bluuebunny/crossref_metadata_2025 huggingface dataset:
Anesthetic dose‐adjusted intraoperative alpha power in association with biomarkers of preclinical Alzheimer’s disease, preoperative attention function, and postoperative delirium
Authors: Reese Melody , Cooter Mary , Roberts Kenneth C , Woldorff Marty G. , Browndyke Jeffrey N. , Shaw Leslie M. , Waligorska Teresa , Zetterberg Henrik , Blennow Kaj , Berger Miles ,   the MADCO‐PC, INTUIT, and MARBLE Investigators
Published: January 2025

Background

Postoperative delirium (POD) is characterized by fluctuating attention after surgery and is associated with increased risk of developing Alzheimer’s Disease (AD). While the neurophysiological changes that underlie POD and increased risk of AD are unclear, recent data has raised the possibility that an exaggerated brain response to anesthetics may be a biomarker for POD risk and preclinical AD‐like pathology. Thus, we examined whether anesthetic‐dose‐adjusted intraoperative brain activity is associated with POD or preoperative brain vulnerabilities (preclinical AD‐like pathology, preoperative inattention) that may contribute to risk of POD (and later AD).

Method

82 patients from 3 prospective cohort studies of non‐cardiac, non‐neurologic surgical patients age ≥60 who had sufficient 32‐channel intraoperative electroencephalographic (EEG) data and received a gas anesthetic for ≥80% of their surgery were included. Other data included preoperative cerebrospinal fluid (CSF) samples, preoperative cognitive testing, and delirium scores (before surgery and twice daily for ≤5 days after surgery). Univariable associations were evaluated between 8‐12Hz anesthetic‐dose‐adjusted frontoparietal EEG alpha power and 1) preoperative CSF AD biomarkers (pTau181p, Aβ42, pTau181p/Aβ42), 2) preoperative attention function, and 3) POD incidence and severity. To account for the brain’s response to anesthetics, alpha power was dose‐adjusted as follows: (alpha power at each minute of surgery) / (2.5 – age‐adjusted minimum alveolar concentration at each minute of surgery) and summarized by patient across minutes as the mean of median‐filtered alpha.

Result

Lower dose‐adjusted intraoperative frontoparietal alpha power was found among patients 1) with (vs. without) preoperative pTau/Aβ pathology (Table 1), and 2) among those who scored worse on timed preoperative attention tasks (Table 2). Low dose‐adjusted alpha power was also associated with increased odds of POD and moderate‐to‐severe delirium symptomology (Table 3). The conclusions were similar for unadjusted alpha power, though only dose‐adjusted values were associated with POD severity. Overall, the results suggest that, regardless of our anesthetic‐dose‐adjustment, low intraoperative frontoparietal alpha power is associated with CSF pTau/Aβ pathology, attention function, and POD.

Conclusion

Future studies are needed to determine whether there are causal pathways between preoperative brain vulnerabilities, intraoperative frontoparietal alpha power, and POD. Understanding these pathways will improve our ability to identify at‐risk patients for targeted interventions.
Poor Colonoscopy Bowel Prep in Cognitively Impaired 85‐Year‐Old with Low Education: Another Case Example
Authors: Burt Juliana S , Joffe Yonah , Eversole Kara , Kimmet Faith , Estores David , Arias Franchesca , Chapin Benjamin A , Price Catherine C.
Published: January 2025

Introduction

Colonoscopies are routine procedures performed primarily on adults over the age of 50; however, there is little known about the influence of social determinants of health on successful completion of colonoscopies. Inadequate at‐home bowel preparation can result in increased procedure duration, decreased cancer detection, and may necessitate a repeated colonoscopy, putting undue stress on the patient. Research suggests neurocognitive disorder is a risk factor for poor bowel preparation in older adults; however, lower education may confound neurocognitive findings, independently contributing to risk of incomplete colonoscopies. Research reports patients with a high school diploma were significantly more likely to have inadequate bowel prep compared to patients with college education. The present case study underscores the importance of considering social determinants of health when scheduling patients for colonoscopies.

Case Presentation Demographics

JR is an 85‐year‐old non‐Hispanic Black male referred for preoperative neuropsychological testing prior to a scheduled colonoscopy. He was raised in the rural South and became truant after the 4th grade. He currently lives alone, receiving limited assistance from family.

Background

Five months prior to the scheduled colonoscopy, JR was admitted to hospital due to fecal impaction and rectal pain; he was referred for a colonoscopy to follow up his symptoms. Neuropsychological Testing: revealed 3rd grade reading level and deficits in list learning, delayed recall, and semantic fluency. Problem: The patient arrived disorientated to the purpose of the visit, believing he would undergo the colonoscopy on the day of the neuropsychological evaluation. Consequently, JR completed his bowel preparation the night before and had slept on his bathroom floor. Notably, the procedure was scheduled 13 days later. Outcome: Due to unnecessarily early completion of bowel prep and resultant need for more preparatory medication, the procedure was rescheduled for four weeks later. At the time of this report, JR’s procedure date has not arrived.

