bluuebunny/crossref_metadata_2025 huggingface dataset:
Single Cell Approaches Reveal Perturbed Brain Vascular Molecules in Alzheimer’s Disease
Authors: İş Özkan , Wang Xue , Reddy Joseph S. , Patel Tulsi , Min Yuhao , Quicksall Zachary , Heckman Michael G. , White Launia , Kouri Naomi , Deniz Kaancan , Tutor‐New Frederick Q , Carnwath Troy , Oatman Stephanie R , Carrasquillo Minerva M. , Nguyen Thuy , Petersen Ronald C. , Kantarci Kejal , Nho Kwangsik , Saykin Andrew J. , Dickson Dennis W. , Murray Melissa E. , Allen Mariet , Ertekin‐Taner Nilufer
Published: December 2022

Background

Inter‐cellular communication within the gliovascular unit (GVU) is critical for cerebral blood flow regulation, maintenance of the blood‐brain‐barrier (BBB) properties, and brain energy metabolism. Although numerous cell biology studies demonstrate the role of the GVU for BBB breakdown in Alzheimer’s disease (AD), the precise molecular changes contributing to its pathophysiology are unclear.

Method

We performed single nucleus RNA sequencing (snRNAseq) of temporal cortex tissue in 24 AD and control brains to understand the transcriptional changes in the cells of GVU. We acquired the snRNAseq profile of 79,751 total brain cells that comprise 6,541 astrocytes and 2,210 vascular cells. The latter formed three distinct vascular clusters characterized as activated pericytes, endothelia and resting pericytes. We identified differentially expressed genes (DEGs) and their enriched pathways in these clusters and detected the most transcriptional changes within activated pericytes. Using our data and a knowledge‐based predictive algorithm, we discovered and prioritized molecular interactions between vascular and astrocyte clusters, the main cell types of the GVU of the BBB.

Results

Vascular targets predicted to interact with astrocytic ligands have biological functions in signalling, angiogenesis, amyloid ß metabolism and cytoskeletal structure. Top astrocytic and vascular interacting molecules include both novel and known AD risk genes such as APOE, APP and ECE1. We validated gene expression changes using qPCR. We are in the process of evaluating these gene expression changes in antemortem blood from AD and control participants.

Conclusion

Our findings provide valuable information into the transcriptional changes in predicted vascular‐astrocytic partners at the GVU, highlighting insights into the molecular mechanisms of BBB breakdown in AD.
Obstructive sleep apnea risk is associated with decreased executive processing speed in older women but not in men: A longitudinal analysis of the Canadian Longitudinal Study on Aging
Authors: Legault Julie , Thompson Cynthia , Moullec Grégory , Baril Andree‐Ann , Martineau‐Dussault Marie‐Ève , André Claire , Carrier Julie , Gosselin Nadia
Published: December 2022

Background

Studies investigating the possible links between obstructive sleep apnea (OSA) and cognitive dysfunction have yet led to heterogenous results. Individual characteristics, such as sex and age, could moderate this association and explain part of this heterogeneity. Here, we characterized the sex‐ and age‐specific association between OSA risk and cognitive performance using longitudinal data from the community‐based Canadian Longitudinal Study on Aging (CLSA) comprehensive cohort.

Method

Our sample included 25,393 participants aged 45 to 85 years at baseline (mean = 63 years; 51% women; 78% with post‐secondary degree), recruited between 2011 and 2015 across Canada. Participants with Alzheimer’s and Parkinson’s diagnosis or with history of stroke and of traumatic brain injury were excluded. Participants’ risk for OSA was measured at baseline using the STOP‐B questionnaire, based on risk factors and symptoms of OSA. Participants scoring ³ 3/5 were classified as being at high‐risk for OSA. Neuropsychological tests assessed memory (Rey Auditory Verbal Learning Test), executive functioning (Mental Alternation, Animal Fluency, Controlled Oral Word Association and Stroop tests) and psychomotor speed (Choice Reaction Time) at baseline and at 3‐year follow‐up. We calculated changes (follow‐up – baseline) in each cognitive continuous score and conducted sex‐specific age‐stratified (45‐59; 60–69; 70–85 years) analyses of covariance (ANCOVAs) to estimate the predictive role of baseline OSA risk, adjusting for socio‐demographic, lifestyle and medical comorbidities. The level of significance was set at p<0.05, after false‐discovery rate correction.

Results

In the whole sample, results show a decline over time only for executive functioning (Mental Alternation, Animal Fluency and Stroop) at 3‐year follow‐up. When analyses were performed according to age and sex, being at high‐risk for OSA was associated with increased reaction times only in women aged 70–85 years (Stroop word: [F = 12.486; 95%CI ‐5.440 to ‐1.554]; Stroop color: [F = 7,870; 95%CI ‐9.843 to ‐1.738]).

Conclusion

Although changes in executive functioning were noted over time in the whole sample, being at high‐risk for OSA only increased the risk of slower processing speed for older women. These findings suggest that the possible detrimental effects of OSA on cognitive health depend on participants’ age and sex.
Memorability of Word‐Pairs: Developing a Method for Generation of Calibrated Stimulus Sets for Repeat, Remote, Automated Testing
Authors: Kaula Alexander J , Cormack Francesca K , Taptiklis Nick
Published: December 2022

Background

Verbal‐Paired Associates (VPA) is widely used measure of memory. However, the memorability characteristics of the word‐pairs are not well‐understood, and the task currently suffers from ceiling effects (Uttl et al. 2002). Here we describe a data driven process for word‐pair selection, yielding precise estimates of memorability at the item and list level. This allows tuning of task difficulty to participant characteristics, and the development of many well‐calibrated parallel forms for longitudinal automated testing.

