bluuebunny/crossref_metadata_2025 huggingface dataset:
Smoking Gun? Effect of smoking history on cognition in AD and MCI
Authors: Crawford‐Holland Lucas M , Rabin Jennifer S. , Fornazzari Luis R , Schweizer Tom A. , Fischer Corinne E. , Munoz David G. , Kumar Sanjeev , Black Sandra E. , Freedman Morris , Borrie Michael , Frank Andrew R , Pasternak Stephen H , Pollock Bruce G. , Rajji Tarek K. , Seitz Dallas , Tang‐Wai David F. , Tartaglia Carmela , Kwan Donna , Tan Brian
Published: December 2022

Background

Many lifestyle factors have been associated with lower rates of cognitive decline in AD and MCI patients, however the effect of tobacco smoking remains unclear. This study examined how longitudinal cognitive performance in AD and MCI patients varied for those with versus without smoking history.

Method

The study included all 126 patients from the Ontario Neurodegenerative Disease Research Initiative (ONDRI) AD/MCI cohort. The patients were divided into those with a history of cigarette smoking (n = 67) vs without (n = 59), defined as greater than two years of daily smoking. To measure longitudinal cognition, MoCA scores were taken three times with one year elapsing between assessments.

Result

Linear mixed effects models were performed, with MoCA score as the dependent variable. Time point, smoking history, sex, education, age, clinical diagnosis (AD vs MCI) and number of languages spoken were fixed effects and subject was a random effect. The presence of smoking history had a significant effect on MoCA score (χ2(1) = 4.5, p = 0.034), improving the average score by 1.37 points ± 0.66 (standard errors). A strong interaction was also found between smoking history and time point (χ2(1) = 8.2, p = 0.0042), as the positive effect of smoking history on MoCA score increased with time. No other significant interactions were found.

Conclusion

Our findings indicate that smoking history may improve longitudinal cognition in AD and MCI patients. It is unclear whether smoking history is simply a mediating variable for another protective factor, or whether these results arise from cigarette smoking itself affecting some stage of disease progression. Smoking has been consistently associated with a lower risk of developing Parkinson’s disease (PD), however the mechanism for such protection remains unclear. Further research into any association between smoking history and longitudinal cognition in AD and MCI might indicate whether a similar protective association is found in AD and MCI as exists in PD. However, it must be remembered that smoking is associated with many serious diseases, particularly lung cancer, and remains one of the biggest causes of preventable death worldwide.
A Target Enablement Package for the Inhibition of SHIP1 as a Therapeutic Strategy for the Treatment of Alzheimer’s Disease
Authors: Richardson Timothy I , Jesudason Cynthia D , Lobb Karen L , Durst Gregory L , Clayton Brent , Massey Steven M , Beck Daniel E , Zhang Zhong‐Yin , Dong Jiajun , Lin Jianping , Miao Jinmin , Putt Karson S , Mesecar Andrew D , Hamdani Adam K , Lendy Emma K , Souza Sarah , Jacobson Marlene , Salvo Jerry Di , Chu Shaoyou , Mason Emily R , Oblak Adrian L , Soni Disha , Quinney Sara K , Silva Larissa L , Kandasamy Murugesh , Masters Andrea R , Rizzo Stacey J Sukoff , Doolen Suzanne , Huang Kun , Zhang Jie , Lamb Bruce T , Palkowitz Alan D
Published: December 2022

Background

Recent evidence including GWAS and differential gene expression comparing normal to affected Alzheimer’s brain tissue have identified risk and protective variants in genes such as TREM2, PLCG2 and INPP5D that are essential to microglia function. INPP5D encodes SHIP1, a multi‐domain protein with a phosphatase that converts PI(3,4,5)P3 to PI(3,4)P2, a SH2 domain that interacts with receptor ITAMs and competes with SYK, and a proline rich region that binds many other proteins. SHIP1 therefore limits microglia activation in multiple ways. Inhibition of SHIP1 early in disease would increase microglial protective functions and reduce the rate of disease progression and cognitive decline in Alzheimer’s patients.

Method

We performed a screen of 50K compounds at the SHIP1 phosphatase, analyzed a publicly available fragment‐based screen, and evaluated inhibitors reported in the literature. We utilized the malachite green assay with PtdIns(3,4,5)P3‐diC8 and SHIP1 Ptase‐C2 to measure inhibitory potency. A Cellular Thermal Shift Assay was used to confirm target engagement in cells. A high‐content imaging assay measuring phagocytosis, cell number, and nuclear intensity was implemented using the BV2 and HMC3 cell lines to characterize cellular pharmacology and cytotoxicity. Mouse microglia were assayed to demonstrate similar activity in primary cells. Inhibitors predicted to have drug‐like properties were subjected to assays measuring solubility, cellular permeability, and mouse microsomal stability. A physiological based pharmacokinetic model was compared to measured exposure in vivo for select compounds upon oral administration in mice.

Result

SHIP1 inhibitors have been compared head‐to‐head in a set of assays relevant to both enzyme inhibition and microglia activation. Structurally distinct, novel, and selective SHIP1 inhibitors have been discovered. The enzyme mode of action, cellular activity and drug‐like properties were determined. Pharmacokinetic profiles were determined for inhibitors with sufficient cellular potency and drug‐like properties for in vivo studies in mice.