Discussion

This case supports research suggesting neurocognitive impairment and lower education are predictive of patients’ poor preoperative planning and bowel preparation. Moreover, this case highlights the need for increased family involvement and attention from providers for patients of advanced age, lower education, and neurocognitive impairment referred for colonoscopies.
Trends in Alzheimer’s Disease clinical outcome assessments in phase 2 and 3 clinical trials from 1993 to present
Authors: Gary Sarah T , Davis‐Aoki Reina , Verma Prateek , McDowell Bryan
Published: January 2025

Background

Clinical outcome assessments (COAs) are an important part of clinical trials to measure what is meaningful to patients and caregivers. This study aimed to examine trends in Alzheimer’s Disease (AD) COAs used in clinical trials, given the FDA’s recent emphasis on patient‐focused drug development and early AD.

Method

ClinicalTrials.Gov was programmatically accessed through its API on January 19, 2024. Phase 2 and 3 Interventional AD trials were further analyzed for inclusion of 6000+ COAs in the primary or secondary outcome measures field.

Result

997 studies were identified with start dates from 1993‐2025. COAs as primary or secondary outcomes have increased over time (50.0% of studies from 1993‐1999, 57.4% from 2000‐2009, 64.0% from 2010‐2019, 69.1% from 2020‐2023). The increase is mainly driven by an increase in COAs in the primary outcome (40.0% of studies from 1993‐1999 vs. 53.1% from 2020‐2023). ADAS‐Cog was the most common primary COA (19.1% of all studies) followed by CDR (7.0%), CIBIC+(3.3%) and ADCS‐ADL (2.9%). The percentage of studies using ADAS‐Cog as the primary outcome is trending downward, with only 13.0% of studies using ADAS‐Cog as primary in the past 5 years. The MMSE was the most common secondary COA (19.6% of all studies), followed by ADAS‐Cog (16.0%), NPI‐C (15.8%), and ADCS‐ADL (14.5%). Reference to mild cognitive impairment (MCI) in the primary/secondary outcome is trending upward, with no studies in the 90s, 2.2% in the 2000s, 4.6% in the 2010s, and 11.1% from 2020‐2023. In addition, there has been an increase in COAs for preclinical AD and MCI (e.g. PACC, MoCA, iADRS).

Conclusion

Even with the rise in biomarkers and focus on preclinical AD, COAs remain an important part of AD clinical trials, as shown by the continued and increasing usage as primary and secondary outcomes. Historically, ADAS‐Cog has been the gold standard in AD studies, and many approved AD studies have utilized it as primary endpoints with small delta between study drug and placebo. In recent times AD trials are shifting towards MCI‐AD and this has led to new endpoints like PACC and MoCA which are sensitive in identifying early cognitive deficits in patients.
A highly accurate blood test for Alzheimer’s disease pathology has performance equivalent or superior to clinically used CSF tests
Authors: Salvadó Gemma , Barthélemy Nicolas R. , Schindler Suzanne E. , He Yingxin , Janelidze Shorena , Collij Lyduine E. , Saef Benjamin A. , Henson Rachel L. , Chen Charles D. , Gordon Brian A. , Li Yan , Joie Renaud La , Benzinger Tammie L.S. , Morris John C. , Mattsson‐Carlgren Niklas , Palmqvist Sebastian , Ossenkoppele Rik , Rabinovici Gil D. , Stomrud Erik , Bateman Randall J. , Hansson Oskar
Published: January 2025

Background

With the emergence of Alzheimer's disease (AD) disease‐modifying therapies, identifying patients who could benefit from these treatments becomes critical. We evaluated whether a precise blood test could perform as well as established cerebrospinal fluid (CSF) tests in detecting amyloid‐β (Aβ) plaques and tau tangles.

Method

Plasma %p‐tau217 (ratio of phosporylated‐tau217 to non‐phosphorylated mid‐region tau) was analyzed by mass spectrometry in the Swedish BioFINDER‐2 cohort (n=1,422) and the US Knight ADRC cohort (n=337, Table 1). Matched CSF samples were analyzed with clinically used and FDA‐approved automated immunoassays for Aβ42/40 and p‐tau181/Aβ42. The primary and secondary outcomes were detection of brain Aβ or tau pathology (Braak I‐IV), respectively, using PET imaging as the reference standard. Main analyses were focused on individuals with cognitive impairment (mild cognitive impairment and mild dementia), which is the target population for available disease‐modifying treatments. We assessed accuracy, positive and negative predictive values, and sensitivity of each biomarker, using cut‐offs derived at 90% specificity for a one cut‐off approach. We also tested a two cut‐off approach using cut‐offs derived at 95% specificity and 95% sensitivity, classifying participants as positive (above higher cut‐off), negative (below lower cut‐off) or intermediate (between these two cut‐offs).

Result

Plasma %p‐tau217 was clinically equivalent to FDA‐approved CSF tests in classifying Aβ PET status, with an area‐under‐the‐curve (AUC) for both cohorts between 0.95‐0.97 (Figure 1A‐B). Plasma %p‐tau217 was generally superior to CSF tests in classification of tau‐PET with AUCs of 0.95‐0.98 (Figure 1C‐D). In cognitively impaired sub‐cohorts (BioFINDER‐2: n=720; Knight ADRC: n=50), plasma %p‐tau217 had an accuracy, positive predictive value and negative predictive value of 89‐90% for Aβ PET (Figure 2A) and 87‐88% for tau‐PET status (Figure 2C), which was clinically equivalent to CSF tests. These statistics further improved up to 95% using a two cut‐off approach (Figure 2B‐2D, respectively).