Method

For model development we recruited a total of 185 participants aged 18‐40 years without psychiatric diagnoses, chronic medication, or historical head injury using the Prolific online testing platform. We used Cambridge Cognition’s NeuroVocalix software to automatically deliver and score Learning and Recall phases of VPA.

In a series of experiments, we explored the contributions of item‐level, pair‐level, list‐level, and study‐level properties to the probability of subsequent recall. At the item‐level, we considered word‐concreteness and word‐frequency. To capture the semantic relatedness of word‐pairs, we trained the GloVe neural network model (Pennington et al, 2014) to predict the co‐occurrence of words from a corpus of transcribed English. This yields high‐dimensional vectors, from which we could calculate the semantic cosine distance between items in a word‐pair. At the list‐level we considered order effects (primacy and recency), and at the study level we considered practice effects.

Data from these experiments was combined in a linear mixed effects logistic regression model to yield predicted memorability estimates for new sets of word‐pairs. These test sets were then deployed with a cohort of 43 older adults (aged 55 years and upwards) to evaluate this prediction.

Result

Modelling showed significant contributions of item‐level, pair‐level, list‐level, and study‐level factors to probability of recall. When applied to the new set of words and tested with our older cohort, we found that this model‐derived measure was a robust predictor of recall (r = .931, p < 10‐6).

Conclusion

We have a robust method of predicting, for a given word‐pair, what the likelihood of recall will be. This enables the generation of sets of word‐pairs with well‐understood memorability characteristics, for use in automated, repeat, remote assessment.
Latent profiles of physical actigraphy patterns among older adults: Differential relationships with cognition and vascular burden by sex
Authors: Paolillo Emily W , Lee Shannon Y. , Djukic Nina , VandeBunte Anna M. , Saloner Rowan , Kramer Joel H. , Casaletto Kaitlin B
Published: December 2022

Background

Physical activity (PA) is well‐known to benefit cognition and vascular health, yet it is less clear how specific PA patterns relate to cognitive and vascular outcomes and whether these relationships differ by person‐specific factors. Thus, we characterized empirically‐derived latent profiles of PA among older adults and examined their associations with cognition, vascular burden, and person‐specific factors (e.g., sex).

Method

124 older adults from the UCSF Memory and Aging Center (Meanage = 72.2; SDage = 8.4; 54% women; 83% non‐Hispanic White) wore a FitbitTM during waking hours for 30 days. Minute‐level Fitbit data were used to calculate daily averages for three distinct PA metrics: step count, sedentary time (0 steps/minute), high‐intensity time (≥120 steps/minute). Composite memory and executive functioning z‐scores were calculated for a subset of participants (n = 86) who completed neurocognitive testing. Vascular burden was estimated via a count of vascular conditions. Homogenous subgroups with similar PA patterns were identified via latent profile analysis (LPA). ANCOVAs and Poisson regression examined independent and interactive effects of PA group and sex on cognition and vascular burden, respectively, covarying for age and education.

Result

LPA identified 3 latent PA classes: Class1 (high overall activity but low intensity; n = 59), Class2 (low overall activity and low intensity; n = 49), and Class3 (high overall activity and high intensity; n = 16). PA class membership was associated with executive functioning and vascular burden, driven by better outcomes in Class3 than Class2 (executive: mean difference = 0.59, p = 0.013; vascular: b = ‐0.84; p = 0.028). PA class was not related to memory (p = 0.32). There was an interaction between class and sex on executive functioning (F2,78 = 3.20; p = 0.046) and vascular burden (b = 2.37; p = 0.032). In males, Class3 demonstrated the best executive functioning (vs. Class1 p = 0.038; vs. Class2 p = 0.057) and the least vascular burden (vs. Class1 p = 0.025; vs. Class2 p = 0.022). In contrast, there was no clear relationship between PA class and cognition or vascular burden among women (ps>0.05).

Conclusion

Differential PA patterns relevant to cognitive and vascular health can be identified using actigraphy in older adults. Sex‐differences emerged suggesting men may require higher intensity PA to improve cognitive and vascular health, whereas specific PA patterns did not significantly predict outcomes in women.
Improved automated cerebral microbleed (CMB) detection
Authors: Mead Aaron K , Bermudez Camilo L , Cogswell Petrice M , Wiste Heather J. , Gebre Robel K , Vemuri Prashanthi , Knopman David S. , Petersen Ronald C. , Jack Clifford R. , Graff‐Radford Jonathan , Gunter Jeffrey L.
Published: December 2022

Background

Cerebral Microbleeds (CMBs) are tracked in anti‐amyloid drug safety monitoring. T2*GRE or SWI MRI images are visually assessed for the presence of CMBs. Automated methods tuned for sensitivity often have unacceptably high false positive rates requiring extensive human cleanup.

