine‐learning and quantitative EEG using [BFV] is a viable approach to assess and track patients’ cognitive impairment regardless of disease status across all impairment levels, raising the possibility that a brief EEG scan could shed light on patient health normally accessible only through extensive cognitive and neuropsychological testing.
Mosaic Loss of Chromosome Y in Peripheral Blood Cells and Cognitive Status in the Amish
Authors: Song Yeunjoo E. , Miskimen Kristy L. , Laux Renee A. , Fuzzell M. Denise , Fuzzell Sarada L. , Miller Sherri D. , Main Leighanne R. , Osterman Michael D. , Lynn Audrey , Prough Michael B. , Slifer Susan H. , Adams Larry D. , Caywood Laura J. , Clouse Jason E. , Herington Sharlene D. , Dorfsman Daniel A. , Vance Jeffery M. , Cuccaro Michael L. , Ogrocki Paula K. , Lerner Alan J. , Scott William K. , Pericak‐Vance Margaret A. , Bush William S. , Haines Jonathan L.
Published: December 2022

Background

Mosaic loss of chromosome Y (mLOY) refers to acquired aneuploidy in a fraction of somatic cells. In aging men, has been suggested as a possible biomarker for increased risk of numerous diseases, including Alzheimer’s disease (AD). We investigated mLOY as a risk factor for AD in the Mid‐Western Amish, a founder population with homogeneous lifestyle, reducing the effect of confounding environmental factors.

Method

The median of the log R ratio (mLRRY) from SNP array data within the male‐specific region of chromosome Y was used to measure the degree of mLOY. A mLRRY value lower than the 99% confidence limit of the experimental distribution was scored to estimate the frequency of mLOY. The cognitive status was assigned via consensus review of cognitive examination results. Men in 3 age groups (65‐74, 75‐84, >=85) were included. The linear mixed model with a polygenic component to account for relatedness and a transformation to address non‐normality was used to estimate familial correlations and heritability. A likelihood ratio test of association was performed with age at blood sampling and age of cognitive exam as covariates.

Result

After extensive QC, 533 participants (mean age=75.42±6.17) were included and 39 (7.9%) had a detectable level of mLOY. mLOY frequency increased with age (p<1.0x10‐6): 1.0% (65‐74; n=103), 8.4% (75‐84; n=334) and 14.3% (85+; n=96). Heritability of mLOY was 0.53 and the residual sibling correlation was 0.27 (n=201, p<1.0x10‐2). A subset of 423 individuals were assigned to the cognitively impaired (n=134) or unimpaired (n=289) groups and mLOY was significantly higher in the cognitively impaired group (p<0.0001). .

Conclusion

The sibling correlation was significant for mLOY. We observed the same trend as reported in other European descent populations: mLOY increased with age and was more frequent in cognitively impaired individuals. The frequency of mLOY in Amish was lower than reported, overall and in each age stratum. Our results along with the lower prevalence of AD in Amish reinforces as a promising biomarker for the risk of AD.
Leveraging the use of meta‐analysis summary statistics to improve gene expression prediction models
Authors: Mews Makaela , Naj Adam C. , Below Jennifer , Bush William S.
Published: December 2022

Background

Genetically regulated gene expression as assessed via Transcriptome‐wide association studies (TWAS) can be used to elucidate the mechanistic basis Alzheimer’s Disease. A limitation of current TWAS approaches is the requirement for individual‐level datasets with both genotypes and gene expression measures to produce effective prediction models. We sought to improve the predictive performance of existing gene‐based models by leveraging easily accessible summary statistics that are powered by large sample sizes.

Methods

Brain cis‐eQTL data produced from a large‐scale meta‐analysis was restricted to data from European‐descent individuals and samples taken from Brain‐Cortex (Average_N=2,547). The effect size estimates, and their standard errors from the individual cohorts (N=14) were used to re‐run a meta‐analysis excluding GTEx data via METAL.