Conclusion

Blood plasma %p‐tau217 demonstrated performance clinically equivalent or superior to clinically used FDA‐approved CSF tests in the detection of AD pathology. Use of high performance blood tests in clinical practice can improve access to accurate AD diagnosis and AD‐specific treatments.
Application value of structural MRI combined with ASS1 in early diagnosis of Mild Cognitive Impairment
Authors: Chen Lele , Fan Xiang , Shan Hui , Yu Keyan , Lu Gaigai , Wei Zhuonan , Cheng Guanxun
Published: January 2025

Background

Mild cognitive impairment (MCI) refers to a transitional stage between the cognitively unimpaired (CU) and dementia, which is probable in the Alzheimer's disease (AD) continuum. Neuropsychological assessments and structural MRI are primary clinical examinations applied for diagnosing MCI. Hippocampal volume (HV) and medial temporal lobe atrophy (MTA) as recognized AD biomarkers are the most frequently used imaging markers in clinical application. However, HV or MTA is not sensitive enough in the early stage of AD. Recently, blood‐based biomarker analysis has demonstrated great potential for early AD diagnosis because it is simple and less invasive. It has been shown that argininosuccinate synthetase (ASS1) expression is increased in Alzheimer's disease neurons and glial cells, which also correlates with inducible nitric oxide synthase (iNOS) expression, and that there is a link between the increased NO production observed in Alzheimer's disease brains and iNOS expression. We aim to study whether ASS1 can provide additional value compared with HV in diagnosing MCI and validate the diagnostic utility of the combined model.

Method

Twenty MCI patients and 20 CU were recruited and underwent neuropsychological assessment, MRI examinations, and the collection of blood. Protein quantification was analyzed by high‐resolution tandem mass spectrometry (MS/MS), and the ROC curve was plotted for selected biomarkers. The automated structure tool and SPSS 26.0 were used to analyze the HV and ASS1. We investigated the area under curve (AUC) of HV, and the combined model using both ASS1 and HV based on the logistic regression. The Delong test is used to compare the combined model with the single HV.

Result

The AUC of diagnosing MCI by HV was 0.788 (95%CI: 0.629 ‐0.901). When combining HV with ASS1, the AUC increased to 0.938 (95%CI: 0.813‐0.989). The Delong test results indicated a significant difference between the single HV and the combined model. (P=0.0188).

Conclusion

Combining plasma ASS1 could provide significantly additional value in detection of MCI, which also means plasma ASS1 and HV may be a potential early biomarker combination in diagnosing early AD.
Proteomic study of cerebrospinal fluid in patients with vascular cognitive impairment‐no dementia
Authors: Peng Sisi , Zhang Junjian
Published: January 2025

Background

Vascular cognitive impairment (VCI), including vascular cognitive impairment‐no dementia (VCIND) and vascular dementia, is a cognitive impairment syndrome caused by cerebrovascular disease and its risk factors. Among people over 60 years old, the prevalence of VCIND is about 15‐20%. VCIND, as the early stage of VCI, has become a focus of current research due to the fact that its patients are at greater risk of developing dementia and can benefit greatly from early intervention. The etiology and pathology of VCI are highly heterogeneous. Analyzing the key molecules in the development of VCI through omics approaches is conducive to a multidimensional understanding of the disease nature of VCI, and is important for identifying its targets for intervention.

Method

We screened for differential proteins in the cerebrospinal fluid (CSF) of VCIND patients and healthy control subjects by proteomic assays based on ultra‐performance liquid chromatography‐mass spectrometry (UPLC‐MS). Differential proteins and scores of cognitive assessments were subjected to pearson correlation analysis to screen out the differential proteins with correlation coefficients greater than 0.75. We constructed a mouse model of bilateral carotid artery stenosis (BCAS) and a cellular model of oxygen glucose deprivation (OGD), and targeted the differential proteins screened in CSF in the classic animal and cellular models of VCI mentioned above.

Result

We found significant between‐group differences in MoCA (p<0.001) and DSST (p<0.001) scores in non‐demented VCI patients compared to healthy controls. 75 differential proteins were screened in the cerebrospinal fluid of non‐demented VCI patients (fold change = 1.5, p<0.05), of which 38 were up‐regulated and 37 were down‐regulated. In cerebrospinal fluid, Cerebellin‐2 (Cbln2) was the only protein with a correlation over 0.75 for both MoCA and DSST assessment, and was significantly negatively correlated with cognitive assessments. Cbln2 expression was significantly higher in hippocampal tissues of BCAS mice as well as in OGD‐treated neuronal cells, which follows the same trend as the clinical findings.

Conclusion

Cbln2 is a potentially important molecule in early stage of VCI.
Neuroanatomical Correlates of Functional Capacity in Activities of Daily Living in the Alzheimer´s Disease Continuum
Authors: Henriquez Fernando , Contreras Patricio Riquelme , Campo Cecilia Gonzalez , Lillo Patricia , Thumala Daniela , Martínez‐Pernía David , Okuma Cecilia , Demanet Michele , Saguez Rodrigo , Herrero Joaquin , Henriquez Rodrigo , Aboitiz Francisco , Chonchol Andrea Slachevsky
Published: January 2025

Background

The Alzheimer's Disease (AD) continuum is composed of Subjective Cognitive Decline (SCD), Mild Cognitive Impairment (MCI), and Alzheimer's Disease Dementia (ADD). Changes in grey matter volume (GMV), characteristic of the AD continuum, are related to cognitive and activities of daily living (ADL) impairments. ADLs are divided into three domains: i) Basic (BADL), ii) Instrumental (IADL), and iii) Advanced (AADL), and their study is critical for understanding the evolution and adequate follow‐up of patients. To date, the neuroanatomical basis of impairment in ADL has not been addressed. This work aimed to study the relationship between GMV and the ADL domains in the AD continuum.