Method

Assume contemporaneous T2*GRE and T1‐weighted images. CMB detection (Figures 1,2) has three steps: 1) Segmentation outputs from the T1‐weighted image are resampled into the T2*GRE image voxel raster; 2) Normalized cross‐correlation of the T2*GRE with a CMB template identifies “candidate CMBs”; 3) a neural network using voxel patches centered on each candidate CMB rejects false positives. Patches presented to the network are 4D and include five contrasts drawn from the T2*GRE, correlation, T1‐weighted, WM probability and CSF probability images. The simple network architecture consists of convolutional blocks followed by dense blocks. The system is trained using images from ADNI, ARIC, MCSA, and the Mayo Clinic ADRC that have been previously visually graded for CMBs (Table in Figure 3). Importantly, we include participants with and without CMBs in our data reflecting the fact that the majority of people (even the elderly) have no CMBs. Data is split 70:10:20 by subject for training, validation, and testing. Various network configurations were evaluated.

Result

High candidate detection sensitivity can be achieved at the expense of presenting hundreds to thousands of false positive candidates per input image to the rejection network. Our best performing network configuration to date has AUC 0.982 (95% bootstrap CI 0.971 to 0.990 based on the 10% validation subset). Choosing an operating point with 95% sensitivity in the validation set and admits, on average, 0.6 false positive CMB candidates per input T2*GRE image. Sensitivity is hindered by a small number of obvious errors in the ground truth visual assessment. Validation loss tracks training loss with no indication of over‐fitting. Example patches are shown in Figure 4.

Conclusion

Excessive false positive detection requires significant human correction and effort, preventing automated CMB detection from being widely adopted. We have an automated detection system that is sensitive (95%) and provides excellent false positive rejection (<1 false positive CMB/input image) reducing needed human effort.
Gamma Sensory Stimulation at 40Hz for a 6‐month Period Reduces White Matter Atrophy in Alzheimer’s Disease Patients
Authors: Da Xiao , Hempel Evan , Mrozak Holly , Malchano Zach , Vaughan Brent , Megerian Jonathan Thomas , Hajos Mihaly , Cimenser Aylin
Published: December 2022

Background

Although white matter atrophy is observed in normal aging, it is more pronounced in Alzheimer’s Disease (AD) patients. Recently, advanced magnetic resonance imaging (MRI) provided more detailed information which linked changes in white matter to elevated risk and progression of AD. White matter degeneration, myelin loss, and oligodendrocyte damage in AD patients suggest that white matter can be a mechanistically important target in AD patients. Recently, clinical benefits of 40Hz gamma sensory stimulation have been demonstrated in AD patients. Here, we studied the effects of 40Hz gamma sensory stimulation on white matter in patients with clinical presentation of AD spectrum and compared our results to historical data.

Method

The data presented here is from Overture study (NCT03556280) and the Alzheimer's Disease Neuroimaging Initiative (ADNI1) database. Overture study data included treatment group participants who received 1‐hour daily 40Hz gamma auditory‐visual stimulation at home for a 6‐month period and placebo group. Analysis between the groups suggested a difference in white matter atrophy favoring the treatment group. To compare our treatment group with a larger control group, we studied ADNI1. We included a subset of each population so that baseline distributions (age, MMSE, white matter volume) are matched and had Month 6 MRI data. The resulting populations contained N=16 participants from Overture study and N=64 participants from ADNI1. Overture study structural MRI were acquired using 1.5 Tesla MRI and cerebral white matter segmentation was performed using FreeSurfer as it was done in ADNI1. Age, MMSE, white matter volume adjusted least‐square means method is used to assess the percentage changes in white matter volume within 6‐month period.

Result

The Overture study treatment group participants exhibited 0.38±0.82 percentage increase (volume in % of total intracranial volume) and ADNI1 study participants exhibited ‐2.45±0.40 percentage decrease in white matter volume after 6‐month period (p<0.004).

Conclusion

Our results suggest that 40Hz gamma sensory stimulation therapy for 6‐month period may reduce white matter atrophy, protect axons, and possibly prevent myelin and oligodendrocyte damage in AD patients. Given the crucial role of white matter connecting expansive brain regions, preventing or reducing its atrophy may diminish AD disease progression.
Intergenerational educational attainment among Latino and White men and women and incident risk for dementia and cognitive impairment without dementia
Authors: Meza Erika , Chen Yea‐Hung , Allen Isabel Elaine , González Hector M , Glymour M. Maria , Torres Jacqueline M
Published: December 2022

Background

Late life cognitive outcomes may depend on an individuals’ and their parents’ educational attainment levels. We evaluate the association of intergenerational education on dementia/Cognitive impairment without dementia (CIND) risk for Latino compared to White men and women.

Method

We analyzed data from 26,643 US Health and Retirement Study (HRS) Latino and non‐Hispanic white participants from 1998‐2016 (new entry cohorts enrolled every 6 years). Age‐eligible (50+ years at enrollment) respondents without probable dementia/CIND at baseline were included in the analyses with follow‐up waves every 2 years. Exposure was a 4‐category variable based on participants’ and parents’ (highest of mother’s or father’s) education in years: 1) first‐generation high‐school graduate (participant≥12; parents’ education<12); 2) multi‐generation (both≥12: reference); 3) only parents graduated high school but not respondent (participant<12; parent(s)≥12); and 4) neither parents nor participant completed high school (both<12). Probable dementia/CIND cases were classified using the Langa‐Weir 27‐point scale. We used Cox proportional hazard models to evaluate the association between education and dementia/CIND risk and included interactions to evaluate effect modification by gender and race/ethnicity.