Conclusion

Inhibition of SHIP1 is a novel therapeutic strategy for treatment of Alzheimer’s. We identified structurally distinct molecular scaffolds with varying degrees of enzyme inhibition, cellular activity, and exposure in mice. Recommendations for use of probe molecules in target validation studies and the development of lead‐like molecules for clinical studies will be made.
Single domain antibody‐based non‐invasive in vivo imaging of tau pathology
Authors: Jiang Yixiang , Lin Yan , Krishnaswamy Senthilkumar , Wu Qian , Pan Ruimin , Liu Mengyu , Kuo Min‐Hao , Kong Xiang‐Peng , Congdon Erin E. , Sigurdsson Einar M.
Published: December 2022

Background

Numerous studies have shown that the extent of pathological tau protein in the brain correlates strongly with the severity of Alzheimer’s dementia at the time of death, and similar association with functional phenotypes have been seen in other tauopathies. In recent years, several dye‐based imaging probes with selectivity for tau aggregates have been developed. However, all are β‐sheet binders with varying affinity for different amyloids, and thereby lack specificity for tau lesions. In contrast, single domain antibodies (sdAbs) are specific for their target and because of their small size have much greater access into the brain than standard whole antibodies.

Method

To examine sdAbs’ suitability as non‐invasive in vivo imaging probes for tauopathies, we immunized a llama with a full‐length recombinant tau protein followed by boosters with human brain‐derived pathological tau proteins. Phage display libraries were generated from its peripheral blood mononuclear cells and screened for binding to tau proteins using various assays, resulting in a prototype sdAb deemed promising for in vivo imaging. Subsequently, this anti‐tau sdAb was labeled with a near‐infrared tag (680 nm), and injected intravenously in tauopathy and control mice, followed by imaging using an In Vivo Imaging System (IVIS). After the imaging, brains were extracted for tissue analysis.

Result

Intravenous injection of labeled sdAb resulted in a strong in vivo brain signal detected through the intact head in two different models of transgenic tauopathy mice, but not in wild‐type or transgenic α‐synucleinopathy mice. Importantly, the in vivo brain signal correlated strongly with insoluble (r = 0.9839, p < 0.0001) and soluble (human tau (CP27) and phospho‐tau (PHF1): r = 0.9603 and 0.9459, p < 0.0001) tau protein within the brain. Furthermore, postmortem analysis revealed extensive co‐localization of the sdAb imaging probe with tau aggregates within neurons in the endosomal‐lysosomal system, indicating their interaction in these degradation pathways.

Conclusion

Overall, this specific sdAb imaging ligand has great potential as an in vivo diagnostic marker for Alzheimer's disease and related tauopathies, and sdAb‐based imaging may be applicable to a variety of protein conformational disorders.
Unsupervised learning on electronic health records to uncover heterogeneity in Alzheimer’s disease and related dementias
Authors: West Matthew , Magdamo Colin G. , Serrano‐Pozo Alberto , Blacker Deborah , Hyman Bradley T. , Das Sudeshna
Published: December 2022

Background

Alzheimer’s Disease (AD) is a heterogenous disease with distinct etiologies, disease courses, and/or age of onset, which may be associated with different clinical features. Here, we aim to use unsupervised learning techniques on electronic health records (EHRs) from a group of memory clinic patients to characterize heterogeneity in this disease population.

Method

We identify a patient dataset (N = 9,249) within the Mass General Brigham (MGB) system who had at least two encounters at the memory clinic, and were 50 years or older at their last visit. We also define a subset (N = 3,638) of these patients with at least one substantial visit note by an MGB memory specialist. Pre‐trained embeddings for associated ICD codes are used to encode patient EHRs in the first dataset, and transformer‐derived Clinical BERT embeddings of free text are used to encode the patient notes dataset.1,2 For each dataset, we cluster these patient representations using hierarchical clustering and test for enrichment of ICD codes within clusters using chi‐squared tests. Significant codes following Bonferroni correction are retained, and clusters are then characterized based on their most significantly enriched codes.

Result

We identify four clusters within the ICD dataset and three clusters within the patient notes dataset. In the ICD dataset, clusters of patients are identified with increased prevalence of type 2 diabetes and kidney disease (N = 205), chronic pain (N = 669), cardiovascular and other age‐related diseases (N = 2,149), as well as a cluster mostly defined by focal neurological diseases (N = 6,226). In the notes dataset, clusters were identified by enrichment of codes for hydrocephalus and Lewy body disease (N = 1,565), and again with cardiovascular and other age‐related diseases (N = 336), and focal neurological diseases (N = 1,737).

Conclusion

In this study, we demonstrate the potential to leverage pre‐trained embeddings from both structured and unstructured data in EHRs to characterize patient heterogeneity in a group of patients with Alzheimer’s Disease and related dementias. In the future, we plan to further characterize these clusters in terms of disease course and underlying mechanism.

1. Choi et al., Learning low‐dimensional representations of medical concepts. AMIA Summits. Transl. Sci. Proc. 2016, 41 (2016).

2. Alsentzer et al., Publicly available clinical BERT embeddings. arXiv:1904.03323 (2019).
The Carer Assessment of medicaTion management guidanCe for people living with dementia at Hospital discharge (CATCH): Preliminary analysis for a national cross‐sectional survey
Authors: Sawan Mouna J , Jeon Yun‐Hee , Chen Timothy , Gnjidic Danijela
Published: December 2022

Introduction

Medication therapy management for people living with dementia is a major contributing factor to adverse events after discharge from hospital. Carers play an important role in overseeing medication management for the person with dementia. We aimed to evaluate medication management guidance provided to carers of people with dementia at hospital discharge.