Method

A cross‐sectional study of 77 SCD, 30 MCI, and 23 ADD, matched for age, sex, and education, was conducted. ADLs were assessed with the Technology‐Activities of Daily Living Questionnaire (T‐ADLQ). A voxel‐wise regression analysis (with the SPM module) was performed to explore the association between GMV and the domains of ADLs. Total Intracranial Volume (TIV) was entered as a covariate. The analysis was performed for each patient group (MCI and ADD) in tandem with the SCD group to increase sample size, data variance, and statistical power.

Result

Regression analysis for ADD‐SCD (Figure 1a) shows that in ADD patients (Table 1), AADLs were associated with decreased GMV in temporal, frontal, parietal, and insular regions. IADLs were also associated with temporal, frontal, parietal, and insular areas but were more widely distributed. BADLs were associated with temporal, frontal, and insular structures. The MCI‐SCD analysis (Figure 1b) shows that in patients with MCI (Table 2), AADLs were associated with temporal areas and IADLs with temporal, frontal, and parietal regions. BADLs had no significant associations.

Conclusion

Associations between ADL domains with decreased GMV were more widely distributed in ADD compared to the MCI group, with a pattern similar to the neurodegenerative progression in the AD continuum. This finding highlights the potential of diverse neuroanatomical markers of functional capacity at different stages of the AD continuum. Such markers could hold significant relevance for the classification and follow‐up of patients from an ADL perspective, thereby improving the understanding of the consequences in daily life.
The Digital Clock and Recall can predict functional impairment in individuals with and without cognitive impairment and triage those in need of further assessment
Authors: Ciesla Marissa C , Toro‐Serey Claudio , Jannati Ali , Gomes‐Osman Joyce Rios , Banks Russel , Showalter John , Tobyne Sean , Pascual‐Leone Alvaro
Published: January 2025

Introduction

Evaluation of functional dependence in activities of daily living (ADLs) and instrumental activities of daily living (iADLs) is necessary for dementia diagnosis. ADL and iADL questionnaires are typically employed, but with progressive cognitive impairment, a care partner must step in to assist with these tests, causing logistical burdens. Pre‐screening tools that triage patients in need of formal functional assessment would optimize clinical workflows. Here we evaluated whether the Linus Health Digital Clock and Recall (DCRTM), a brief automatically‐scored test of multiple cognitive domains, could concurrently predict functional impairment among individuals with and without cognitive impairment.

Methods

We collected data from 922 participants in the Bio‐Hermes‐001 multi‐site study (age mean±SD = 72±6.6; 57% female; years of education mean±SD = 15±2.71; primary language English), classified as cognitively unimpaired (n = 402), mild cognitively impaired (n = 298), or probable Alzheimer’s dementia (n = 242) based on clinical consensus and neuropsychological evaluation. We split participants, each including 2000 speech and drawing DCR metrics and age, into training (80%) and test (20%) sets, ensuring equal rates of functional impairment across sets (Functional Activities Questionnaire ≥ 6; 25% rate). We performed recursive feature elimination on 10‐fold cross‐validated random forests (5 repetitions) on the training set to identify the best model and feature set. Model performance was evaluated on the test set.

Results

The optimal model (500 features) classified functional impairment with 0.77 sensitivity, 0.82 specificity, 0.90 negative predictive value (NPV), 0.61 positive predictive value (PPV), 0.86 area under the receiver operating characteristic curve (AUC), and 0.80 accuracy. The most predictive features were the duration of speech during recall and the placement of clock components.

Conclusion

The DCR, a brief digital cognitive assessment with automatic scoring that can be completed in primary‐care settings, can also be used to identify individuals in need of further evaluation and engagement of care partners as informants. The high NPV can reassure healthcare professionals when no further assessment of ADLs and iADLs is indicated. These results also enable identifying care partners who are likely to benefit from receiving personalized recommendations or training to assist them in caregiving tasks and alleviate caregiver burden.
Tau deposition is associated with neurite abnormalities in white matter tracts and cortical grey matter regions in dementia with Lewy bodies
Authors: Mak Elijah , Reid Robert I. , Przybelski Scott A. , Lesnick Timothy G. , Schwarz Christopher G. , Senjem Matthew L. , Raghavan Sheelakumari , Vemuri Prashanthi , Jack Clifford R. , Min Hoon‐Ki , Jain Manoj K. , Miyagawa Toji , Forsberg Leah K. , Fields Julie A. , Savica Rodolfo , Graff‐Radford Jonathan , Jones David T. , Botha Hugo , St. Louis Erik K , Knopman David S. , Ramanan Vijay K. , Dickson Dennis W. , Graff‐Radford Neill R , Ferman Tanis J , Petersen Ronald C. , Lowe Val J. , Boeve Brad , O'Brien John T , Kantarci Kejal
Published: January 2025

Background

Dementia with Lewy bodies (DLB) frequently co‐occurs with Alzheimer’s disease (AD) pathologies, exacerbating disease progression. Biophysical models of diffusion imaging data, such as Neurite Orientation Dispersion and Density Imaging (NODDI), may reveal novel insights into the neurobiological substrates of AD on cortical and white matter microstructural injury.