Result

Our sample was 9% Latino, 46% men and 31% were classified with probable dementia/CIND during follow‐up from 2000‐2016 (mean follow‐up: 9 years). Compared to multi‐gen, first‐gen graduates showed higher dementia/CIND risk (HR:1.49 [95% CI: 1.40, 1.60]) independent of demographic factors. The magnitude of increased risk was smaller for men compared to women (interaction term:0.78 [0.70, 0.89]) and did not vary for Latinos compared to whites. Compared to multi‐gen, only parent graduate showed higher dementia/CIND risk (HR:2.21 [2.05, 2.37]), and the magnitude of risk was greatest for Latino compared to white men (interaction term:1.31 [0.77, 2.23]). Lastly, compared to multi‐gen, neither‐graduates showed higher dementia/CIND risk (HR:2.37 [2.14, 2.64]); association did not vary by gender or race/ethnicity.

Conclusion

While all groups showed increased risk for dementia/CIND compared to multi‐gen high school graduates, the most disadvantaged were downwardly mobile Latino men. Our findings suggest declines in dementia risk potentially attributable to growing educational attainment may persist in the future and be especially marked for racial/ethnic groups historically excluded from educational policies rendering high school completion.
Blood plasma profiles of neuropsychiatric symptoms in older people
Authors: Rabl Miriam , Clark Christopher , Dayon Loic , Bowman Gene L. , Popp Julius
Published: December 2022

Background

Neuropsychiatric symptoms (NPS) in older people worsen the patients’ and caregivers’ quality of life and are associated with cognitive decline. A better understanding of the biology underlying NPS may lead to novel ways for early detection and more targeted treatment. This study tested the hypothesis that NPS are associated with altered protein levels in blood plasma and these proteins improve prediction of NPS in a memory clinic setting. Additionally, we explored the association of the protein patterns with persistent NPS and cognitive decline.

Method

We performed a cross‐sectional and longitudinal study in older people with and without cognitive impairment. NPS were recorded through the Neuropsychiatric Inventory Questionnaire (NPI‐Q) while cognition was assessed through a comprehensive neuropsychological test battery collected at baseline and follow‐up visits. Shotgun proteomic analysis based on liquid chromatography‐mass spectrometry identifying 420 proteins were conducted in blood plasma samples of all participants. Multivariate linear regression and correlation analysis were used.

Result

Eighty‐five subjects with a mean age of 70 (± 7.4) years, 65% female and 54% with mild cognitive impairment or mild dementia were divided into groups with (NPI‐Q score > 0) and without NPS. We found 15 plasma proteins with altered baseline levels in participants with NPS. The model which best predicted the occurrence of NPS at baseline contained clinical data (age, sex, education years, cognitive impairment) and additionally the 15 altered proteins. Comparing this model with a reference model containing just the clinical data, the prediction of NPS significantly improved (from receiver operating characteristic area under the curve (AUC) 0.72 to AUC 0.89, p = 0.001) with a specificity of 87 % and a sensitivity of 72% (Fig. 1). Preliminary results indicate that five out of the 15 proteins were associated with persisting NPS and six with cognitive decline at follow‐up (mean: 3.4 ± 1.3 years).

Conclusion

Using a proteomic approach, we identified a panel of blood proteins associated with NPS in older people. These findings showed the potential of this approach to identify protein biomarkers of pathological changes underlying NPS and to detect novel treatment targets to reduce NPS and related cognitive decline.
Recommending exercise to boost mental sharpness in your aging patients? What clinicians need to know to prescribe right, measure better, and increase buy‐in
Authors: Gomes‐Osman Joyce Rios
Published: December 2022

Background

As our population ages, many individuals are at risk of developing age‐related cognitive decline. A wealth of scientific evidence supports that being physically active may prevent or delay the onset of cognitive impairment and dementia and related functional impairments. However, key barriers remain: 1) optimal exercise parameters for cognitive brain health have not been fully elucidated; 2) while most clinicians recommend physical activity, and older adults recognize its health benefits, the overwhelming majority of older adults fail to regularly participate in regular physical activity. Key preliminary results from two studies will be presented and discussed.

Method

Fifty‐one sedentary aging participants at risk for cognitive decline (age 62.9±6.8, 76.9% female) participated in Study 1. All participants completed an eight‐week moderate to high intensity exercise protocol and underwent assessments of neurocognitive and cardiorespiratory performance. In Study 2, a separate sample of fifteen individuals (68.1±6.5 years, 76.8% female) participated in a focus group to discuss factors influencing their exercise engagement.

Result

Study 1: All participants combined demonstrated significant improvements in cognition (measured by the Repeatable Battery for the Assessment of Neuropsychological Status [RBANS]) and cardiorespiratory fitness assessed by pre‐to‐post improvements in heart rate recovery (HRR) after eight weeks of exercise (p<0.05). Additionally, multiple regressions revealed a relationship between cognition (RBANS list learning [ß = .22] and RBANS list recognition [ß = 1.86] and fitness (p<0.05).