To perform gene‐based elastic‐net regressions using the produced summary statistics, the lassosum R package produced by Mak et al. 2017 was applied to genotype data from the 1,000 Genomes data (GRCh38) serving as a reference panel and GTEx_v8 genotype, normalized Brain‐Cortex gene expression, and covariate data (N=205) serving as a testing panel for model validation and dynamic selection of the optimal mixing/penalty parameters. The maximum R2 produced by this pipeline was compared to elastic‐net models generated by PredictDB using Brain‐Cortex GTEx_v8 data where the mixing parameter was set at 0.5.

Results

Our pipeline produced gene‐based models that had an improved predictive performance averaging 9.8% (SD: 7%) based on R2 over PredictDB models in 93.7% of genes tested (N=3,965) when restricting our pipeline to SNPs found in PredictDB. The optimal mixing parameter dramatically differed from PredictDB with a median of 0.009 highlighting the utility of including variants with small effects. Even restricting the mixing parameter to 0.5 for genes with a converged model, our pipeline outperformed PredictDB in 85% of genes (N=369). By examining expression prediction metrics to genes from the KEGG Alzheimer’s Disease pathway (hsa05010), our pipeline had improved performance in 100% of matched genes (N=30).

Conclusion

We demonstrate improvement upon existing TWAS reference panels and increase gene‐expression predictive performance by leveraging the power of summary statistics. Our findings show AD association studies based on TWAS approaches may be improved by meta‐analysis reference panels.
Persistent neurological and cerebrovascular deficits following ischemic stroke in a transgenic mouse model of Alzheimer’s disease
Authors: Clary Briana L , Nwafor Divine C , Hernandez Chloe G , Golestanian Omid , Macom Rhiannon V , Brown Candice
Published: December 2022

Background

Tissue nonspecific alkaline phosphatase (TNAP) is one of the most abundant enzymes in brain cerebral microvessels, although its function in human health and disease remains less clear. Our lab has demonstrated that the loss of TNAP activity in cerebral microvessels is linked to diminished blood‐brain barrier function and decreased cerebrovascular integrity in mouse models of sepsis, ischemic stroke, and Alzheimer’s disease (AD). While it is widely known that stroke and AD are comorbid, the relationship between existing AD and its impact on outcomes following ischemic stroke is less clear. The goal of this study was to assess the impact of a moderate cortical ischemic stroke on post‐stroke sensorimotor deficits and AD‐like neuropathology in a mouse model of AD. We hypothesized that post‐stroke loss of TNAP activity is accompanied by a persistent loss of cerebral blood flow (CBF), exacerbated sensorimotor deficits, elevated neuroinflammation, and increased beta‐amyloid deposition.

Method

Male and female APPSwID/iNOS‐/‐ (CVN‐AD) mice, 10‐12 months old, were subjected to a cortical photothrombotic stroke (AD+PTS) or sham (AD+sham) surgery and euthanized at seven days post‐stroke. Daily neurological scores, corner test, and rotarod were performed to assess sensorimotor deficits. CBF was assessed by laser speckle contrast imaging (LSCI) prior to euthanasia. Saline‐perfused and 4% paraformaldehyde fixed tissue sections underwent histological staining to quantify infarct volume, cerebral microvessel TNAP activity, and microhemorrhages. Immunostaining assessed astrogliosis, via glial fibrillary acidic protein (GFAP), microgliosis, via Iba‐1, and beta‐amyloid deposition.

Result

Ischemic stroke impaired performance on the corner test (p=0.0054) and rotarod (p=0.0138) in PTS+AD compared to sham+AD mice. At seven days post‐stroke CBF was diminished (p<0.0001) while Iba‐1 immunolabeling revealed increased microgliosis in the ipsilateral cortex (p<0.0001) and ipsilateral hippocampal CA1 (p=0.0022) in PTS+AD compared to sham+AD mice. A preliminary quantification of TNAP activity in the non‐infarcted ipsilateral hemisphere revealed a trending decrease in PTS+AD mice. No sex differences were observed.

