bluuebunny/crossref_metadata_2025 huggingface dataset:
AssociatIion of metabotropic glutamate receptor 5 with amyloid deposition in Alzheimer's disease's patient and mouse models
Authors: Savoldelli Serena , Kong Yanyan , Maschio Cinzia , Konetiko Uwe , Mu Linjing , Klohs Jan , Nitsch Roger M. , Ni Ruiqing
Published: January 2025

Background

Metabotropic glutamate receptor 5 (mGluR5) modulates excitatory glutamatergic synaptic transmission and plays an important role in learning and memory, and in the pathphysiology of Alzheimer’s disease (AD). Here, we aimed to assess the alterations of mGluR5 in the hippocampus of AD patients and mouse model, and the association with amyloid pathology.

Method

Immunofluorescence staining was performed on postmortem brain tissue from 35 AD patients and 36 control patients, as well as on the brain tissue slices from 15 months‐old 3×Tg and arcAβ mouse models of AD amyloidosis. Autoradiography was performed on brain tissue slices from arcAβ mice using mGluR5 tracer [18F]PSS232. Proteomic profiling and pathway analysis were performed on hippocampal tissue from six 15 months‐old 3xTg mice and six age‐matched wildtype mice.

Result

Reduced levels of mGluR5 were observed in the hippocampus of AD patients compared to non‐demented control. Ex vivo autoradiography revealed a reduced level of [18F]PSS232 in the hippocampus and striatum of arcAβ mice compared to nontransgenic littermate mice. Reduced mGluR5 immunoreactivity was observed near 6E10‐positive Aβ plaques in the hippocampus. In contrast, upregulated levels of Shank3, Grin2a, Grin2b, and Grm5; and upregulation of glutamatergic pathway (GO and KEGG pathway enrichment analyses) were detected in hippocampal tissue from 3xTg mice compared to wildtype mice.

Conclusion

This study revealed a reduction in the level of mGluR5 in the hippocampus of AD patients, and a strain‐dependent alteration of mGluR5 in mouse models of AD.
Research Lumbar Puncture Recruitment, Safety and SOPs in Black/African American and white middle‐age participants
Authors: Likos Kelly D. S. , Hu William T. , Verble Danielle D , Trotti Lynn Marie , Benameur Karima , Scorr Laura M , Butts Brittany , Wharton Whitney
Published: January 2025

Background

The Wharton Lab has collected CSF for over 10 years as a primary endpoint in NIH/NIA funded longitudinal observational studies and clinical trials in cognitively normal individuals with a parental history of Alzheimer’s disease (AD). LPs provide vital data on AD risk and progression and time specific information on efficacy for clinical interventions, yet few investigators include research LPs, for fear of clinical implications, lack of specialized clinicians, and perceived unwillingness of participants to consent to LPs, particularly in minoritized participants

Method

Comprehensive data is collected on willingness to take part in LP, safety, and procedure specifics, including side effects. Twenty milliliters of CSF are obtained using fluid drip or aspiration methods. Twenty‐four hours post LP, the study team contacts the participant for LP follow up using a standardized questionnaire (potential side effects, severity, and home care initiated). Daily follow‐up with the participant occurs until side effects subside

Result

Our data in 122 participants enrolled (1R01AG066203‐02) indicate that 1) show that research LPs are safe and well tolerated and 2) cognitively normal, middle‐aged participants are willing to undergo multiple LPs, regardless of race, ethnicity, and gender.

Participants were 51.1% Black or African American and 45.2% Non‐Hispanic White, 76.3% female and have an average BMI of 27.8. 9.6% of individuals self‐excluded because of LP requirement. Of 139 LPs preformed, 93.9% of LPs were successful. 13.1% of participants reported a headache 24‐hours post LP. 78.8% of participants reported no side effects. Headache(n=10) and lower back pain(n=4) were the most common side effects. When side effects occurred post LP, 16.3% initiated home care suggested by the research team, with hydration being the most common(n=6).

LPs were most successful with a 22 Whitacre needle, followed by a 22 Quincke needle

Conclusion

Data show that research LPs are safe and well tolerated in diverse cohorts, and that individuals are willing to take part in research LPs. Regular LP discussion and education for potential subjects is encouraged. Increased education and discussion of research LPs with the research team provides opportunities to discuss the procedure with the potential participant during the recruitment, consent, and screening processes
Implementation of Blood‐based Biomarkers in a Large Dementia Care Clinic: Case‐based Report from the UCSF Memory and Aging Center
Authors: Breithaupt Andrew , Bui Nhat Minh , Gonzalez Yasmeen , Joie Renaud La , Ljubenkov Peter A. , Possin Katherine L , Rojas Julio C. , soleimani‐meigooni David N. , Staffaroni Adam M. , Stephens Melanie , Tsoy Elena , Windon Charles , Boxer Adam L. , Rabinovici Gil D. , Miller Bruce L. , VandeVrede Lawren , Ellingson Tara
Published: January 2025