Methods

This was a cross‐sectional survey disseminated across Australia. Data was captured using the Carer Assessment of medicaTion management guidanCe for people with dementia at Hospital discharge (CATCH) tool. The CATCH tool included 30 items and was developed using a multi‐method approach involving content validation and pretesting with carers of people with dementia. The tool utilized a 5‐point Likert scale, and multiple‐choice responses. We included carers responsible for managing the medications of the person with dementia, and the person with dementia has had at least one discharge from the hospital. Electronic and hardcopy distribution of the survey occurred Australia wide through advertisement. Data collection started on April 24th, 2022, and is currently ongoing. Quantitative data was descriptively analyzed.

Results

To date, 30 participants completed the survey with a median age 66 (IQR 16.5) and 28 were female. Most participants (n = 21) were provided guidance on the day of discharge by the doctor (n = 12) or nurse (n = 7) in written form. Most (n = 18) found that discharge summary and medication list was easy to understand. The most common medication information provided related to administration instructions (n = 13), medication purpose (n = 11) and possible benefits of medications (n = 8). However, some participants reported that they were not given information about possible side effects (n = 8), medications that might increase confusion (n = 7) and how long the medication should be used for (n = 12). Some (n = 12) reported that they were not asked if the person with dementia had any problems taking their medications.. Most (n = 20) stated that medication management guidance could be improved.

Conclusion

Our preliminary findings suggest that there are opportunities to improve guidance in medication therapy management provided to carers at discharge. Targets for interventions around comprehensive guidance on all aspects of medication use tailored specifically for the people with dementia are needed.
Introducing rrAD420, an anatomical template and multi‐modal atlas for older adults
Authors: Scheel Norman , Keller Jeffrey N. , Binder Ellen F. , Vidoni Eric D , Burns Jeffrey M. , Stowe Ann M , Kerwin Diana R. , Vongpatanasin Wanpen , Cullum Munro , Zhang Rong , Zhu David C
Published: December 2022

Background

Risk Reduction for Alzheimer’s Disease (rrAD) is a recently completed randomized controlled trial assessing the effects of aerobic exercise training and pharmacological cardio‐vascular interventions on neurocognitive function in hypertensive older adults with a family history of dementia or subjective cognitive decline. The comprehensive neuroimaging protocol included anatomical, functional, and physiological MRI scans, obtained at baseline and after two years of intervention. 420 older subjects (68.8±5.9 years) were scanned on five different 3T MRI scanners (two Siemens, two GE, and one Philips). Brain atrophy and ventricular enlargement are common in this elderly study population, leading to substantial deviations from the standard MNI152 template (25.02±4.9 years). Severe artifacts might occur when transforming non‐normative brains into MNI standard space. Using the high‐quality baseline data of this study, we aim to integrate images from multiple modalities to create a reference that is better suited to investigate older populations.

Methods

For each subject, we acquired T1 MPRAGE, T2 FLAIR, ASL, DTI, and resting‐state fMRI. Each scan underwent rigorous manual quality control and linear sequence‐specific high precision alignment to the T1 image. All T1 images then underwent non‐linear DARTEL registration into a common space to create cohort‐specific transformations. We then transformed all images into the new common space, namely
rrAD420
(Figure 1). Averages across subjects make up cohort‐ and modality‐specific templates (Figure 2). Seed‐based and data‐driven decompositions of resting‐state fMRI and DTI data created functional and structural connectivity atlases (Figure 3). Anatomical dual regression transforms common brain atlases from MNI into rrAD420 space, facilitating cross‐referencing.

Results

The rrAD420 templates and atlases integrate multimodal neuroimaging data of older populations into a common space, accounting for cohort‐specific distinctions, such as cortical atrophy and enlarged ventricles. It provides references to commonly used brain parcellations which are integrated with functional and structural atlases created from the rrAD cohort. Thus, rrAD420 provides a reference framework for comprehensive multimodal MRI analyses of elderly cohorts.

Conclusions

Through rrAD420, longitudinal multi‐modal image analyses can now be carried out using templates unique to this population. Furthermore, rrAD420 should also apply to older populations in general, facilitating data integration, and biomarker detection.
Development of fully automated plasma immunoassay using by HISCLTM series for classification of neurological disorders
Authors: Ishiki Kengo , Watanabe Shunsuke , Yamashita Kazuto , Miura Masahiro , Iwanaga Shigeki , Sato Toshiyuki
Published: December 2022

Background

ATN classification system (A: β‐amyloid (Aβ) deposition, T: pathogenic tau accumulation, N: neurodegeneration) has been widely accepted as a research framework for not only characterization of Alzheimer's disease (AD), but also for discrimination of AD from other neurological disorders (OND) such as Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Currently, the different pathological processes are represented by the biomarker normality/abnormality which is diagnosed by neuroimaging and/or measuring the biomarker levels in cerebrospinal fluid. A simple diagnostic method needs to be established to evaluate pathological processes in routine clinical practice. Blood‐based biomarkers would be appropriate for clinical applications because of their simplicity and accessibility. We have developed plasma Aβ1‐40, Aβ1‐42, threonine‐181 phosphorylated tau (p‐tau181), and tau immunoassays and reported that the plasma biomarker levels were significantly different between AD, mild cognitive impairment (MCI), and cognitively normal (CN) groups, suggesting the possibility of characterizing AD. Here, we present the results of the ATN biomarker profile of OND samples using our fully automated assay.

Method

We measured Aβ1‐40, Aβ1‐42, p‐tau181, and tau using commercially available plasma samples on a fully automated immunoassay platform, HISCLTM series. The platform can achieve high degrees of sensitivity and requires only 30 µl of sample and 17 minutes to complete the measurement per assay. The plasma ATN biomarker profiles were evaluated in AD, MCI, CN, and OND groups.