Conclusion

Sensorimotor deficits and microgliosis were increased while CBF was decreased at seven days post‐stroke in PTS+AD compared to sham+AD mice. These and other indices will be compared with age‐matched wild‐type mice in ongoing experiments.
Reducing the Effects of Aging on Cognition with Therapeutic Intervention of an Oral multi‐Nutrient combination (REACTION): Study Design and Baseline Results
Authors: Camargo Christian J , McInerney Katalina , Merritt Stacy S , Modjeski Marisa , Counotte Danielle , Rundek Tatjana
Published: December 2022

Background

Alzheimer’s Disease (AD) is the most common cause of dementia, and the risk of developing AD increases with age. Age‐related cognitive decline (ARCD) refers to the cognitive changes that can occur in individuals because of aging. Research suggests that the underlying mechanism behind ARCD is a loss of synaptic plasticity and altered dendritic spine morphology. Similarly, the cognitive changes in AD are also thought to arise from impaired synaptic plasticity and dendritic spine loss. Souvenaid, contains a specific combination of precursors and cofactors for phospholipid biosynthesis, and has shown beneficial effects on memory, cognition, and brain atrophy in prodromal AD. In addition, data from this previous study imply a stronger effect would be expected in participants at earlier stages of prodromal AD. To test the effect of Souvenaid in ARCD, the REACTION (Reducing the Effects of Aging on Cognition with Therapeutic Intervention of an Oral multi‐Nutrient combination) pilot study was developed.

Method

REACTION1 is a 6‐month single‐center randomized, double‐blind placebo‐controlled pilot clinical trial. The study factors in local COVID‐19 restrictions and is conducted fully virtually. Participants will be aged 55‐89 with ARCD, and screened and randomized to the oral multi‐nutrient combination (Souvenaid) or placebo on a 1:1 basis.

The main outcome of this trial is feasibility (recruitment rate and time, adherence rate and retention rate). Other outcomes include memory (e.g. Ray Verbal Learning Task), cognition (e.g. Oral Trail Making Test), and quality of life (e.g. Amsterdam IADL Questionnaire) outcome measures.

Result

Of 141 inquiries over 7 months, 60 eligible participants were recruited. 54 were successfully screened for randomization. As of 3 Feb 2022, 47 participants have been randomized to placebo or Souvenaid (6 are awaiting randomization, 1 withdrew prior to randomization.) Detailed baseline characteristics of the study population will be presented at the meeting, including descriptive statistics on demographics and the inclusion criteria such as the RBANS, MoCA and SCD 9‐item brief screening tool score.

Conclusion

With the rapidly growing prevalence of ARCD and limited pharmacological curative treatment options currently available, nutritional interventions may potentially play an important role to prevent or delay the onset of ARCD.

1. Clinicaltrial.gov identifier: NCT04147624
Development and validation of AI‐based tools for brain amyloid‐β detection using MRI
Authors: Devanarayan Viswanath , Charil Arnaud , Nelson Todd , Qi Xin , Murali Leema , Reyderman Larisa , Irizarry Michael C , Koyama Akihiko , Dhadda Shobha
Published: December 2022

Background

Non‐invasive methods for brain amyloid‐b (Ab) detection are needed for effective patient care, and for faster and more cost‐effective screening of patients in clinical trials. Using MRI and other patient screening data from internal clinical trials, we employ artificial intelligence (AI) algorithms to develop brain Aβ positivity detection tools and validate their performance in independent datasets.

Method

Training dataset included structural MRI and several cognitive assessments obtained during screening of 1960 patients from a clinical trial. Volumetric measures from 207 brain regions were generated by BioClinica using their proprietary imaging pipeline. Over 85% of these patients had mild cognitive impairment (MCI), and approximately 50% were Aβ positive based PET visual read (mostly using Florbetaben).

Signatures for detecting brain Aβ positivity were derived via several AI algorithms such as Bayesian elastic‐net, neural network, regularized random forests, and stochastic gradient boosting. These models included demographics and clinical features, and the added value of ApoE and MRI features were assessed. Performance accuracy was first assessed via 10‐fold cross‐validation within the training set. Signatures from the best performing algorithm were evaluated in two independent test sets: a clinical trial cohort (n=1853) and an ADNI cohort (n=1092).