Several new blood‐based biomarkers (BBMs) of Alzheimer’s disease and related neuropathologies have completed late‐stage validation and are beginning to be used in the clinical setting. However, the role of BBMs in various clinical settings, especially their specific context‐of‐use, remains an open question for the field. Several studies are beginning to systematically collect information on BBM real‐word diagnostic performance, but as BBMs transition from research settings to clinical implementation, experience from clinical providers in specialty centers can inform and guide use. In this session, BBM implementation at a large specialty care center, the University of California San Francisco (UCSF) Memory and Aging Center (MAC), will be discussed. The UCSF MAC is a division of the Department of Neurology dedicated to the diagnosis and care of patients with cognitive problems and their families, and the MAC has 32 clinicians who collectively evaluate over one thousand new patients a year with cognitive concerns. Additionally, the MAC recently launched an Alzheimer’s Infusion Core, dedicated to evaluating patients for the newly approved disease‐modifying treatments (DMT). Within the context of the UCSF MAC, integration of BBMs into clinical care will be reviewed using a case‐based format, including a description of overall provider usage, impact on differential diagnosis and subsequent management, and perceived role in the work‐up for patients interested in DMTs. Additional discussion will touch upon logistics and challenges to implementation, with a road map for future clinical integration.
Real world implementation of blood biomarkers in primary care
Authors: Willis Deanna R , Brosch Jared R. , Fowler Nicole R , Hammers Dustin B. , Summanwar Diana
Published: January 2025

Primary Care (PC) clinicians are faced with numerous competing demands and priorities for maximizing patient care. These challenges make the implementation of strategies for early detection of Alzheimer’s Disease (AD) complex. Few real‐world implementation projects about early detection of AD in PC exist. From 2022‐2023 the Davos Alzheimer’s Collaborative (DAC) Health System Preparedness Flagship project included seven United States academic affiliated PC clinics. We implemented digital cognitive assessments using the Linus Health Core Cognitive Evaluation at routine PC encounters. Patients who failed the cognitive assessment were offered, as part of a research pilot, C2N Diagnostics’ blood biomarker (BBM) test, PrecivityAD, with results disclosure. PCPs were approached to receive education about BBM for AD and to consent to deliver results themselves or defer delivery to the research team. Of the patients approached for BBM, more than half declined. Providers were split on their willingness to deliver results. For patients whose provider did not elect to deliver results or who was unable to deliver results in the timeframe needed, a trained Registered Nurse was trained and observed to disclose results. This session will share perspectives on these real‐life facilitators and barriers to implementing cognitive screening and BBM in PC and how more fully engaging the whole primary care team may help mitigate some of these barriers.
Performance of plasma NTK biomarkers to detect amyloid‐β pathology in cognitively unimpaired individuals at risk of Alzheimer’s disease
Authors: Escalante Armand González , Milà‐Alomà Marta , Brum Wagner Scheeren , Ashton Nicholas J. , Ortiz‐Romero Paula , Minguillon Carolina , Shekari Mahnaz , Anastasi Federica , del Campo Marta , Quijano‐Rubio Clara , Kollmorgen Gwendlyn , Gispert Juan Domingo , Zetterberg Henrik , Vilor‐Tejedor Natalia , Blennow Kaj , Suárez‐Calvet Marc
Published: January 2025

Background

Alzheimer disease (AD) plasma biomarkers change in the preclinical stage of AD. However, the robustness of the discrimination performance of these biomarkers, as well as their association with longitudinal primary pathology (amyloid and tau) changes, is less understood. We aimed to determine the ability of baseline and longitudinal plasma amyloid‐β (Aβ)42/40, p‐tau181, GFAP and NfL to detect primary pathology in CU individuals at risk of AD.

Method

Plasma biomarkers were measured using the NeuroToolKit (NTK), a panel of robust prototype biomarker assays (Roche Diagnostics International Ltd, Rotkreuz, Switzerland), in CU participants of ALFA+. We assessed their performance for detecting early signs of amyloid‐positivity (as defined by CSF Aβ42/40 <0.071 or amyloid PET ≥12 Centiloids) using ROC analyses. We simulated the impact of random variability on each biomarker’s detection performance. Finally, we tested the baseline and longitudinal association of plasma biomarkers with longitudinal changes of primary pathology over three years.

Results

We included 403 CU participants (49.3‐73.6 years old), 135 (33.5%) were CSF amyloid‐positive (Table 1), and 345 had amyloid PET available (15.7% PET amyloid‐positive). Plasma Aβ42/40 had the highest performance for Aβ‐positivity discrimination [AUC(CSF):0.87, AUC(PET):0.90], followed by p‐tau181 [AUC(CSF):0.72, AUC(PET):0.81]. Adding plasma NTK ApoE4 significantly improved the performance of plasma p‐tau181 and GFAP [AUC: 0.79 and 0.81]. Plasma Aβ42/40 was the most sensitive biomarker to the addition of random variability, while the others remained moderately stable (Figure 1). In PET amyloid‐negative individuals, lower baseline plasma Aβ42/40 was associated with longitudinal increases in amyloid PET Centiloids and CSF p‐tau181. In the low‐Aβ‐burden group (CSF amyloid‐positive, PET amyloid‐negative), higher baseline plasma p‐tau181 was associated with longitudinal increases in CSF p‐tau181. Plasma GFAP changed concurrently with amyloid, both CSF and PET, before amyloid PET becomes positive (Table 2).