Method

A cohort of 57 DLB patients on the DLB spectrum (33 clinically probable DLB and 14 prodromal DLB) and 57 cognitively unimpaired (CU) controls underwent NODDI and PET imaging with [18F]‐Flortaucipir and [11C]‐PiB (Table 1). NODDI parameters were derived from white matter tracts and grey matter regions using the JHU “Eve” and Mayo Clinic Adult Lifespan Template atlases, respectively. Conditional logistic models were used to compare these parameters between the two groups, accounting for the 1:1 matching on age and sex. The associations of tau and amyloid‐β with NODDI parameters across the white matter tracts were examined with linear regressions. A region‐by‐region approach was adopted to evaluate the relationships of tau and amyloid‐β with grey matter NODDI, adjusting for age, APOE, and local grey matter volumes.

Result

DLB spectrum patients exhibited extensive white matter abnormalities relative to CU, including lower fractional anisotropy, higher mean diffusivity (MD), and lower tissue‐weighted neurite density (tNDI). In grey matter, these deficits were paralleled with higher MD and lower tNDI and ODI, primarily in the temporoparietal and posterior cortices. Regression models revealed significant associations of elevated [18F]‐Flortaucipir uptake with deficits in temporal and limbic white matter tracts and a temporal‐lobe pattern of higher MD and lower tNDI in the cortex (Figure 1). No associations were observed with [11C]‐PiB in the DLB spectrum.

Conclusion

These findings demonstrated an in vivo relationship between tau deposition and neurite deficits that spatially aligned with the canonical AD “cortical signature” of neurodegeneration in both white matter tracts and grey matter regions in DLB. Our study underscores the detrimental impact of AD pathology in DLB and provides a rationale for further investigations into the underlying mechanisms of AD in DLB. Future longitudinal studies tracking the progression of these changes could inform therapeutic strategies for DLB in the presence of AD pathologies
The effect of comorbidities on Alzheimer’s disease/cognition by race/ethnicity and the mediating role of AD pathologies measured by blood biomarkers
Authors: Wang Shanshan , Nguyen Uyen‐sa , Hall James , Petersen Melissa , O'Bryant Sid E. , Nandy Rajesh
Published: January 2025

Background

The study aims to assess the associations of comorbidities (hypertension, dyslipidemia, diabetes, chronic kidney disease [CKD], and depression) with mild cognitive impairment (MCI), Alzheimer’s dementia (AD dementia), and cognition by race/ethnicity; and to examine whether blood AD biomarkers mediate the associations.

Method

We used data from the baseline and visit 2 of the Health & Aging Brain Study‐Health Disparities (HABS‐HD) study. 2057 participants were included in the cross‐sectional analyses, and 792 participants, who were cognitively normal at baseline and had follow‐up data, were included in the longitudinal analyses. Race/ethnicity was categorized into Latinos, non‐Hispanic Black, and non‐Hispanic Whites. Blood AD biomarkers included amyloid β40 (Aβ40), amyloid β42 (Aβ42), total tau, phosphorylated tau 181(p‐tau 181), and neurofilament light chain (NfL). Blood AD biomarker changes between the two visits were calculated. Global cognition was assessed by the Mini Mental State Examination (MMSE). Causal mediation analyses were used.

Result

In the cross‐sectional analyses, the odds of AD dementia and MCI increased with higher levels of Geriatric Depression Scale (GDS) scores across all races/ethnicities. In the longitudinal analyses, those with CKD (β=‐0.431, 95% CI: ‐0.812, ‐0.049) and higher levels of GDS score (β=‐0.027, 95% CI: ‐0.050, ‐0.004) were negatively associated with global cognition at visit 2. While triglyceride (β=0.002, 95% CI: 0.0003, 0.003) and hemoglobin A1c (β=0.086, 95% CI: 0.002, 0.170) values were positively associated with global cognition at visit 2. Changes in Aβ40 and Aβ42 were found to be significantly associated with global cognition in both the overall sample and the Latino sample. The natural indirect effect of triglyceride on global cognition through changes in Aβ40 (β=0.0002, 95% CI: 0.00002, 0.0006) was found to be significant among the overall sample, with 15.80% of the association being mediated via changes in Aβ40.

Conclusion

Our study is the first to examine the mediating role of blood AD biomarkers in associations of various comorbidities with AD and cognition by race/ethnicity. We found that changes in Aβ40 mediated the associations between triglyceride and global cognition, providing evidence that amyloid pathology might be the underlying mechanism.
Study Design of the Evaluation of Self‐Mediated Alternatives for Risk Testing Education and Return of Results ‐ E‐SMARTER: A randomized trial from the Alzheimer’s Prevention Initiative program
Authors: Langlois Carolyn , Bradbury Angela R. , Wood Elisabeth MCarty , Harkins Kristin , Erickson Claire M , Largent Emily A. , Egleston Brian L , Reiman Eric M. , Grill Joshua D , Roberts J. Scott , Karlawish Jason , Langbaum Jessica B.
Published: January 2025

Background

Availability of amyloid modifying therapies will dramatically increase the need for disclosure of Alzheimer’s disease (AD) related genetic and/or biomarker test results. The 21st Century Cares Act requires the immediate return of most medical test results, including AD biomarkers. A shortage of genetic counselors and dementia specialists already exists, thus driving the need for scalable methods to responsibly communicate test results. The current study builds off our API Generation Program in which we demonstrated the safety and effectiveness of disclosing APOE and brain amyloid results via telemedicine to cognitively unimpaired adults.