Result

Signatures using cognitive assessments and demographics achieved 62.2% accuracy for detecting brain Aβ positivity when evaluated via cross‐validation, which improved to 75.2% when adding ApoE, and to 77.9% when including MRI.

When tested in two independent cohorts, signatures with cognitive assessments and demographics achieved accuracy of 64.5% and 65.8% respectively, which improved to 71.9% and 74.3% when adding ApoE, to 76.7% and 77.5% when including MRI, and to 83.6% and 84.8% when considering 2/3 of the test‐sets that were predicted with high‐confidence (i.e., subjects predicted with > 70% probability as brain Aβ positive or negative).

Conclusion

These results demonstrate the potential of non‐invasive AI tools based on cognitive assessments, ApoE and MRI for detecting brain Aβ positivity in clinical trials and patient care. Results reported here may be refined further using impending additional data prior to final presentation.
Relationship between clinician rated amyloid status and traditional AD biomarkers in cognitively healthy older adults
Authors: Green Zachary D. , Kueck Paul J. , John Casey S. , Vidoni Eric D , Burns Jeffrey M. , Morris Jill K.
Published: December 2022

Background

Accumulating evidence suggests that Alzheimer’s Disease (AD) plasma biomarkers aid in screening for at‐risk individuals, tracking disease progression, and monitoring response to interventions. Plasma amyloid‐β (Aβ) and phosphorylated tau (pTau) have shown promise in predicting cerebral deposition of Aβ, while neurofilament light chain (NfL) serves as a more global marker of neurodegeneration. However, blood collection protocols often differ, and it is important to confirm the relationship between blood biomarker values and established neuroimaging markers for AD neuropathology.

Method

Here, we examined which blood biomarkers could predict clinician rating of cerebral amyloid status. We leveraged available clinical, cognitive, and neuroimaging data for 140 cognitively healthy older adults (65+, mean 72 ± 6.4) who participated in the Alzheimer’s Prevention Program (APP) study and had blood specimens available. Participants were assessed by a trained clinician and neuropsychometric test battery to exclude the presence of MCI or dementia syndromes. Cerebral amyloid burden was measured by Florbetapir (18F) positron emission tomography and images were rated by three trained clinicians as “elevated” or “non‐elevated”. Biomarkers were measured in plasma collected in acid citrate dextrose (ACD) tubes using a Quanterix Simoa® HD‐X platform, and included NfL, Aβ42, Aβ40, and p‐tau181.

Result

Plasma Aβ42/40 ratio was significantly lower in the “elevated” group than in the “non‐elevated” group (p < 0.001), while NfL (p =0.008) and p‐tau 181 (p = 0.001) were both significantly higher. Aβ42/40 ratio was able to discriminate the rating groups in a ROC analysis with an AUC of 0.835, significantly outperforming p‐tau 181 (AUC = 0.640) and NfL (AUC = 0.572).

Conclusion

Despite collecting samples with ACD rather than the traditional EDTA as an anti‐coagulant, expected group differences were observed. Our results suggest that Aβ42/40 ratio is useful in discriminating clinician‐rated elevated cerebral amyloid status, which has important implications regarding disclosure of blood biomarker results from different collection protocols in the context of AD risk.
Increased Bridging Characteristics in Social Networks are Associated with Increasing Amygdala Volume and Grey Matter Density
Authors: Manchella Mohit K. , Logan Paige E. , Perry Brea L , Peng Siyun , Risacher Shannon L. , Saykin Andrew J. , Apostolova Liana G.
Published: December 2022

Background

Social connectedness has been linked to decreased rates of cognitive decline particularly among older adults (Fratiglioni et al., 2004). Several studies have demonstrated that access to an expansive network of diverse, and loosely connected individuals (i.e., social bridging) plays a particularly unique role in conferring resilience against cognitive decline (Perry et al., 2021). We explored the association of social bridging with cortical atrophy measured by gray matter density (GMD) in cognitively normal (CN), subjective cognitive decline (SCD), mild cognitive impairment (MCI), and Alzheimer’s Disease (AD) participants from the Social Networks and Alzheimer’s Disease (SNAD) at the Indiana Alzheimer Disease Research Center.