Conclusions

Plasma Aβ42/40 had the best performance in detecting Aβ pathology, but its discrimination performance was more sensitive to measurement variability. Plasma Aβ42/40 and p‐tau181 predict longitudinal changes in amyloid and tau pathology. Plasma GFAP changed concurrently with amyloid pathology. Overall, our study showed that different blood‐based biomarkers offer distinct information in preclinical AD, making each of them valuable for diagnostic, prognostic or monitoring purposes.
The US‐Based DIAMOND Lewy Toolkit: Overview and management of motor symptoms
Authors: Leverenz James B , O'Brien John T , Taylor John‐Paul
Published: January 2025

Lewy body dementia (LBD) clinically is characerized by a complex myriad of cognitive, behavioral, motor, sleep and autonomic symptoms that can be challenging to manage, particularly in the context of the fluctuations that are so characteristic for these patients. The DIAMOND Lewy Toolkits offer a resource to support clinicians in recognizing and managing this range of symptoms observed in LBD. This session will provide a guided introduction to the DIAMOND Lewy Toolkits, offering a framework to leverage the toolkits in support of patient centered care. In addition to an overview of the DIAMOND Lewy program (Dr. Leverenz), he will focus on motor symptom management. Subsequent speakers will address neuropsychiatric and sleep symptoms (Dr. Chiadi), cognition and autonomic dysfunction (Dr. Scharre) and the adaptation of the DIAMOND Lewy Tool kits in the U.S. (Dr. Amodeo).
Misperception of night‐to‐night sleep quality in Alzheimer’s and Lewy body disease
Authors: Washburn Alex , Winer Joseph R. , Romero America , Yutsis Maya , Henderson Victor W. , Poston Kathleen L. , Zeitzer Jamie M , Mormino Elizabeth
Published: January 2025

Background

Objective sleep measures obtained from actigraphy (wrist‐worn accelerometry) reveal sleep disruption patterns and may serve as indicators of neurodegenerative disease. However, whether individuals’ subjective account of their sleep quality corresponds to objective sleep measurements from the previous night is an area little studied. In particular, whether neurodegenerative disease modifies these associations is unknown.

Method

N=111 participants including healthy controls (HC) and individuals with Alzheimer’s disease (AD) and Lewy body (LB) disease were recruited from the Stanford Alzheimer’s Disease Center and the Stanford Aging and Memory Study, with a mean of 6.3 ± 1.4 days of paired actigraphy/questionnaire data. Each morning, participants rated their overall sleep quality, sleep depth, well‐restedness, and mental alertness on a 0‐4 Likert scale, which were combined into a latent subjective sleep score using confirmatory factor analysis (Figure 1). Nightly sleep duration and wake after sleep onset (WASO, time awake after falling asleep) were objective actigraphy‐derived variables of interest. Linear mixed models were used to assess differences in the relationship between objective sleep variables and the subjective sleep score between disease etiologies.

Result

Across all participants, subjective sleep scores were associated with the previous night’s objective recording. However, this association showed an interaction with etiology such that increasing WASO predicted reduced subjective sleep quality in HC participants, whereas for participants with AD and LB, subjective sleep quality did not relate to WASO (Figure 2a). In contrast, subjective sleep quality was predicted similarly by sleep duration in AD, LB, and HC participants: as sleep duration increased, subjective sleep quality increased (Figure 2b). These relationships also held when binning by cognitive impairment status (normal, mild cognitive impairment, dementia) or MoCA score rather than etiology.

Conclusion

A significant difference in how objective sleep disruption predicts subjective sleep quality for AD and LB participants relative to HC participants suggests that individuals' perception of their night‐to‐night sleep quality may be impaired in the context of neurodegenerative disease.
Multi‐tissue metabolomics analyses identify disrupted processes in Alzheimer’s Disease
Authors: Wang Ciyang , Timsina Jigyasha , Ali Muhammad , Heo Gyujin , Liu Menghan , Ruiz Agustin , Pastor Pau , Sung Yun Ju , Cruchaga Carlos
Published: January 2025

Background

Brain1,2, cerebrospinal fluid (CSF)3,4, and plasma5,6 metabolomics have been informative in identifying disrupted metabolism pathways in Alzheimer’s disease (AD). However, many AD‐focused metabolomics studies profiled a relatively small number of individuals and metabolites3–6, especially for CSF. In addition, past studies were limited to one or two tissues. Here we present a large‐scaled three‐tissue metabolomics study for Alzheimer’s disease.

Method

The cohorts of our study include Knight‐ADRC, DIAN, ADNI, Barcelona‐1, and Fundació ACE. In this study, 362 brain samples (N.ctrl = 27, N.AD = 335), 1,974 CSF samples (N.ctrl = 855, N.AD = 1,119), and 2,369 plasma samples (N.ctrl = 1,274, N.AD = 1,095) were included. The HD4 Metabolon platform was used to measure metabolomics of plasma, CSF, and brain samples. There were 797, 456, and 1,508, metabolites quantified in brain, CSF and plasma tissues. Linear regression model including age, sex, post‐mortem interval was used to identify differentially present metabolites. FDR correction was applied to the analyzed metabolites.

Result

The analyses in brain, CSF, and plasma identified 3, 65, and 553 metabolites differentially presented in AD compared to healthy controls after FDR multiple‐test correction. There were 31 metabolites shared between plasma and CSF, in which 28 having consistent direction of effects. Of the 31 CSF‐plasma shared metabolites, four metabolites (3‐hydroxyisolutyrate, alpha‐hydroxyisovalerate, ergothionenine, guaiacol sulfate), belonging to the branched‐chain amino acids (BCAAs) or xenobiotics, were nominally significant in brain. The two BCAA‐related metabolites, 3‐hydroxyisolutyrate and alpha‐hydroxyisovalerate, were replicated in another brain study1. Higher 3‐hydroxyisolutyrate7 has been associated with obesity, a risk factor for AD. We found that ergothioneine level was low in AD and a recent study showed that this metabolite improved amyloid beta clearance8 in a mouse model. Using metabolites differentially abundant in the plasma tissue, we found BCAA biosynthesis, taurine metabolism, starch and sucrose metabolism, and tryptophan metabolism pathways being altered in AD.