Result

All plasma biomarker levels were significantly different between the AD and CN groups. Plasma p‐tau181 showed the most significant difference between the AD group and OND group. The median plasma p‐tau181 concentration in AD groups was more than twice higher compared to OND groups.

Conclusion

Our results indicated the possibility of discriminating AD from OND by plasma p‐tau181 and tau levels. Our fully automated plasma assay system may have a potential to be a simple diagnostic method to evaluate the pathological process in routine clinical practice for discriminating AD from OND based on ATN classification system.
Subjective reports of problems remembering names reflect performance on neuropsychological tests for recalling proper names.
Authors: Van Hulle Carol A. , Basche Kristin E , Hale Madeline R , Koscik Rebecca Langhough , Sanson‐Miles Leah , Johnson Sterling C. , Hermann Bruce P , Mueller Kimberly D
Published: December 2022

Background

Subjective memory complaints (SMC) are common in middle‐aged adults. Associations between SMC and cognitive ability have been inconsistent perhaps because SMC measures rarely specifically match measured cognitive domains. We examined the relationship between objective and subjective evaluations of participants’ ability to recall proper names.

Method

N = 1254 participants enrolled in the Wisconsin Registry for Alzheimer’s Prevention (WRAP), who were cognitively unimpaired at baseline and had paired SMC and proper noun recall for 1–7 visits were included in these analyses (median visits = 4. A proper name (PN) delayed recall score (0‐9) was created from item‐level data from the Wechsler Memory Scale‐Revised Logical Memory II subtest. Participants also completed the Memory Functioning Questionnaire (MFQ), a 17 item self‐appraisal (1‐ major problems to 7‐ no problems) of frequency of forgetting. We examined the association between the MFQ item “frequency of forgetting names” (FFN, M = 4.0 [1.3]) with PN score (M = 4.3 [2.2]) at most recent visit using OLS linear regression. Age, sex, years of education, APOE risk score, and number of visits (i.e practice effects) were included as covariates. We also examined a baseline FFN*age at visit interaction to characterize changes in PN score over time (linear mixed effects models; random intercepts).

Result

Sample characteristics are shown in Table 1. For participants with multiple visits, PN score was fairly stable between baseline and most recent visit (r = 0.54), as was FFN (r = 0.61). FFN was significantly associated with concurrent PN score (b = 0.14 [beta = 0.09], p = <.001, see Table 2, Figure 1). Excluding 82 participants who converted to cognitively impaired at their last visit did not change these results (beta = 0.10, p <.001). In longitudinal analyses, the baseline FFN*age interaction was not significant (estimate = .01, p = .26), although PN score declined slightly with age (estimate = ‐0.07, p <.001).

Conclusion

Measures of SMC tend to focus on broad ratings (e.g., how would you rate your memory), and often do not correlate with objective measures among unimpaired people. These results demonstrate a significant association between subjective appraisal of and objective performance on name recall.
Investigating a new neocortical mask for Centiloid quantification
Authors: Bourgeat Pierrick , Dore Vincent , Benzinger Tammie L.S. , Tosun Duygu , Li Shenpeng , Goyal Manu S. , LaMontagne Pamela , Jin Liang , Rowe Christopher , Weiner Michael W. , Morris John C. , Masters Colin L , Fripp Jurgen , Villemagne Victor L
Published: December 2022

Background

The Centiloid (CL) project was developed to harmonise the quantification of Amyloid PET scans to a unified scale. The neocortical mask used for quantification was obtained using a private dataset of 19 mild AD patient and 25 older controls imaged using 11C‐PiB. The mean difference SUVR images were smoothed, subtracted and thresholded at 1.05 SUVR. While this threshold was chosen to maximise areas of specific Amyloid binding while avoiding areas of non‐specific binding, it was not evaluated in terms of agreement between different tracers or group separation. In this study, we created a new mask using an independent dataset of 11C‐PiB images, and investigated its impact on inter‐tracer agreement, tracer variability and group separation.

Method

Using the AIBL and OASIS databases, 63 mild AD (MMSE=20‐24;CL>20) and 63 Healthy controls (MMSE>=28;CDR=0;CL<20) matched based on age and gender, were selected. Their 11C‐PiB images were spatially normalised using the SPM CL pipeline and transformed into SUVR using the whole cerebellum. A mean AD‐HC difference image was computed and thresholds of [0.6‐1.2] SUVR were explored. The resulting masks were evaluated in the 5 Amyloid tracers using the GAAIN head‐to‐head calibration datasets in terms of inter‐tracer agreement, variance in the young controls (YC) and YC‐AD effect‐size (ES). The recalibrated CL were evaluated on the AIBL dataset with the ES on the HC‐AD and HC‐MCI using baseline and rate of change (CL/yr).

Result

Using a higher threshold resulted in a smaller neocortical mask, better targeting regions of high Amyloid update. In the GAAIN dataset, the smaller masks led to higher R2 for each 11C‐PiB/18F‐Tracer pairs and higher YC‐AD ES. They also led to a lower variance in the YC for all tracers except for Flutemetamol. In AIBL, while it increased the ES at baseline, it decreased in the HC‐MCI when using CL/yr.