Method

The Evaluation of Self‐Mediated Alternatives for Risk Testing Education and Return of Results (E‐SMARTER) is a decentralized, randomized trial to evaluate self‐directed, scalable eHEALTH platforms for communicating APOE, brain amyloid, and plasma ptau217 test results, as well as to characterize the clinical impact of learning this information. E‐SMARTER will enroll approximately 600 cognitively normal adults aged 60‐80. Participants will be randomized to receive results either via telehealth videoconference or by eHealth platform. Participants randomized to the eHealth arm will be offered either the ADWebPortal or ADChatbot but can switch between platforms or request to speak with a healthcare provider during the sessions.

Result

Study design and available participant demographics will be presented. Participants will complete online assessments evaluating their experience with the disclosure modalities as well as the impact of AD biomarker and genetic results disclosure. Participants complete assessments at baseline, prior to the initial APOE/amyloid PET disclosure session, and at approximately 0‐2 days, 6 weeks, 6 months, and 12 months following disclosure. pTau217 plasma levels will be assessed at 6 months after APOE/amyloid disclosure. PTau217 disclosure follow‐up assessments will be collected approximately 0‐2 days and 6 weeks after disclosure of pTau217 results. A final combined APOE/Amyloid and 6‐Month pTau217 follow‐up assessment will be collected approximately 12 months following the initial APOE/Amyloid disclosure.

Conclusion

The E‐SMARTER study addresses the need for practical and scalable methods to responsibly communicate AD genetic and/or biomarker results. The E‐SMARTER eHEALTH platforms will be made available to support healthcare providers in returning genetic and/or biomarker results to individuals in clinical and research settings.
Health‐Related Behaviours in Octogenarians and Nonagenarians with Robust Cognitive Longevity: Progress and Initial Data from thee SuperAging Research Initiative
Authors: Roberts Angela C , Ooteghem Karen Van , McIlroy Bill , Culum Ivan , Beyer Kit B , Thai Vanessa , Aulakh Nimrit , Li John , Dunne Ciara , Lim Andrew , Swartz Richard H , Finger Elizabeth , Maher Amanda Cook , Okonkwo Ozioma C , Goldstein Felicia , Huentelman Matthew J. , Geula Changiz , Rogalski Emily J
Published: January 2025

Background

SuperAgers—individuals age 80+ with episodic memory performance at least as good as those 20‐30 years younger—provide a unique perspective on cognitive resilience and resistance in aging. The SuperAging Research Initiative (SRI), spearheaded by The University of Chicago and involving multiple academic partners, investigates factors underpinning robust cognitive aging. One key SRI project, leverages a fully remote data collection paradigm to: 1) discern activity patterns that characterize SuperAgers and 2) explore the 'complexity hypothesis in aging'—whether dynamic physiological responsiveness is a hallmark of exceptional cognitive aging. Here we report on feasibility and initial outcomes from this project.

Method

Participants don wearable sensors, including an ECG sensor (chest) and two inertial measurement units (wrist, ankle), for a 10–12‐day period of continuous data collection whilst performing their usual daily activities. The protocol includes a virtual orientation and periodic check‐ins to ensure wear‐compliance and provide technical support. Structured sensor‐wear breaks facilitate protocol compliance and acceptance.

Result

To date, recruitment efforts have led to enrollment of 91 individuals (Mean age = 84.1 years; 62 women), which approximates half of the total SRI sample. Reasons for ineligibility or non‐enrollment include dermatological contraindications, ‘busy’ lifestyles, and perceived participation burden. Initial analyses of 44/58 participants who have completed data collection show exceptional adherence (>95% sensor wear compliance) (Table 1). Limited data loss due to sensor non‐wear and/or sensor failure demonstrates high data quality (Table 1). Notably, participants demonstrate a high level of independence, with study partner assistance required in < 5% of cases. Withdrawals have been minimal (3%) and primarily attributed to skin irritation due to undisclosed dermatological contraindications. Initial data are provided in Figure 1 and Table 2 including daily activity summary data and group comparisons between SuperAgers and Controls. Updated data will be presented at the conference.

Conclusion

Wearable technologies are feasible for remotely assessing daily activities of octogenarians and nonagenarians with high compliance. Objective quantitative data hold promise for expanding our understanding of lifestyle factors relevant to superior cognitive aging. Insights from this study may influence preventive intervention strategies against age‐associated neurological diseases and in support of enhancing cognitive longevity.
Changes in cognition of ADRD patients: effects of social isolation proxies, utilising data from UK electronic health records
Authors: Myers James A C , Stafford Tom , Vaci Nemanja
Published: January 2025

Background

Marital status and living status are components of social isolation (SI), a modifiable factor thought to impact cognitive resilience, which has the potential to impact cognition throughout the course of Alzheimer’s and related dementia (ADRD) diagnosis. Electronic health records (EHRs) offer access to large scale clinical data, capable of longitudinal analyses.

Method

Cognitive function measurement – Montreal Cognitive Assessment (MoCA) – data, demographic (including marital and living status as SI proxies) data and ADRD diagnosis data from patients aged 50+ years from Oxford Health NHS Foundation Trust (UK) were extracted using natural language processing algorithms from EHRs dated 1995 to 2022. Longitudinal multilevel models were used to predict cognition as a function of the interaction between diagnosis duration and SI proxies, controlling for age, sex and diagnosis cause.