Study 2: The focus group revealed that participants felt providers’ physical activity recommendations were too general, and did not consider their physical and contextual limitations, leading them to feel less likely to follow through with them.

Conclusion

Our data suggests that committing to a regular exercise regimen, even for a brief two‐month period, can promote improvements in cardiorespiratory fitness and cognition. We discuss the potential utility of heart rate recovery, an easy clinical measure that takes just a few minutes, to estimate cardiorespiratory fitness that appears to be relevant for exercise‐induced improvements in cognition. We discuss simple strategies to effectively translate current guidelines into the needs of the individual, considering the challenges and demands of the clinical setting.
Rate of memory decline is associated with neuronal nuclear protein (NeuN) positive cells count in middle temporal gyrus in the Adult Changes in Thought (ACT) autopsy cohort
Authors: Mukherjee Shubhabrata , Ariza Jeanelle , Gibbons Laura E , Rachleff Victoria M , Travaglini Kyle J , Latimer Caitlin S , Melief Erica J , Campos John S , Gabitto Mariano , Miller Jeremy A , Ding Yi , Levi Boaz , Long Brian , Kaplan Eitan S , Hodge Rebecca D , Larson Eric B , Crane Paul K. , Lein Ed S , Keene C. Dirk ,   Seattle AD Brain Cell Atlas (SEA‐AD)
Published: December 2022

Background

The trace of memory has not been well studied in middle temporal gyrus (MTG). Although neuronal loss is minimal in most cortical regions of the aging brain, changes in synaptic physiology of ageing neurons may contribute to altered connectivity. In the Adult Changes in Thought (ACT) autopsy cohort, we explored if memory decline is associated with NeuN (neuronal nuclear protein), a biomarker for mature neurons, in MTG.

Method

ACT study participants were 5,763 older adults randomly sampled from an integrated healthcare delivery system in King County, Washington. We standardized composite memory scores to N(0,1) at baseline. We calculated slopes of memory decline over time using mixed‐effects models, where time was parameterized as years before death.

Among 69 individuals who underwent brain autopsy, we measured NeuN positive cell count from whole slide image analysis using HALO in five tissue layers (molecular, external granular, external pyramidal, internal granular, internal pyramidal + multiform) from brain tissue in MTG. In each layer, we normalized NeuN positive cell count over the tissue area. We derived an average NeuN positive cell count (ANPCC) by averaging the values across the layers (Figure 1).

We regressed ANPCC on memory slope, adjusting for age at death and sex. In secondary models, we added disease severity (Braak staging) and presence of APOE ε4 alleles separately. We also analyzed layer‐specific ANPCC.

Result

64 individuals were included for analysis (Table 1).

Memory decline in this sample was 0.10 units per year, similar to the entire cohort. Slower decline in memory (β = 0.10; p‐value = 0.002) was significantly associated with increased average ANPCC (Table 2). Adjusting for Braak staging and APOE ε4 gave similar results. Findings were statistically significant across all but the molecular layer.

Conclusion

ANPCC is associated with slower memory decline in multiple neocortical layers in MTG, irrespective of disease staging or APOE genotype. Since Alzheimer’s disease afflicts adult neuronal populations, survival mechanisms in mature neurons are likely to be either reversed or circumvented during neurodegeneration. Further analyses are needed to understand the functional range of NeuN and processes that lead to loss of NeuN immunoreactivity in cells.
Towards the development of a reference measurement procedure for the quantification of neurofilament light chain
Authors: Coppens Salomé , Drinkwater Giles , Mussell Chris , Hirtz Christophe , Quaglia Milena
Published: December 2022

Background

Neurofilament‐light chain (Nf‐L) is an early marker monitoring axonal damage which occur in many forms of dementia. During neurodegeneration, Nf‐L is released into biological fluid and is quantifiable in cerebrospinal fluid (CSF) and blood. Currently, its quantification is performed by immunoassays. While those ones are sensitive and precise, the development of a reference measurement procedure (RMP) using mass spectrometry (MS) approaches traceable to the International System of Units (SI) is essential to achieve standardisation.

Following the characterisation of three commercially available proteins as potential primary calibrator, one has been chosen and used for the method development. Here, we present the purity assessment and quantification traceable to the SI of the primary calibrator and preliminary data on the development of Nf‐L quantification in CSF by LC‐MS.

Method

A recombinant Nf‐L protein from Promise was characterized, SI traceably quantified via amino acid analysis and used as primary calibrator for the development of a LC‐MS method for Nf‐L. A triple quadrupole (QQQ) mass spectrometer coupled to a capillary liquid chromatography (LC) was used to set up a multiple reaction monitoring (MRM) method to monitor Nf‐L tryptic peptides and assess the potential of developing a RMP for Nf‐L.

Result

The homogeneity of Nf‐L from Promise was assessed on 3 aliquots prepared at 1.7 nmol/g. The mass fraction content in each vial was estimated at 1nmol/g ± 0.02 nmol/g.

A LC‐MRM method was developed to monitor Nf‐L tryptic peptides and assess their suitability for the development of a RMP. Fifteen peptides were selected. The limit of detection in solution is 1 ng/g for 6 peptides. The sample clean‐up was developed using Nf‐L spiked in artificial and real CSF. Several solid‐phase extraction cartridges were assessed in term of recovery and volume load. The use of protein precipitation was also assessed to increase the sensitivity. Preliminary experiments show a sensitivity of 100ng/g. Immunocapture will be used to achieve the required sensitivity.