Conclusion

Our study performed the first multi‐tissue metabolomics analyses on Alzheimer’s disease. We identified concordant effects across tissues for many differentially abundant metabolites. The shared metabolites throughout tissues were closely linked to the Alzheimer’s disease.
Different phosphorylated tau isoforms in biochemical diagnosis of Alzheimer’s disease
Authors: Dulewicz Maciej , Kac Przemyslaw Radoslaw , Gonzalez‐Ortiz Fernando , Karikari Thomas K , Kulczynska‐Przybik Agnieszka , Mroszko Barbara , Turton Michael , Harrison Peter , Maler Juan Manuel , Oberstein Timo Jan , Kornhuber Johannes , Hanrieder Jörg , Zetterberg Henrik , Blennow Kaj , Lewczuk Piotr
Published: January 2025

Background

In the context of Alzheimer's disease (AD), blood‐based biomarkers have become increasingly important for various clinical purposes, such as screening patients and tracking the progression of the disease. Tau is a protein that stabilizes microtubules in nerve cells. In AD, different isoforms of tau become hyperphosphorylated, leading to the formation of neurofibrillary tangles, which are a key pathological feature of the AD. Measuring levels of different phosphorylated tau in the blood can provide insights into the extent of tau pathology in the brain. Phosphorylated tau (pTau) serves as a blood biomarker signaling the existence of AD‐related alterations, with pTau217, pTau181, and pTau231 proving to be significant indicators in this context. The primary goal of this study is to investigate the diagnostic utility of measuring plasma pTau217, pTau181 and pTau231 levels in identifying possible AD cases. This study intends to evaluate how effectively the concentrations of pTau217, pTau181 and pTau231 in the blood can differentiate individuals with CSF biomarker‐confirmed AD in comparison to CSF biomarker‐negative control group.

Method

Plasma concentrations of pTau217, pTau181 and pTau231 were measured by in‐house Single molecule array (Simoa) assays developed at the University of Gothenburg (UGOT p‐tau217, pTau181 and pTau231). The quantitative assessment of classical biomarkers (Aβ‐42, Aβ‐42/Aβ‐40, tTau, and pTau181) in the CSF of patients with possible AD according to the Erlangen Score algorithm (ER 2 and 3) and controls (ER 0) were performed by Lumipulse.

Result

Significantly The levels of pTau217, pTau181 and pTau231 correlated positively with CSF tTau, pTau181 and negatively with CSF Aβ1‐42 and Aβ ratio. The greatest effect size was observed for pTau217 (d=1.63), moderate for pTau181 (d=0.57) and pTau231 (d=0.3) respectively.

Conclusion

The results of the present study indicate that plasma pTau217 could be the most valuable blood biomarker for AD diagnosis among the tested isoforms.
Left frontoparietal control network connectivity moderates the effect of amyloid on cognitive decline in preclinical Alzheimer’s disease
Authors: Boyle Rory , Shirzadi Zahra , Coughlan Gillian T , Seto Mabel , Properzi Michael J , Klinger Hannah M , Townsend Diana L , Yuan Ziwen , Scanlon Catherine E , Jutten Roos J , Papp Kathryn V , Amariglio Rebecca E , Johnson Keith A , Rentz Dorene M , Chhatwal Jasmeer P. , Sperling Reisa A , Schultz Aaron P , Buckley Rachel F ,   The A4 Study Team
Published: January 2025

Background

Stronger default mode (DMN) and bilateral frontoparietal control network (FPCN) resting‐state functional connectivity are associated with reduced β‐amyloid (Aβ)‐related cognitive decline in cognitively unimpaired older adults, who were predominantly Aβ negative. This suggests that these networks might support cognitive resilience in the face of early AD pathology but it remains unclear whether these effects are apparent in preclinical AD. We investigated whether left‐FPCN, right‐FPCN, and DMN connectivity moderated the effect of Aβ on cognitive decline using a large multi‐site dataset from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study.

Method

Cognitively unimpaired participants with elevated Aβ on screening amyloid‐PET (n=1,062, mean age=71.9 years, 60% women, see Table 1), underwent functional MRI (3T) at baseline. We obtained connectivity estimates of the left‐FPCN, right‐FPCN, and DMN using template‐based rotation (Figure 1). Cognition was measured using the Preclinical Alzheimer’s Cognitive Composite (PACC; average follow‐up including open‐label extension period =280 weeks [SD=115]). We examined three‐way linear and quadratic interactions between functional connectivity and Aβ burden with time in mixed effects models (model 2 = DMN, 3 = left‐FPCN, 4 = right‐FPCN).

1. PACC∼time + covariates×time

2‐4A. PACC∼FC×time + covariates×time

2‐4B. PACC∼FC×Aβ×time + covariates×time

2‐4C. PACC∼FC×Aβ×time + FC×Aβ×time2 + covariates×time

Covariates included age, education, APOEe4 status, ICV‐adjusted gray matter volume, treatment group (Solanezumab vs placebo), and head motion. We modeled random effects of intercept and slope for each participant and included scanner as a random effect.