Method

We analyzed baseline data of 176 SNAD participants (63 CN, 54 SCD, 47 MCI, 12 AD). Social bridging metrics were collected via in‐person interviews of egocentric social network data. MCI and AD were combined into a cognitively impaired group, resulting in 3 diagnostic groups (CN, SCD, CI). Demographic and biomarker differences across groups were analyzed using ANOVA. Pooled linear regressions were run with ROIs as the dependent variables and diagnosis, age, sex, education, and social bridging as regressors. A voxel‐wise multiple linear regression of GMD images in SPM12 yielded statistical maps across the pooled sample.

Result

Table 1 shows the demographic and biomarker comparisons of all groups. The linear regression showed greater social bridging was associated with larger left and right amygdala volume (both p=0.01), and trending larger left frontal thickness (p=0.055), and left and right insula thickness (both p=0.09). Figure 1 and Figure 2 show scatterplot distribution of significant and trending brain regions versus bridging by diagnostic group with regression p‐values and lines. Statistical maps show increasing social bridging is associated with increasing GMD lateralized to the left hemisphere with a frontotemporoparietal pattern (Figure 3).

Conclusion

We found that the effects of particular social enrichment on GMD, such as social bridging, are localized to regions primarily involving motivation and emotion. The left lateralization suggests this hemisphere’s propensity for protection against cognitive decline via social mechanisms. Future work should investigate potential associations between social bridging and amyloid and tau deposition.
Implications of Response Patterns in Questions of Early Life Adverse Events as a Risk Factor for Lower Cognitive Function in the Multi‐Ethnic Study of Atherosclerosis
Authors: Culkin Margaret C. , Hughes Tim M. , Peavey Jeremy J. , Molina‐Henry Doris P. , Seeman Teresa E. , Merkin Sharon S. , Hayden Kathleen M.
Published: December 2022

Background

Early‐life disadvantage may increase the risk for later cognitive decline. Recently, other aspects of early‐life adversity (ELA) have received attention but their associations with cognitive decline in later life has not been widely studied. Due to the sensitivity of such questions and the potential for systematic bias, we examined (1) predictors of response patterns to ELA questions, and (2) among those who completed ELA questions, we examined whether responses were associated with cognitive decline in the Multi‐Ethnic Study of Atherosclerosis (MESA).

Method

ELA was self‐reported via a 7‐item telephone assessment of socioemotional and physical threat or deprivation at MESA annual follow‐up call in 2019. Descriptive statistics were grouped by completion status: not completed, partially completed, and fully completed. Continuous variables were compared across groups with t‐tests; categorical variables were compared with chi‐square tests. Cognitive function was measured using the Cognitive Abilities Screening Instrument (CASI) at MESA Exams 5 (2010‐2012) and 6 (2016‐2018). Multinomial logistic regression was used to determine predictors of completion group membership. Cognitive decline from Exam 5 to 6 by completion group was assessed using multivariable linear regression.

Result

Of the 3,990 participants interviewed, the mean age was 59.2y (SD = 8.8), 55% were female, and 40% were White (n = 1,604), 13% Chinese (n = 508), 26% Black (n = 1,036), and 21% Hispanic/Latino (n = 842). The odds of partial response was higher for those born outside of the U.S. (2.17, CI 95%: 1.53‐3.09), and among participants who spoke Spanish (2.82, CI 95%: 1.74‐4.58) or Chinese (2.04, CI 95%: 1.08‐3.88) at baseline. Among participants with completed ELA (n = 3,173), one component of childhood adversity: how often was your household well‐organized/managed, was associated with better Exam 6 CASI score (β = 0.80, SE = 0.33; p = 0.015) adjusting for age, race, education, gender, language, years in the U.S., socio‐economic status (SES), and parental birthplace. There was no significant association between cognitive change from Exam 5 to Exam 6 and ELA completion.