Conclusion

While using a smaller neocortical mask improved inter‐tracer agreement and reduced variance in YC, the results in AIBL indicate that it might not be as sensitive to detect early changes as highlighted with poorer HC‐MCI ES.
The effect of genetic background and immunophenotype on microglial response to AD pathology
Authors: Cornelissen Tom
Published: December 2022

Background

A major hurdle in developing effective treatments for Alzheimer’s Disease (AD) is the fact that pathological hallmarks, such as amyloid beta (Aβ) plaques, develop decades before the first clinical symptoms emerge. Moreover, the risk of developing AD is strongly influenced by genetic background. In addition, the role of microglia in the disease pathway is undeniable, albeit dual and complex. We therefore aim to determine the influence of patient genetic background and immunophenotype on the microglial response to AD pathology.

Method

Subject material was sequenced and underwent deep immunophenotyping. Based on their scores patient iPSCs were divided in a high risk and low risk group of developing AD. This microglial response is determined by (i) their phagocytic capacity and (ii) their (change in) morphology. iPSC cells were differentiated into microglia (Mancuso et al., 2019), followed by RT‐qPCR to verify their identity. When microglia are incubated with pHrodo beads, these are phagocytosed and transported to the acidic lysosome, yielding a pH dependent increase in fluorescence, measured with an Operetta confocal microscope. Microglial morphology was recorded in an Incucyte and tracked and scored (e.g. amoeboid, rod‐like, size, motility …) automatically by AI based software. The change in morphology was assessed after addition of stressors such as LPS or Aβ1‐42.

Result

Phagocytotic capacity of a reference microglia strain, measured by pHrodo intensity, reached a maximum level approximately 2 hours after addition of the pHrodo beads. When cytochalasin D, an Actin polymerization inhibitor, was added to the medium, the phagocytosis process is inhibited and baseline pHrodo intensity levels are observed. In addition, the addition of LPS seemed to change the morphology of microglia to a more elongated rod‐like shape with less motility.

Conclusion

The phagocytic capacity of microglia could be dependent on the genetic background and immunophenotype of the iPSC strain. Similarly, the effect on morphology (e.g. more rod‐like shape) as an answer to stressors (e.g. LPS) could be dependent on the microglia strain. The differential microglial response based on genetic background and immunophenotype might yield insight into the further segmentation of different types of Alzheimer’s Disease and personalized therapeutic approaches.
Clinical performance and robustness of blood‐based biomarkers for early detection of amyloid pathology associated with Alzheimer’s disease
Authors: Blennow Kaj , Kurka Hedwig , Suridjan Ivonne , Jethwa Alexander , Hastreiter Maximilian , Carboni Margherita , Kollmorgen Gwendlyn , Rabe Christina , Bittner Tobias , Fowler Christopher , Masters Colin L. , Zetterberg Henrik , Hansson Oskar
Published: December 2022

Background

Accurate and robust blood‐based biomarkers (BBBMs) of Alzheimer’s disease (AD) are required for identification of symptomatic patients with low likelihood of amyloid pathology before confirmatory diagnostic evaluation. Further evidence on the clinical performance and robustness of BBBMs is required to identify patients for clinical trials and in routine clinical practice. We evaluated the clinical performance and robustness of amyloid‐β 1–42 (Aβ42), amyloid‐β 1–40 (Aβ40), apolipoprotein E4 (ApoE4), phosphorylated‐tau 181 (pTau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NFL) as BBBMs of AD.

Method

Analyses were performed retrospectively using plasma samples from AIBL, BioFINDER, and CREAD cohorts, comprising cognitively normal individuals and patients with subjective/objective cognitive impairment, mild AD, or amyloid screen failure. BBBMs were measured at two laboratories using automated Elecsys® prototype immunoassays (cobas e 601 and e 411 analyzers; all Roche Diagnostics International Ltd). Clinical performance of single BBBMs and combinations of BBBMs (using logistic regression) was assessed using area under the receiver operating characteristic curve (AUC‐ROC) analysis. Negative percent agreement (NPA), prevalence‐adjusted negative and positive predictive values (NPV and PPV), and screen‐out rate were compared at 85% positive percent agreement (PPA). Robustness, defined as the change in clinical performance when adding ±10% bias and random variability, was calculated at 85% PPA.

Result

Across cohorts, the best performing single BBBM was pTau181 (AUC: 81.6–89.3). The best performing combined BBBM models across cohorts were pTau181+Aβ42 (AUC: 85.6–93.4), pTau181+ApoE4 (AUC: 83.7–91.8), and pTau181+Aβ40 (AUC: 84.8–90.2); clinical performance for these combined BBBM models in terms of NPV and PPV was comparable, providing high NPVs (>90%) and screen‐out rates (>50%). For combined BBBM models including Aβ42 or Aβ40, robustness at 85% PPA was lower compared with models not including Aβ42 or Aβ40 across cohorts. Considering both clinical performance and robustness, pTau181 and pTau181+ApoE4 were the best performing single and combined BBBM models, respectively, across cohorts.

Conclusion

Across cohorts, pTau181+ApoE4 was the best performing BBBM model for detecting patients with low likelihood of amyloid pathology. These findings support the suitability of these BBBMs to inform diagnostic assessments for patients with low likelihood of AD.
The Utility of Blood Based Biomarkers in Detecting Neurological Complications of COVID‐19 in Critically Ill Patients
Authors: Cooper Jennifer G , Stukas Sophie K , Grey Rebecca , Ghodsi Mohammad , Ahmed Nyra , Hoiland Ryan , Thiara Sonny , Foster Denise , Harper Megan , Panenka William J , Silverberg Noah Noah , Stoessl Jon A. , Sossi Vesna , Sekhon Mypinder S , Wellington Cheryl L
Published: December 2022

Background

Neurological and neuropsychiatric complications have been documented in patients with COVID‐19. This study aims to investigate the utility of two neurological blood‐based biomarkers to predict neurological complications and mortality due to COVID‐19 in the intensive care unit (ICU). Neurofilament light (NF‐L) is a marker of axonal damage and glial fibrillary acidic protein (GFAP) is a marker of astrocytic activation.