Result

‘Lifelong single’ marital status significantly predicted reduced cognition intercept scores for the MoCA dataset (𝛽 = ‐1.61, SE = 0.67, t = ‐2.42, p = 0.016). No significant marital status predictors for slope were found. Living in supported accommodation significantly predicted steeper slopes for cognition (𝛽 = ‐2.37, SE = 0.33, t = ‐7.20, p < 0.001). No living status levels significantly predicted slopes.

Conclusion

Worldwide ADRD incidence is predicted to increase dramatically within the next 30 years, therefore studies investigating the impact of modifiable factors on the rates of cognitive change in ADRD patients are valuable to enhancing understanding of patient care. SI data extracted from EHRs can be used to predict differences in patient cognition scores.
Converging mitochondrial MicroRNA Patterns: Ischemic Stroke and Alzheimer's Connections
Authors: Vijayan Murali , Reddy Hemachandra
Published: January 2025

Background

The present study delves into the intricate molecular connections between ischemic stroke (IS) and Alzheimer's disease (AD) through an analysis of mitochondrial microRNA (miRNA) patterns. By exploring their shared signatures in the context of IS and AD, our aim is to unravel potential common pathways, understand shared molecular mechanisms, explore diagnostic and therapeutic opportunities, gain a comprehensive understanding of neurodegeneration, and advance the field of biomarker research.

Method

To explore these intriguing questions, mitochondria were isolated from postmortem brains of individuals with IS, AD, and healthy controls (n=10 each). Subsequently, miRNA extraction was carried out using the isolated mitochondria. Following this, a comprehensive analysis of global miRNA profiles in mitochondrial fractions was performed for all three groups, utilizing Hiseq 2000 or 2500 Sequencing & Pipeline filter (Illumina Inc). Furthermore, we employed the Ingenuity Pathway Analysis (IPA) software to elucidate the biological processes, cellular components, and molecular pathways associated with potential mitochondrial miRNAs.

Result

Our results unveil distinct transcriptomic signatures in healthy control, IS, and AD groups. Particularly noteworthy is the identification of significant common mitochondrial miRNA alterations in both IS and AD. Furthermore, the application of IPA to mitochondrial miRNAs reveals their involvement in key signaling pathways, including calcium, Ras, P13K‐Akt, MAPK, and axon guidance. All of these pathways play central roles in the pathogenesis of both ischemic stroke and Alzheimer's disease.

Conclusion

Our study is the first to delineate common mitochondrial miRNA signatures in the states of IS and AD. Furthermore, this comprehensive miRNA‐seq analysis reveals the interconnectedness of these two prevalent neurological disorders at the molecular level, offering valuable insights for future therapeutic interventions and diagnostic strategies.
INTERCEPT‐AD: Understanding the Patient Experience and Expectations for Treatment Through Qualitative Interviews Among Trial Participants with Early Alzheimer’s Disease and Their Study Partners
Authors: Johnston Kelly , Presnall Carrie , Merikle Elizabeth , Cline Stephanie , Feaster Todd , Siemers Eric
Published: January 2025

Background

Incorporation of the patient voice into drug development has been recognized as fundamental; recent legislation has addressed the importance of collecting patient experience data. Qualitative patient interviews conducted in tandem with clinical trials, often in later phases, are among the most common means of eliciting these data. To assess aspects of patient experience earlier in development, we conducted semi‐structured qualitative interviews following participation in the phase 1 ACU‐001 (INTERCEPT‐AD) trial, a study evaluating the safety and tolerability of the Aβ oligomer‐targeting monoclonal antibody ACU193, among a subset of participants with mild cognitive impairment (MCI) or mild Alzheimer’s disease (AD) and their study partners. Interview topics included disease experience and expectations for treatment.

Method

Interviews followed the end‐of‐study visit and included both participants and study partners. Participants were asked to report their most problematic symptoms, to describe what they would hope to gain from a new AD treatment, and what changes would be meaningful. The interview guide was developed in accordance with FDA Patient Focused Drug Development guidance. Principles of qualitative thematic analysis guided the coding and analysis of transcripts, with additional features drawn from grounded theory, conforming to best practices.

Result

Twenty‐eight participants and their study partners were interviewed. Participants reported a broad array of problems consistent with AD. The most frequent included difficulty with memory or cognitive functioning (96.4%), getting lost (71.4%), mood (60.7%), and difficulty communicating (57.1%). Within each of these groupings, specific problems varied among participants; higher numbers of participants reported forgetting appointments, names, and losing things (81.4%) and getting lost while driving (90.0%), while fewer reported feeling isolated (5.9%) and experiencing confusion (11.1%). Nearly every participant desired treatment that would keep the disease from getting worse or slow progression (89.3%), which was equated with maintenance of functional abilities. Maintaining the ability to recognize loved ones and communicate were also stated as important benefits of a new treatment.