Conclusion

A LC‐MRM based method and a sample clean‐up procedure were developed for the quantification of Nf‐L in CSF. A first assessment of sensitivity was carried out and the utilisation of immunocapture is on‐going to reach the required sensitivity.
Towards Fair ML‐based Language Assessment Methods for Detecting Alzheimer’s Disease
Authors: Parsapoor Mahboobeh
Published: December 2022

Background

Alzheimer's disease (AD) tends to affect the parietal lobe, which is responsible for language functions in the patient's brain. Thus, one significant impairment associated with AD is language impairment which is the cause that patients with AD have deficits at the word level (vocabulary size in speech can be an early sign of cognitive impairment [1]), sentence‐level, and discourse‐level of their languages. Thus, language disorders can be considered as markers to diagnose AD in a patient at its earliest stage [2]. The recent progress in the machine learning (ML) domain has revolutionized the early detection of AD in particular developing and deploying ML‐based language assessment (MLLA) methods for detecting AD at its mild cognitive impairment stage [3]. The ML community needs to develop fair MLLA methods for detecting individuals with AD.

Method

To develop a fair MLLA first we should consider how we can formulate the fairness for developing a MLLA method and how potential bias in language data can be identified and quantified, how text preprocessing, data augmentation and word embedding techniques can be applied without adding biases to MLLA, how can we identify protected and unprotected linguistic features? and finally how can we protect underserved groups in the deployment process of MLLA methods?

Result

We suggest a fair ML pipeline includes 1) preprocessing (i.e., eliminating sources of bias in data collection and data sharing, text augmentation and text preprocessing, defining unknown sensitive features including linguistic diversity, which are highly correlated with sensitive attributes such as races and genders. Note that sensitive attributes can be used to alleviate the bias). 2) In‐processing (i.e., adjusting machine learning process, e.g., using a regularization approach). 3) Post‐processing (i.e., adjusting trained model).

Conclusion

The development of fair MLLA methods is crucial to ensure all groups are treated fairly and there are no results that unfairly harm any subgroups of our population. Using our suggested pipeline, we can foster the confidence of clinical services to use MLLA methods and motivate patients to accept the results.
Transfer Learning based Deep Encoder Decoder Network for Amyloid PET Harmonization with Small Datasets
Authors: Shah Jay , Chen Kewei , Reiman Eric M. , Li Baoxin , Wu Teresa , Su Yi
Published: December 2022

Background

The existence of multiple amyloid tracers with varied characteristics poses a significant challenge to standardized interpretation and quantification of amyloid PET data. We previously demonstrated that a deep learning model using a residual inception encoder‐decoder network (RIED‐Net) architecture improved harmonization of florbetapir (FBP) and PiB PET. However, scarcity of head‐to‐head comparison datasets of other amyloid PET tracer may limit the ability to generalize this approach to the other amyloid PET tracers. In this research, we investigate the performance of RIED‐Net model trained on smaller datasets and explore transfer learning (TL) approaches which can leverage multiple different datasets and address the data scarcity issue.

Method

We previously trained our RIED‐Net model using PiB‐FBP data from Open Access Series of Imaging Studies (OASIS) (N=92) and tested the performance in the independent Global Alzheimer’s Association Interactive Network (GAAIN) (N=46) dataset. We now use the same procedure to train the RIED‐Net model using the smaller GAAIN dataset and evaluate the model performance. We then examine the feasibility of a TL approach by comparing the model performance between RIED‐Net model directly trained on the PiB‐florbetaben (FBB) from GAAIN (N=35) and the TL approach in which we started with the optimal RIED‐Net model for PiB‐FBP data and fine‐tuned the network parameters using the GAAIN PiB‐FBB data. A cross‐validation (CV) approach was used to evaluate model performance based on difference before and after harmonization in terms of correlation between mean cortical SUVR (mcSUVR) measurements from different tracers.

Result

RIED‐Net model trained using the smaller GAAIN PiB‐FBP data improved the agreement of mcSUVR measurements as measured by Pearson correlation from r=0.93 to r=0.96 (p<0.01) on test‐set. For PiB‐FBB harmonization, the TL approach provided numerically better agreement in mcSUVR from r=0.96 (direct train) to r=0.97 (with TL), demonstrating the potential benefits of applying TL based technique to address the issue of smaller sample size.

Conclusion

We demonstrate our RIED‐Net model can achieve improved harmonization even when trained on a relatively small training set. We also demonstrate the potential of transferring knowledge learned from one tracer pairs to improve the harmonization model of other related tracer pairs.
The Learning of Memory Support System in Individuals with Mild Cognitive Impairment
Authors: Koay Jun Min , Locke Dona E. , Shandera‐Ochsner Anne , Chandler Melanie
Published: December 2022

Background

The syndrome of mild cognitive impairment (MCI) is classified into different subtypes– amnestic MCI (aMCI) and non‐amnestic MCI based on cognitive domains impacted, while different underlying disease etiologies cause the impairments. The Memory Support System (MSS), a memory‐support tool which utilizes a calendar/planner, has been shown to have positive impact on daily functioning in MCI (Chandler et al., 2017). We have previously shown that cognitive impairment severity and personality traits are associated with MSS learning (De Wit et al., 2021; Khayoun et al., 2021). In this study, we hypothesized that 1) participants with single domain aMCI (SD‐aMCI) will have higher MSS learning scores than multi‐domain aMCI (MD‐aMCI), and 2) participants with suspected Alzheimer’s disease (AD) etiology will have lower MSS learning scores than other etiologies.