Methods

Patients with respiratory failure were prospectively enrolled from the ICU at Vancouver General Hospital. COVID‐19 patients were excluded if the diagnosis was an incidental secondary finding upon ICU admission or if their enrollment was >10 days after ICU admission. Control patients were excluded if their enrollment was >4 days after ICU admission or if their primary diagnosis was non‐respiratory. Plasma samples were collected upon admission study enrollment, with additional samples collected on day 7 and day 14 from COVID‐19 patients. Plasma NF‐L and GFAP were quantified using the Quanterix Simoa HD‐X analyzer. Group comparisons were performed using a Mann‐Whitney test. Trajectory analysis was performed using a Wilcoxon test or Friedman one‐way ANOVA. Area under receiver operating curve (AUROC) analysis was calculated to predict neurological complications and mortality during ICU stay.

Results

Of the 242 patients enrolled, 209 were confirmed positive for SARS‐CoV‐2 while 33 served as ICU controls. Median age was 61 years for the COVID‐19 group, 64 years for controls. Upon ICU admission, NF‐L was 32% lower and GFAP was 24% lower in those with COVID‐19 compared to controls after correcting for age. NF‐L concentrations increase by doubling each week of ICU stay, while GFAP remained stable. Over the course of their ICU stay, 16% COVID‐19 patients were diagnosed with a neurological complication and 17% died. Plasma NF‐L and GFAP demonstrated a moderate to strong ability to predict neurological complications (AUROC: NF‐L=0.702; GFAP=0.722) and mortality (AUROC: NF‐L=0.815; GFAP=0.809) during ICU stay.

Conclusions

Upon ICU admission, NF‐L and GFAP were lower in patients with COVID‐19 compared to controls. NF‐L, but not GFAP, increased over the course of ICU stay in patients with COVID‐19. Both markers were able to predict neurological complication or ICU mortality with moderate to strong accuracy.
Pharmacologic Stabilization of Retromer Rescues Endosomal Pathology Induced by Defects in the Alzheimer’s gene SORL1
Authors: Knupp Allison , Mishra Swati , Young Jessica E.
Published: December 2022

Background

Defects in the Sortilin‐related receptor 1 gene, SORL1, are highly pathogenic Alzheimer’s disease (AD), on par with other causal AD genes. SORL1 is a key regulator of endosomal trafficking in neurons, and loss of SORL1 function disrupts trafficking pathways that are vital for neuronal health. SORL1 has been found to interact with retromer, a trafficking complex that is a ‘master conductor’ of endosomal outflow. Here we rely on retromer pharmacological chaperones that stabilize retromer in vitro, and thus enhance retromer function in cells to test the hypothesis that they will correct AD‐associated neuronal pathologies.

Method

We used an isogenic series of human induced pluripotent cell lines either deficient in SORL1 expression (SORL1 KO or SORL1+/−) or harboring a one copy of a missense variant linked to increased risk for AD (SORL1Var). We treated neurons derived from these hiPSCs with the established retromer chaperone, TPT‐260, and tested whether they corrected indicators of AD’s defining endosomal, amyloid, and tau pathologies.

Result

We observed that TPT‐260 treatment was able to correct all of these pathological indicators, however the degree of rescue of some of the phenotypes was dependent one whether the neurons harbor at least one functional copy of SORL1 or whether they are fully deficient.

Conclusion

More than just validating that SORL1‐retromer acts a trafficking functional unit in neurons, our work sheds new light on how SORL1‐retromer is linked to AD’s cardinal pathologies and illuminates how this pathway can be therapeutically harnessed.
In vivo imaging of the mouse cholinergic projection system using [18F]FEOBV
Authors: Onuska Kate M. , Shanks Hayley R. C. , Qi Qi , Prado Vania , Thiessen Jonathan , Hicks Justin , Fox Matthew , Prado Marco , Schmitz Taylor W.
Published: December 2022

Background

Positron emission tomography (PET) with the [18F]‐Fluoroethoxybenzovesamicol ([18F]FEOBV) radiotracer is a promising tool for in vivo imaging of VAChT – a protein found specifically in the cholinergic system. However, the sensitivity and specificity of [18F]FEOBV uptake to known changes in VAChT protein levels remains untested. The aim of this study is therefore to use [18F]FEOBV in mouse lines where VAChT protein expression is held under precise genetic control to determine whether [18F]FEOBV brain uptake reflects the endogenous levels of VAChT present in different genetic mouse models.

Method

6‐month‐old VAChT conditional forebrain knock‐out mice (VAChTNkx2.1‐Cre‐flox/flox, n = 6), VAChT hyper expressing mice (VAChTChAT‐ChR2‐eYFP, n = 6), and littermate controls (VAChT flox/flox , n = 6; C57BL/6J, n = 6), received an intravenous injection of [18F]FEOBV and were imaged dynamically on a microPET scanner for 2 and a half hours.

Result

When compared to controls, VAChT conditional forebrain knock‐out mice demonstrated decreased [18F]FEOBV uptake in striatal regions of the mouse brain (Figure 1, left panel). In contrast, VAChT hyper expressing mice displayed widespread increases in brain [18F]FEOBV uptake when compared to controls (Figure 1, right panel).