Result

The three‐way quadratic interaction of connectivity and Aβ burden with time was statistically significant for the left FPCN (p‐value corrected for multiple comparisons =.047, Figure 2), with a moderate effect size. That is, stronger left FPCN connectivity was associated with less cognitive decline in those with elevated Aβ. The pattern of effects were similar, but not statistically significant once all covariates were included, for the right FPCN and DMN.

Conclusion

In a very large multi‐site clinical trial dataset, individuals with stronger left FPCN connectivity showed reduced Aβ‐related cognitive decline. This effect was specific to the left‐FPCN, in line with previous cross‐sectional findings. Our finding demonstrates that this protective effect of left FPCN connectivity can be observed in preclinical AD.
A novel whole‐brain imaging pipeline for amyloid‐beta plaque integrated with downstream iterative immunolabeling in pre‐clinical Alzheimer’s Disease animal models
Authors: Sasner Michael , Garceau Dylan , Elk Kevin J , Kamelin Peter , Yew Elijah , Chidambaram Ritesh , Ragan Tim
Published: January 2025

Background

Alzheimer’s Disease (AD) has a strong spatial‐temporal component to its progression, where different brain regions are affected by amyloid‐beta (Aβ) plaque deposition at varying time points and in distinct cell types. Standard imaging and analysis platforms can neglect these details, as they lack the ability to pair high‐yield whole‐brain imaging with region‐specific or high‐resolution analysis. Here we describe a novel high‐throughput whole‐brain imaging pipeline to quantitatively track plaque progression as a function of brain region across time, while also producing indexed tissue sections for secondary staining and analysis that can be registered back to the original brain image.

Method

Aβ plaques in novel knock‐in mouse models of familial AD were labeled with Methoxy‐X04, an Aβ plaque‐specific compound. In some cases, brain vasculature was also labelled with DyLight. The brains were processed on the TissueCyte Serial Two‐Photon Plus (STP+) imaging platform to produce fully aligned multi‐channel volumetric datasets, yielding high resolution 3D models of each brain. Registration to the Allen Mouse Brain Common Coordinate Framework (CCFv3) and region‐specific plaque analysis were conducted to determine plaque size, density, and total number per brain region. By correlating Methoxy and DyLight signals, cerebral amyloid angiopathy (CAA) was also quantified. Indexed brain sections were then used for iterative immunolabeling (IBEX; see Radtke et al, Nat Protocols 2022) to detect vascular and cellular responses to amyloid on representative sections and remapped to the original 3D whole‐brain dataset.

Result

The analysis of whole‐brain plaque distribution in familial AD mouse models revealed distinct spatial‐temporal changes across the brains. STP+ imaging, combined with CCFv3 mapping and secondary analysis of microglial and astrocytic markers allowed for targeted evaluation of Aβ plaques, vascular pathology, and a comparison of regional molecular changes between models.

Conclusion

We demonstrate here that the high sensitivity and precision of the STP+ platform coupled with secondary analysis of cellular responses can facilitate mechanistic understanding of amyloid deposition and cellular responses associated with specific therapeutic approaches. This approach could be very useful to study amyloid‐related imaging abnormalities (ARIA) in preclinical models.
Pilot Study to Probe the Utility of Salivary Lactoferrin as a Stress Biomarker Relevant to Alzheimer’s Disease
Authors: Garbarino Valentina R. , Wang Hanzhou , Yeh Chih‐Ko
Published: January 2025

Background

Approximately 6.7 million people in the US are diagnosed with an Alzheimer’s disease (AD), with greater incidence in women and minorities. Approximately 11 million family members provide uncompensated care to their family members with dementia, with more than 60% reporting high or very high levels of stress, a condition associated with increased risk for AD. Salivary lactoferrin, which plays a role in immune defense, may have utility as a biomarker for assessing stress with particular relevance to AD, allowing for earlier intervention. Decreases in salivary lactoferrin concentration are associated with stress in animal models, and reduced salivary lactoferrin levels have been associated with AD compared to normal cognition. Characterization of lactoferrin as a biomarker for stress is necessary to understand the mechanisms by which lactoferrin may mediate stress and contribute to AD pathogenesis.

Methods

To probe the relationship between salivary lactoferrin and traditional indicators of stress, we utilized blood and saliva samples from females aged 49‐79 who serve as family caregivers for a parent/spouse with AD. Data was stratified by self‐reported ethnicity, Hispanic (N= 9) or non‐Hispanic (N= 9). Levels of salivary cortisol, IgA, and lactoferrin, and plasma C‐reactive protein were determined by enzyme‐linked immunosorbent assay.

Results

Neither salivary cortisol (Mean Difference ± SEM, ‐0.010 ± 0.045; P=0.827) or lactoferrin levels normalized to salivary flow‐rate (59.77 ± 372.1; P= 0.875) were significantly different between groups. Lactoferrin concentration normalized to salivary flow rate was positively correlated with cortisol levels in non‐Hispanic females (Y = 6502*X – 440.0; R2= 0.5037; P= 0.0322). This correlation did not exist in the samples from Hispanic participants. Though there was a correlation between salivary cortisol and IgA levels in non‐Hispanic female participants (Y= 3.055e‐006*X +0.063; R2= 0.5627; P= 0.02), lactoferrin levels were not correlated with salivary IgA or plasma CRP.