Conclusion

Factors associated with acculturation including country of participant’s birth and language preference predicted completion status on questions of ELA. Future studies should be mindful of the potentially differential response patterns and the implications for interpretation when analyzing ELA data.
Inhibitory Control of Saccadic Eye Movements and Cognitive Impairment in Mild Cognitive Impairment
Authors: Opwonya Julius
Published: December 2022

Background

Mild cognitive impairment (MCI) may occur due to several forms of neurodegenerative diseases and non‐degenerative conditions and is associated with cognitive impairment that does not affect everyday activities. For a timely diagnosis of MCI to prevent progression to dementia, a screening tool of fast, low‐cost and easy access is needed. Recent research on eye movement hints it a potential application for the MCI screening. However, the precise extent of cognitive function decline and eye‐movement control alterations in patients with MCI is still unclear.

Method

Patients with MCI (n = 79) and age‐matched cognitively healthy controls (HC) (n = 170) completed four saccadic eye‐movement paradigms: prosaccade (PS)/antisaccade (AS), Go/No‐go, and a battery of neuropsychological tests.

Result

The findings revealed significantly longer latency in patients with MCI than in HC during the PS task. Additionally, patients with MCI had a lower proportion of correct responses and a marked increase in inhibition errors for both PS/AS and Go/No‐go tasks. Furthermore, when patients with MCI made errors, they failed to self‐correct many of these inhibition errors. In addition to the increase in inhibition errors and uncorrected inhibition errors, patients with MCI demonstrated a trend toward increased correction latencies. We also showed a relationship between neuropsychological scores and correct and error saccade responses.

Conclusion

Our results demonstrate that, similar to patients with Alzheimer’s dementia (AD), patients with MCI generate a high proportion of erroneous saccades toward the prepotent target and fail to self‐correct many of these errors, which is consistent with an impairment of inhibitory control and error monitoring.
TRPM8 as a potential target in neurodegenerative diseases
Authors: Shikha Deep , Dalai Ritesh , Goswami Chandan
Published: December 2022

Background

Cholesterol is required by the neuronal cells for a normal brain functions as it affects membrane fluidity and ion channel functions by disrupting calcium homeostasis and neuronal loss1. Synthesis of cholesterol occurs in glial cells like astrocytes and get transported into neurons and intracellular organelles. Any deregulation in these transport leads to several neurodegenerative diseases2,3. TRPM8 cation channel has been found to contain conserved cholesterol binding motifs in its sequences that indicates its potential role in cholesterol mediated functions4.

Method

Conservation analysis of cholesterol binding motifs has been performed using CARC and CRAC sequences and docking of cholesterol with TRPM8 Cryo EM structure has been performed in Autodock. For in‐vitro studies, peripheral neurons were grown in cholesterol reduced condition. Co‐localization has been studied between TRPM8 and lipid‐raft marker by immunostaining.

Result

TRPM8 has conserved cholesterol binding motifs in its structure. In‐vitro study shows that TRPM8 get localized on cholesterol enriched lipid‐raft on the plasma membrane more when cholesterol is reduced. The recruitment of TRPM8 protein also seems to increase in neuronal cell line after cholesterol reduction.

Conclusion

TRPM8 might have a cholesterol mediated role in neuronal cell dynamics which can be potential target for neurodegenerative diseases.

References:

1. Hong, C. et al. TRP Channels as Emerging Therapeutic Targets for Neurodegenerative Diseases. Front. Physiol.
11, 1‐15 (2020).

2. Liu, J. P. et al. Cholesterol involvement in the pathogenesis of neurodegenerative diseases. Mol. Cell. Neurosci.
43, 33‐42 (2010).

3. Dai, L. et al. Cholesterol Metabolism in Neurodegenerative Diseases: Molecular Mechanisms and Therapeutic Targets. Mol. Neurobiol.
58, 2183‐2201 (2021).

4. Fantini, J. & Barrantes, F. J. How cholesterol interacts with membrane proteins: An exploration of cholesterol‐binding sites including CRAC, CARC, and tilted domains. Front. Physiol.
4 FEB, 1‐9 (2013).