Conclusion

Together, these findings suggest that [18F]FEOBV brain uptake is a sensitive and specific measure of known changes in VAChT protein expression.
A smart audio device Tochie for long‐term care residents to stay connected with family during COVID lockdown
Authors: Hung Lillian , Yang Sophie , Lin Margaret , Chen Irene , Dong Kevin , Young Erika , Liao Deborah , Soltan Ahmed
Published: December 2022

Background

The effects of isolation and loneliness have been exacerbated by the COVID‐19 pandemic. While assistive technology offers potential benefits for long‐term care residents, there is limited evidence on technology adoption in complex care environments in LTC. The voices of older persons, family members and staff perspectives are not adequately included in implementation science literature. The poster report the adoption of Tochie, a smart audio device that allows family members to remotely record and schedule messages, such as daily reminders or comforting audio recordings, to send to their loved ones in LTC care homes during the time of COVID lockdown.

Method

We applied qualitative descriptive design with interview and focus group methods. A total of 25 people in LTC participated in the study, including residents, family members, and care staff from two long‐term care homes in British Columbia, Canada. Each resident was given a device to use with their family member for a four‐week intervention period. The research team checked in with family members and staff weekly via telephone and email to provide support and gather feedback. Pre‐ and post‐intervention focus groups and interviews were held via Zoom and phone correspondence to learn about participants’ experiences using Tochie. Thematic analysis was performed to identify themes.

Result

Four common themes were identified to describe the experience of using Tochie in LTC: (a) fostering emotional connection (b) connecting in creative and personalized ways (c) considering contextual considerations in LTC (d) lessons learned for future developments.

Conclusion

The COVID‐19 pandemic has provided us an opportunity to redefine and reconstruct what it means to “keep in touch” with loved ones in care settings. In our study, residents, families and staff highlighted the ways in which Tochie has enabled and expanded possibilities for family connection. Our findings offer pragmatic insights into challenges and possibilities for future product development and implementation.
Bridging the gap between cellular amyloid metabolism and Alzheimer’s disease clinical data
Authors: Molkov Yaroslav , Zaretskaia Maria , Zaretsky Dmitry V ,   the Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Published: December 2022

Background

Alzheimer’s disease (AD) diagnosis strongly correlates with the density of amyloid deposits. Yet, amyloid fibrils per se are not toxic, which represents a major gap in amyloid‐based theories of AD. Based on the proposed previously amyloid degradation toxicity hypothesis, we present the mathematical model of amyloid turnover that bridges this gap (Fig.1).

Methods

The model suggests that the probability of AD diagnosis is defined by amyloid cytotoxicity accumulated over sickness duration. The cytotoxicity depends on the cellular uptake of soluble beta‐amyloid rather than on amyloid aggregates. Also, after uptake, beta‐amyloid is concentrated intralysosomally and forms fibrillation seeds. They cannot be digested and after exocytosis grow by aggregating more beta‐amyloid. The equations describing the model are solved analytically using two major AD biomarkers as independent variables: beta‐amyloid concentration in the cerebrospinal fluid (CSF‐Aβ42) and amyloid deposits density measured by positron emission tomography (PET). Parameters of the model are inferred using maximum likelihood estimation method from the clinical dataset obtained by ADNI.

Results

The model describes the probability of AD diagnosis as a function of CSF‐Aβ42 and PET and confirms major previously formulated clinical observations (Fig.2). (1) The probability of AD increases with PET, i.e., the density of amyloid deposits; (2) For participants with the same PET, the probability of AD is higher at lower CSF‐Aβ42 levels. For each pair of values (CSF‐Aβ42; PET), the model allows calculating cellular uptake, sickness duration, and accumulated toxicity. Natural limitations on these parameters explain the distribution of CSF‐Aβ42 and PET (Fig.3). Specifically, these values are bound by (1) minimal and maximal cellular uptake; (2) high accumulated toxicity; 3) disease duration.

Conclusions

Existing clinical data allow the inference of kinetic parameters describing beta‐amyloid turnover. The resulting mathematical model predicts positive correlation between the density of beta‐amyloid aggregates and the probability of AD diagnosis in absence of cytotoxicity of amyloid deposits. To the best of our knowledge, this model is the first to mechanistically explain negative correlation between the probability of AD diagnosis and CSF concentration of soluble beta‐amyloid. Finally, natural limitations on model parameters explain the overall distribution of measured CSF‐Aβ42 and PET values.
An integrated systems‐level analysis of the molecular changes resulting from systemic infections in Alzheimer’s disease
Authors: MacBean Lachlan Ford , Smith Adam R. , Smith Rebecca G. , Lunnon Katie
Published: December 2022

Background

To fully understand the molecular consequences of neuroinflammation and systemic infection in Alzheimer’s disease (AD), it is important to scrutinise molecular changes occurring in the brain in individuals with AD after they have had a systemic infection. Recently, several epigenome‐wide association studies (EWAS) have identified robust and reproducible alterations in AD brain samples compared to controls. In the current study we have performed an EWAS comparing bulk brain tissue in individuals with AD and non‐demented controls with or without a systemic infection.

Method

DNA methylation arrays were employed for quantification of DNA methylation in extracted DNA from 276 prefrontal cortex brain tissue samples (controls, n = 72; AD‐diagnosed, n = 86; cognitively normal with infection, n = 48; AD‐diagnosed with infection, n = 70). Methylation values were quality checked and normalised before Analysis of Variance was performed to identify sites of significant differential methylation across all groups. Probes that were significant to AD‐only patients and infection‐only patients, when compared to controls, were removed, leaving only probes that were specifically differentially methylated in infection‐AD cases.