Conclusions

Salivary lactoferrin was positively correlated with cortisol levels in non‐Hispanic female caregivers. Future studies controlling for caregiver stress and potential resilience will be necessary to confirm these relationships and determine the mechanisms by which lactoferrin response to stress differs between Hispanic and non‐Hispanic populations, and may mediate risk of neurodegenerative disease.

Acknowledgements: P30AG044271 and TR002647.
Associations between cognitive enhancement therapy in old age and temporal‐spatial orientation and language: A case study
Authors: Tziannarou Antonia , Christodoulides Constantinos , Hadjiloizou Andrea , Moza Sotiria
Published: January 2025

Background

An 84‐year‐old male, with 16 years of education (retired physics teacher) was admitted to a long‐term rehabilitation centre to receive daily care, with cognitive decline symptoms. This study presents the data from a three‐month cognitive enhancement program.

Methods

In September 2023, the patient underwent the Mini Mental State Examination (MMSE) in Greek, followed by cognitive enhancement sessions (45 minutes, twice a week) for three months. The sessions included exercises such as, reading the calendar, telling the time, planning daily activities, virtual travel videos and media, constructive tasks with cubes, language tasks (e.g., arranging words in the correct order to form sentences, finding synonyms and antonyms, and other). An alternative version of the MMSE was administered in January 2024. The patient’s medication regimen for dementia, depression, cholesterol, and hypertension, had remained unchanged over the last 6 months.

Results

In the preliminary assessment, the patient scored 15/30 on the MMSE. He scored 0/10 on the temporal/spatial orientation task, 0/3 on the delayed recall task, 2/3 on the 3‐command language item, and 0/1 on the language repetition item. Following the cognitive enhancement program, he achieved 20/30 points on MMSE and specifically 3/10 on orientation, 3/3 on the 3‐command item, and 1/1 on the repetition item.

Conclusions

The findings suggest that participating in targeted cognitive stimulation exercises may be linked to positive effects on orientation and language among older individuals, particularly, those with dementia. Our results could be influenced by the novelty of the stimuli in the patient’s life, potentially elevating cognitive demand temporarily and reaching a plateau over time. The study is ongoing to further explore these aspects.
Indiscriminate adjustment for confounders is worse than you think and what can be done about it
Authors: Sinha Harsh , Raamana Pradeep Reddy
Published: January 2025

Background

Training a “robust” predictive model is a non‐trivial task, especially for observational datasets. Datasets often contain confounding variables which must be de‐confounded (also less accurately referred to as “regressed out”) to eliminate the bias in predictive models. Due to the inherent uncertainty and complexity that surrounds the identification of true confounders, typically, all such covariates are regressed out indiscriminately. The prevailing wisdom is that adding more covariates cannot harm the predictive model, rather omitting measured covariates can lead to bias. But, whether inclusion/exclusion covariate has good/bad influence is contingent on the dataset. Therefore, confounding bias induced by an adjustment set must be empirically quantified rather than selecting covariates based on heuristic criteria. We demonstrate an approach to quantify confounding bias that is universally applicable to various machine learning (ML) algorithms facilitating evidence‐based decision making for covariate selection.

Method

In this work, we focus on restricted permutation tests to quantify the confounding bias in ML models. Specifically, the bias is evaluated by summing up the conditional association of residualized features (X) and the target (Y) for an adjustment set C (referred to as residual bias) under the null hypothesis. Using simulated data, we analyze the post‐adjustment residual bias for Random Forest model using various adjustment sets across multiple scenarios.

Result

We demonstrate that 1) adjustment for inappropriate covariates can increase existing confounding bias 2) adjusting for a covariate acting as a mere proxy for a confounder may not be beneficial and 3) finally, adjusting for a true confounder can even increase bias.

Conclusion

We don’t advocate the use of independent criteria to select covariates individually. It is possible that bias induced by one covariate is suppressed or amplified by another covariate. Therefore, we recommend that confounding bias for each adjustment set should be quantified rather than choosing covariates based on availability or out‐of‐convenience. Such choices may enhance predictive accuracy in the training sample but can lead to biased predictions in the population‐of‐interest.
Longitudinal association between synaptic dysfunction and Alzheimer’s disease pathology in preclinical Alzheimer’s disease
Authors: Ourry Valentin , Valdez Alfonso Fajardo , Soucy Jean‐Paul , Ashton Nicholas J. , Nilsson Johanna , Brinkmalm Ann , Zetterberg Henrik , Blennow Kaj , Breitner John C.S. , Poirier Judes , Villeneuve Sylvia
Published: January 2025

Background

Synapse loss in Alzheimer’s disease (AD) is correlates closely with cognitive impairment. Recent evidence suggests that synapse loss is promoted by amyloid‐beta, leading in turn to the spread of tau pathology. We sought to assess: 1) the association in positron emission tomography (PET) between several cerebrospinal fluid (CSF) synaptic biomarkers and amyloid and tau burden, as well as their annual change; and 2) the potential clinical utility of these synaptic biomarkers in preclinical AD.