Conclusion

Problems reported by participants were typical to AD, although there was heterogeneity in overall AD experience. Changes in mood were frequently reported. These findings highlight the need to contextualize clinical trial results by incorporating the patient voice.
Comparison of MRI T2 FLAIR White Matter Hyperintensity Segmentation Algorithms in Clinical Trials
Authors: Scheel Norman , Hubert Josh , Baker Joshua H. , Fernandez Zachary , Yanev Pavel G. , Stowe Ann M , Vongpatanasin Wanpen , Zhang Rong , Zhu David C
Published: January 2025

Background

White Matter Hyperintensities (WMH) appear on T2‐weighted Fluid‐Attenuated Inversion Recovery (FLAIR) Magnetic Resonance Imaging (MRI) and are an important biomarker of cerebral small vessel disease (CSVD), cognitive decline, and stroke. However, manual delineation is laborious and bias‐prone, while automated segmentation has proven challenging. With the recent conclusion of the MICCAI‐Society WMH segmentation challenge, and our large clinical trials, “Risk Reduction for Alzheimer’s Disease” (rrAD) and “Hypertension, Intracranial Pulsatility and Brain Amyloid‐beta Clearance in older adults” (HIPAC), we investigated the differences in the total WMH volume segmented by various algorithms to ensure the extraction of accurate and meaningful image‐derived phenotypes.

Methods

The rrAD trial provides 512 2D axial T2 FLAIR scans, fat saturation off (ages 60‐85). The HIPAC study provides 84 3D T2 FLAIR scans, fat saturation on (ages 55‐79). The MICCAI WMH challenge provides a test set of 110 scans of 2D axial T2 FLAIR images, 30 without, and 80 with fat saturation. Our clinical trials and the MICCAI datasets comprise data from over 700 subjects, across 10 scanners and diverse sequences. Three of the best‐performing MICCAI algorithms were selected: PGS, Sysu‐Media‐2, FMRIB‐TrUE‐Net2, as well as the LPA algorithm from SPM. Segmentation results were randomized, and fully blinded expert raters scored a subset of 120 scans.

Results

Figure 1 depicts the average normalized images for each T2 FLAIR contrast. The MICCAI test set shows a median WMH burden of 10‐17 ml, while rrAD subjects presented with relative medians of ≈3−4 ml, and HIPAC subjects with ≈2−3 ml. Figure 2 shows the WMH volume for each segmentation algorithm and dataset. For HIPAC Sysu‐Media‐2 had high false pickup within grey matter regions, while LPA produced high false pickup at the posterior septum pellucidum. PGS scored best in manual ratings.

Conclusions

MRI sequences that use fat saturation change the T2 FLAIR image contrast substantially and impact segmentation performance, we observed better performance with fat saturation off. The MICCAI challenge algorithms outperformed classical methods (PGS leading), detecting small lesions, away from the ventricles. As WMH distribution, shape, and longitudinal tracking are likely more sensitive biomarkers than volume alone, further analysis is warranted.
Gray Matter Alterations Associated with Aging & APOEε4 Genotype in 37,437 Participants from the UK Biobank
Authors: Gleave Emma J , Thompson Paul M. , Rajagopalan Priya
Published: January 2025

Background

Carrying one or more copies of the apolipoprotein E ε4 allele represents the greatest known source of genetic risk for late‐onset Alzheimer’s disease (AD), although the mechanisms are not fully understood. Several smaller‐scale studies have analyzed APOEε4 effects on brain volume, reporting gray matter volume (GMV) alterations in medial temporal and precuneal regions in people with AD and in healthy APOEε4 carriers. Here, we analyzed brain images from a large sample of healthy elderly adults in relation to ε4 carrier status, stratifying by age to assess potential group differences.

Method

The Computational Anatomy Toolbox (CAT12) was used to perform a large‐scale voxelwise segmentation of 3D T1‐weighted brain MRI data from the UK Biobank. The statistical relationship between voxel‐wise brain GMV and APOEε4 genotype was assessed using a dominant model for presence or absence of APOEε4 allele across 37,437 subjects (51.7% female; 64.6 (7.7SD) years old), separated into three age bins (Bin1: <60 yrs old; Bin2: 60‐70 yrs old; Bin3: >70 yrs old; Table 1). Linear mixed model analyses for APOEε4 in relation to GMV were performed for the full sample and within each age bin, adjusting for age, sex, genetic ancestry, intracranial volume (ICV), and scan site.

Result

Lower GMV was associated with APOEε4 (standard‐FDR critical P‐value=0.0002; q=0.05), after covarying for age, sex, ancestry, and ICV. Effects were detected in the bilateral mesial temporal lobe structures including bilateral amygdala, posterior hippocampus and punctate foci within bilateral thalami. A large region of association was found in the oldest age‐group (>70yrs; Bin3). Significance maps are shown in Figure 1.

Conclusion

We identified alterations in GMV related to carrying at least one APOEε4 allele in one of the largest neuroimaging samples to date. Extending prior work, even healthy adult carriers of the APOEε4 haplotype demonstrated neurostructural gray matter alterations. Such neurostructural alterations may be more salient in older age, highlighting the need for continued study of ε4 expression mechanisms and their interaction with aging
WMH and AD: is CAA the missing piece? Potential consequences at the anti‐amyloid era
Authors: Charidimou Andreas ,   Department of Neurology, Boston University School of Medicine, Boston, MA, USA
Published: January 2025

Underlying cerebral amyloid angiopathy (CAA) is extremely common in patients with Alzheimer’s disease, contributing to cognitive impairment and hampering anti‐amyloid treatments safety. Distinct patterns of white matter hyperintensities (WMH) are supporting markers of CAA and are now included in the Boston criteria, along other hemorrhagic features of the disease. These WMH patterns includes a multispot WMH pattern in the cortical‐subcortical regions and posterior predominance of WMH. This presentation will focus on THE core imaging markers of CAA, including clinical interpretation of WMH in the context of suspected CAA, associated features and potential relevance for ARIA in anti‐amyloid treatments.