Results

Overall, more significant changes in methylation across the genome can be observed in AD patients who also suffered from systemic infection compared to AD‐only patients and infection‐only patients. By removing probes that are significantly associated with either systemic infections or AD, the remaining significant probes are therefore more likely to be associated with the consequences of infections, specifically within AD patients. Identified genes include AUTS2, a gene implicated in developmental disorders, and ADAR, a protein‐coding gene involved in the control of the innate immune response and controlling the function of certain neurotransmitters.

Conclusion

The exact pathways affected by systemic infection are yet to be scrutinised, however this initial data provides evidence that unique changes to the methylome occur in AD‐diagnosed patients who additionally suffer from a systemic infection. The next steps of this project include isolating microglia to observe methylation changes specific to these cells, as well as incorporating more sample data sets to improve power.
Diversity in Phase 2 and Phase 3 Placebo‐Controlled, Double‐Blind, Lecanemab and Elenbecestat Early Alzheimer’s Disease Studies
Authors: Grill Joshua , Molina‐Henry Doris P. , Sperling Reisa A. , Dhadda Shobha , Tranotti Kate , Harris Russell , Devins Theresa , Swanson Chad J , Kanekiyo Michio , Gee Michelle , Irizarry Michael C , Kramer Lynn D , Aisen Paul , Raman Rema
Published: December 2022

Background

Increasing diversity in clinical trials is a scientific, public health, and ethical imperative. Clinicians need to understand how a drug works in representative disease populations, diverse communities need access to clinical trials, and social justice demands addressing health and healthcare disparities. Several factors contribute to underrepresentation among racial and ethnic groups in Alzheimer’s disease (AD) clinical trials, including barriers to enrollment but also potential differential exclusion based on eligibility criteria.

Method

We evaluated enrollment in four double blind placebo‐controlled clinical trials in early AD that incorporated highly similar enrollment criteria (NCT03887455, NCT01767311, NCT02956486, NCT03036280). We assessed the impact of eligibility criteria. Racial and ethnic information were self‐reported by participants and are reported as mutually exclusive categories. Each trial incorporated PET or CSF to evaluate brain amyloid pathology, as well as typical inclusion and exclusion criteria used in early AD trials.

Result

Across the trials, 10,805 US participants were screened: 889 (8%) were of Black race, 119 (<1%) were of Asian race, and 2,883 (27%) were of Hispanic ethnicity. 2,459 participants were randomized, including 97 (4%) of Black race, 17 (<1%) of Asian race, and 450 (18%) of Hispanic ethnicity. Overall, 23% of those screened were randomized: 27% of non‐Hispanic White participants compared to 11% of Black race participants, 14% of Asian race participants, and 16% of Hispanic ethnicity participants. The distribution of age and disease stage (MCI or mild AD) among screened and randomized participants were similar across the racial and ethnic groups. Females appeared to be more highly represented among Black race and Hispanic ethnicity participants, compared to non‐Hispanic White participants. Five inclusion and exclusion criteria, including AD biomarker criteria, resulted in greater than 60% of screen failures across the trials, with some variability in specific eligibility criteria across racial and ethnic groups.

Conclusion

Early AD clinical trials have high rates of screen failure and exploration of potential differential screen failure among racial and ethnic groups will be important to future trial design choices.
High prevalence of antibodies against Ascaris Lumbricoides in patients with severe Alzheimer’s Disease
Authors: Amanatidou Dionysia , Tsolaki Magdalini , Tsaousi Christine , Christoforou Athina , Papasavva Eleftheria , Anastasiou Anna , Papageorgiou Athanasia , Giahanou Eleftheria , Eleftheriou Phaedra
Published: December 2022

Background

Alzheimer’s disease (AD) accounts for 60‐70% of dementia cases. It is a multi‐factorial process and not all factors that affect its appearance and development have been clarified. Several parasites have been correlated with dementia [1] and development of AD has been associated with Toxoplasma gondii parasitism [2].

In the present study, IgG and IgM antibodies against Ascaris Lumbricoides (AL) antigens were detected in the serum of 60 patients with mild, medium and severe AD, 20 from each group.

Methods

Antigens of AL were adhered to the bottom of ELISA plate (IBL International GMBH) in order to measure the level of IgG and IgM antibodies. Peroxidase labelled Protein A or goat anti‐human IgM were used to bind IgG and IgM antibodies, respectively.

Results

According to the results, 30% of patients with severe AD were positive to IgG antibodies (Ab) against AL antigens (Ab concentration > 9 U/µL) whereas none of the patients with mild and moderate AD was positive (Figures 1, 2). The mean IgG Ab concentration in this group was 2.1 times higher than the mean value of patients with mild and moderate AD (p = 0.001 according to t‐test). Additionally, 35% of patients with severe AD were positive to IgM Abs while 16.7% and 8% of IgM positive samples were found in patients with mild and moderate disease.

Conclusion

The results present a potential correlation of Ascaris lumbricoides infection and antibodies development with Alzheimer’s Disease.

References: [1] Gislaine Cristina Lopes Machado‐Porto etal., Reversible dementia due to neurocysticercosis: Improvement of the racemose type with antihistamines, Dement Neuropsychol, 2015; 9(1): 85‐90. [2] Hossein Mahmoudvand etal., Toxoplasma gondii Infection Potentiates Cognitive Impairments of Alzheimer’s Disease in the BALB/c Mice. J Parasitol (2016); 102 (6): 629‐635.