Methods

Mass spectrometry assays quantified cerebrospinal fluid (CSF) markers of synaptic dysfunction (GAP43, SYT1, SNAP25 and Neurogranin) on 75 older adults (age 67.1 ± 4.8 years, 69.3% female) from the PREVENT‐AD cohort. These persons also had longitudinal amyloid ([18F]‐NAV4694) and tau ([18F]‐AV1451) PET scans performed over approximately 4.5 years. All were cognitively unimpaired (CU) at baseline, but 19 developed mild cognitive impairment (MCI) during follow‐up. We examined: 1) the association between these synaptic dysfunction biomarkers and global Aβ and entorhinal tau burden as well as their annual change, adjusting for age and sex; and 2) synaptic biomarker differences across those with Aβ at baseline vs. those who subsequently developed such pathology, and between individuals who remained CU vs. those who developed MCI during follow‐up. Analyses were considered significant at p=0.05/5=0.01 to account for multiple comparisons.

Results

Amyloid burden was positively associated with increased SNAP25long, while tau burden was associated with all 5 synaptic biomarkers (Figure 1). No association was found between these markers and amyloid and tau annual change. GAP43 and SNAP25 differed in Aβ‐ and Aβ+ groups but showed no difference across amyloid accumulators’ groups (Figure 2). Finally, MCI individuals had higher SNAP25long and GAP43 concentration than CU individuals (Figure 3).

Conclusions

GAP43 and SNAP25, being markers associated with neuronal growth and synaptic vesicle fusion, appear closely related to amyloid and tau burden, but only at baseline, even in preclinical AD. These biomarkers of synapse loss appear also to have clinical relevance, with differences observed in MCI compared to CU individuals. Future studies should explore these biomarkers, alongside pathology reduction, as potential targets for AD prevention to confirm these preliminary findings.
Neuroinflammation in people with Down syndrome and its association with amyloid deposition: a PET imaging study throughout aging
Authors: Mantovani Dimitri Brigide De Almeida , de Oliveira Laura Cavalcanti , Coutinho Artur Martins , da Silva Ana Maria Marques , Forlenza Orestes Vicente , Buchpiguel Carlos Alberto , de Paula Faria Daniele de Paula
Published: January 2025

Background

Down syndrome (DS) is a genetic disorder characterized by trisomy 21, which is linked to molecular alterations, such as neuroinflammation and accumulation of amyloid‐beta (Ab) peptide that can cause early‐onset Alzheimer's disease (AD). This study aims to evaluate the presence of neuroinflammation in individuals with DS in different ages and the association with Ab plaques.

Methods

Age‐matched DS (n=24) and non‐DS individuals (n=15) underwent two hybrid PET/MRI acquisition for neuroinflammation and Ab burden assessment using [11C]PK11195 (∼370 MBq and 60 min acquisition) and [11C]PIB (∼370 MBq and 70 min acquisition) tracers, respectively. Quantification is presented as standard uptake values (SUV 40‐60min) for [11C]PK11195 (PMOD software) and SUVratio (SUVr 50‐70 min) for [11C]PIB using cerebellum grey matter as reference tissue (CortexID software) and cortical areas as a unique VOI called “composite”. Statistical analyses were performed dividing the DS group in <40 (n=13) and ≥40 (n=11) years of age. Differences in [11C]PK11195‐SUV and [11C]PIB‐SUVr were assessed by applying a multivariate one‐way ANOVA test with Bonferroni analysis for multiple comparisons. Correlation analyses were applied between [11C]PK11195‐SUV, [11C]PIB‐SUVr, and age variables.

Results

Significant higher [11C]PK11195‐SUV was found in the occipital lobe (p<0.001), temporal lobe (p<0.001), and cingulum posterior (p<0.0001) when comparing the older to younger DS groups. Significant [11C]PIB‐SUVr differences were found for all groups, with the DS≥40 group showing the highest [11C]PIB uptake, followed by the DS<40 and non‐DS groups. No correlations were found between [11C]PK11195 and [11C]PIB measurements. However, for DS individuals, positive significant correlations with age was observed for [11C]PK11195‐SUV in the occipital lobe (p<0.05), temporal lobe (p<0.01), cingulum posterior (p<0.001), hippocampus (p<0.05), amygdala (p<0.05), striatum (p<0.05), and cerebellum (p<0.05), and for [11C]PIB‐SUVr in the composite VOI (p<0.01).

Conclusion

[11C]PK11195‐PET analysis suggests increased neuroinflammation in older DS subjects. [11C]PIB‐PET results show a higher Ab burden in DS≥40 individuals and early accumulation of Ab in DS<40 individuals in comparison to non‐DS age‐matched subjects. More in‐vivo studies are needed to understand the temporal relationship between neuroinflammation and Ab deposition in the brain of individuals with DS.
Exploring Microtubule Dynamics in Alzheimer's Disease: Longitudinal Assessment Using [11C]MPC‐6827 PET Imaging in APP/PS1 and PS301S Mouse Models
Authors: Damuka Naresh , Gollepalli Krishna Kumar , Krizan Ivan , Bhoopal Bhuvanachandra , Miller Mack , Deep Ojasvi , Bashetti Nagaraju , Kumar JV Shanmukha , Orr Miranda E. , Macauley Shannon L , Whitlow Christopher T , Mintz Akiva , Lockhart Samuel N. , Craft Suzanne , Sai Kiran K. Solingapuram
Published: January 2025

Background

Brains affected by Alzheimer's disease (AD) exhibit senile plaques containing amyloid beta (Aβ) peptides and neurofibrillary tangles, formed when tau becomes hyperphosphorylated and disengages from microtubules (MTs). Early instability in MTs is observed in the AD process, emphasizing its significance in connecting the hallmark pathologies of Aβ/tau‐based degenerative events. While current Aβ and tau PET approaches can characterize disease lesions, they fall short in capturing earlier molecular events. MT‐PET aims to address this gap by targeting these early events, providing crucial insights into AD pathophysiology. The PET radiotracer, [11C]MPC‐6827, capable of tracking and quantifying MT‐based changes in real‐time and in vivo, addresses an urgent unmet need and facilitates the monitoring of MT changes in the early stages of AD. Here we present for the first time a comprehensive longitudinal PET imaging study of [11C]MPC‐6827 in Aβ‐overexpressing (APP/PS1) and tau‐overexpressing (P301S) mouse models of AD.