Method

Participants (mean age = 75.2) underwent daily MSS training between 2017 and 2021 as part of the 10‐day Mayo Clinic HABIT program. The MSS learning success score (LSS) was determined by how far participants progressed in three learning phases of increasing difficulty: Acquisition (0‐2 points), Application (3‐4 points), and Adaptation (5‐6 points; Greenway et al., 2008). Ordinal logistic regression analysis was used to predict MSS learning scores between SD‐aMCI (n = 142) versus MD‐aMCI (n = 119), and AD etiology (n = 213) versus other neurodegenerative etiologies (n = 57). Dementia Rating Scale‐2 scores (Jurica, 2001) were included to control for cognitive severity.

Result

Compared to participants with SD‐aMCI, those with MD‐aMCI had 54.1% lower odds of having higher LSS at training end (p = .004), after controlling for cognitive impairment severity. AD versus other etiology’s impact on LSS was nonsignificant.

Conclusion

Participants with MD‐aMCI showed poorer MSS learning efficiency than participants with SD‐aMCI. Etiology did not impact MSS learning. Results suggest having more than just memory impairment (e.g., additional language or executive dysfunction) reduces MSS learning, regardless of overall impairment level. Additional MSS training may be needed to facilitate learning for these individuals.
Development of stable, orally bioavailable small molecule positive modulators of HGF/MET signaling for the treatment of cognitive impairment.
Authors: Taylor Robert W , Boatman Doug , Johnston Jewel , Kneip Maya , Church Kevin
Published: December 2022

Background

Positive modulators of the HGF/MET system likely represent a valuable therapeutic class with the potential to impact a variety of disorders, including neurodegenerative diseases and indications with cognitive impairment. Preclinical and clinical studies have established the therapeutic potential of fosgonimeton (ATH‐1017), a small molecule injectable positive modulator of the HGF/MET system that is currently in clinical trials in patients with Alzheimer’s disease and Parkinson’s disease. At Athira Pharma, Inc., we have worked to expand the platform of HGF/MET positive modulators by identifying small molecules with a range of properties with the potential to meet therapeutic and delivery needs of patients across neurological diseases.

Method

Building on the MET receptor augmentation activity of fosgonimeton, we designed a screening funnel to evaluate chemical variants with desired physiochemical properties. We synthesized a panel of small molecules intended to promote pharmacokinetic stability and tested each variant for in vitro activity via MET phosphorylation. Active molecules were then tested for in vitro stability, in vivo pharmacokinetics, and in vivo efficacy in a scopolamine‐induced spatial memory test.

Result

We identified a panel of molecules with novel chemistry, biochemical activity in vitro, and favorable physiochemical properties. Among these active molecules, several were selected to move into advanced testing. In pharmacokinetic evaluation, these molecules efficiently distributed to the brain and other target tissues following oral administration. Selected molecules were advanced to in vivo efficacy testing, which resulted in reversal of scopolamine‐induced spatial memory deficits in rats as assessed in the Morris water maze.

Conclusion

Novel, stabilized small molecule positive modulators of HGF/MET demonstrated procognitive effects following oral delivery. Further development of these compounds may have the potential to provide an array of administration options for patients with neurodegenerative or cognitive disorders.
The Added Value of Global Amyloid Burden in Predicting Cognition in the MEMENTO Cohort
Authors: Ackley Sarah F , Calmasini Camilla , Swinnerton Kaitlin N. , Bouteloup Vincent , Chêne Geneviève , Dufouil Carole , Glymour M. Maria
Published: December 2022

Background

Global amyloid‐PET is associated with cognition and cognitive decline, but most research on this association does not account for past cognitive information. We assessed the prognostic benefit of amyloid‐PET measures for future cognition when prior cognitive assessments are available, evaluating the added value of amyloid measures beyond information on multiple past cognitive assessments.

Method

The French MEMENTO cohort (a cohort of outpatients from French research memory centers in order to improve knowledge on Alzheimer’s disease and related disorders, via DPUK) includes older outpatients with incipient cognitive changes, but no dementia diagnosis at inclusion. Global amyloid burden was assessed using positron emission tomography (amyloid‐PET) for a subset of participants at baseline or during follow up; semiannual cognitive testing was subsequently performed. Our analytic sample included 488 individuals who underwent amyloid‐PET scans and with at least 4 subsequent mini‐mental state examination (MMSE) scores available. We predicted MMSE scores using demographic characteristics (age, sex, marital status, and education) alone or in combination with information on prior cognitive measures. The added value of including amyloid burden as a predictor in these models was evaluated by the percent reduction of the mean‐squared error (MSE). All models were conducted separately for evaluating the added value of dichotomous amyloid positivity status compared to continuous amyloid standardized uptake‐value ratio.

Result

Adding amyloid burden to a model adjusting for only demographic characteristics reduced the MSE of predictions by 6.35% (95% CI: [1.50%, 12.63%]) and 12.04% (95% CI: [3.37%, 22.48%]) for binary and continuous amyloid, respectively. If the model included one past MMSE measure, the MSE improvement was only 4.08% (95% CI: [1.12%, 7.93%]) when adding binary amyloid and 7.87% (95% CI: [2.46%, 13.92%]) when adding continuous amyloid.

Improvements in model fit were even smaller with the addition of amyloid burden when more than one past cognitive assessment was included. For models incorporating one or more past cognitive assessments, differences in predictions associated with adding information about amyloid amounted to a fraction of one MMSE point on average.

Conclusion

Global amyloid burden did not appreciably improve cognitive predictions when past cognitive assessments were available.
Synchronized sigmoidal mixed‐effects model for dynamics of cognitive decline relative to onset of Alzheimer’s disease in aging adults in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study.
Authors: Kang Kaidi , Dumitrescu Logan , Mukherjee Shubhabrata , Lee Michael L. , Choi Seo‐Eun , Scollard Phoebe , Gibbons Laura E , Trittschuh Emily H , Mez Jesse B. , Saykin Andrew J. , Gifford Katherine A. , Buckley Rachel F. , Crane Paul K. , Hohman Timothy J. , Gao Xiaoting , Di Jianing , Liu Dandan ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2022

Background

Modeling the dynamics of Alzheimer’s disease (AD) biomarkers over the entire continuum of AD progression is important, yet challenging due to limited resources to collect longitudinal biomarkers from the aging population with fully observed clinical spectrum of AD. This study proposed and applied a synchronized sigmoidal mixed‐effects model to characterize dynamics of longitudinal memory performance using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The model leveraged time to AD onset as the time scale and additionally allowed inclusion of participants without AD onset, drastically expanding future applications.

Method

ADNI participants with observed mild cognitive impairment (MCI) and/or AD onset (n = 312, mean (SD) baseline age 74.9 (6.44) years) were included (Table 1). A memory composite previously built in ADNI was leveraged for all analyses. A synchronized sigmoidal mixed‐effects model was constructed for dynamics of memory performance with parameters for initial memory level, magnitude of decline, and half‐life of decline. For participants with observed MCI but not AD onset, an additional parameter (t0
) quantifying the time from MCI onset to AD was incorporated (Figure 1). We considered random effects for all parameters and allowed t0
to vary by age at MCI onset (nonlinearly), sex, apolipoprotein E (APOE)‐ε4 status and their interactions.

Result

The mean initial harmonized memory score is 0.24 (95% CI: 0.17‐0.32). The mean decline in the harmonized memory score is 1.53 (95% CI: 1.43‐1.64). The mean time when the harmonized memory score declined by half is 0.57 years before AD onset (95% CI: 0.32‐0.82). Female is associated with faster progression from MCI onset to AD (p = 0.002). Age at MCI onset is nonlinearly associated with MCI‐to‐AD progression (p < 0.001) and APOE‐ε4 status interacts with age at MCI onset on MCI‐to‐AD progression (p = 0.002) (Figure 2).

Conclusion

The proposed synchronized sigmoidal mixed effect model can be used to characterize dynamics of AD biomarkers relative to AD onset using participants with and without AD onset. A model to estimate duration of MCI‐to‐AD progression can be simultaneously included for synchronization purpose, which identified gender, age at MCI onset and APOE‐ε4 status as factors associated with MCI‐to‐AD progression.
Neuroinflammation and microglial activation as target for therapeutic strategy: in vitro and in vivo models of study
Authors: Callizot Noelle , Henriques Alexandre , Rouviere Laura , Giorla Elodie , Waly Bilal El , Poindron Philippe
Published: December 2022

Background

Alzheimer's disease (AD) is characterized by the extracellular accumulation of senile plaques composed of beta‐amyloid (Aβ) and the intracellular deposition of neurofibrillary tangles composed of hyperphosphorylated tau (Tp). Aβ oligomers (AβO) induce damage beginning with loss of synapses, followed by neurite network disorganization and neuronal death. Neuroinflammation plays an essential role in the disease. In AD patient brains, reactive microglia are closely colocalized with amyloid plaques, indicating their close link. Aβ‐activated microglia produce neurotoxic cytokines/chemokines which subsequently cause neuronal dysfunction and death.

Method

Using rat primary cultures of cortical neurons and microglial cells, generating a solution of AβO/protofibrils, playing with the concentration and time of exposure, we were able to mimic the early effects (acute neuronal loss) and the neuroinflammatory response.

Result

At the beginning of the exposure, we observed a Aβ phagocytosis, followed by a strong increase of TREM2/OX41 marker associated with cytokines release and CD206 (M2 marker) decrease over the time.

In addition, microglial activation was deeply studied in the hippocampus of aged mice infused with the AβO/protofibril preparation. We observed progressive Tp accumulation associated with neurodegeneration and progressive activation of microglial cells (transition from a phagocytosis stage to a pro‐inflammatory stage with over‐expression of IBA1, CD68 immunoreactivity and production of pro‐inflammatory cytokines).

Conclusion

In this work, we proposed vitro/vivo models showing differential and consecutive microglial responses to Aβ. These models are useful for targeting microglial in the pre‐disease period (in vitro) and for modulating the microglial response in the brain once the disease process is underway, and hold promise as a disease‐modifying treatment strategy.