Methods

Longitudinal [11C]MPC‐6827 PET imaging, biodistribution studies, autoradiography, and behavioral assessments were conducted at multiple time points in APP/PS1 (3 to 22 mo old) and P301S (3 to 13‐mo‐old ) transgenic (TG) and age‐matched wild‐type (WT) mice (n=7/group). Whole‐brain standard uptake values for PET, %injected dose/gram for biodistribution, specific brain uptake for autoradiography, and nesting weight for cognitive assessments were determined and PET correlations for TG mice at different age‐points were calculated.

Results

Longitudinal PET imaging demonstrated a 1.3‐fold (***p<0.0001) and 0.9‐fold (**p<0.005) higher brain uptake in APP/PS1 TG mice from 3 to 22 mo and P301S TG mice from 3 to 13 mo respectively (Figure 1) and uptake increased with increasing Aβ and tau loads in AD brains. Longitudinal PET data positively correlated with biodistribution (Pearson r=0.94), and autoradiography results (r=0.55) and negatively correlated with cognitive data (r=‐0.65) in APP/PS1 mice (Figure 2).

Conclusion

Increased [11C]MPC‐6827 brain PET uptake with both increasing Aβ and tau depositions longitudinally in AD brains (along with corroborating biodistribution and autoradiography results) clearly demonstrate the role of early MT dysregulations in Aβ and tau‐based neurodegeneration processes. These findings highlight the potential of [11C]MPC‐6827 PET as a powerful tool for monitoring MT disintegration early‐on. Ongoing experiments are exploring translational potential in humans.
A clock model of regional tau‐PET accumulation and cognitive decline in sporadic early‐onset Alzheimer’s disease
Authors: Schonhaut Daniel R. , Insel Philip S. , soleimani‐meigooni David N. , Zeltzer Ehud , Windon Charles , Maiti Piyush , Yballa Claire , Zhang Jiaxiuxiu , Mundada Nidhi S , Shankar Ranjani , Amuiri Alinda , Koeppe Robert A. , Dickerson Bradford C. , Carrillo Maria C. , Apostolova Liana G. , Rabinovici Gil D. , Joie Renaud La
Published: January 2025

Background

The timing of tau‐PET accumulation and cognitive decline in sporadic early‐onset Alzheimer’s disease (eoAD, age‐at‐onset<65) has not been established and is needed to optimize tau‐PET as an outcome measure in clinical trials. Here we leverage large‐sample, longitudinal data from the Longitudinal Early‐onset Alzheimer’s Disease Study (LEADS) to model tau‐PET accumulation in three regions relative to cognitive decline.

Method

Longitudinal [18F]Flortaucipir‐PET (FTP) and CDR‐SB scores were acquired in 195 amyloid‐PET‐positive, sporadic eoAD patients with MCI or mild dementia due to AD at baseline (Table 1). FTP scans were referenced against inferior cerebellar GM, and mean SUVRs calculated in three meta‐ROIs comprising temporal, parietal, and frontal association cortices (Figure 1A). Generalized additive models estimated nonlinear relations between: (1) baseline SUVRs and annualized rates‐of‐change in each meta‐ROI, and (2) baseline CDR‐SB and annualized rates‐of‐change in cognition. Integrating these baseline‐by‐change functions yielded regional FTP and CDR‐SB trajectories over time. An exhaustive search algorithm identified optimal time‐shifts between each regional tau trajectory and CDR‐SB progression that minimized the error between model‐predicted and observed data at baseline. This time‐shifting procedure was repeated in a held‐out dataset of 184 eoAD patients to assess out‐of‐sample reproducibility (Table 1).

Result

FTP SUVRs and CDR‐SB scores increased longitudinally in most patients (Figure 1B,C). Baseline SUVR by rate‐of‐change associations were inverted U‐shaped in each meta‐ROI (Figure 1D), and similar associations were found for CDR‐SB progression (Figure 1E). Time‐shift estimation in the training dataset converged on a single, best‐fitting model in which temporal and parietal FTP accumulation led clinical onset by 4.5 years, while frontal FTP accumulation began 0.5 years before clinical onset (Figure 2A). The replication dataset yielded nearly identical results (Figure 2B). We estimate that the full timecourse of FTP accumulation and cognitive decline occurs over ∼16 years from earliest detectable change in FTP.

Conclusion

Tau‐PET accumulation in the frontal meta‐ROI immediately precedes cognitive decline and tracks closely with clinical progression in eoAD, while temporoparietal tau‐PET is prominent at clinical onset and plateaus as dementia worsens. For clinical trials in symptomatic patients, temporal and parietal tau‐PET may therefore aid staging and inclusion criteria, while frontal tau‐PET is likely superior for monitoring longitudinal change.
Unsupervised online reaction time test improves estimation of cognitive function in a large sample of cognitively‐asymptomatic older adults
Authors: Wang Xinyi , Bindoff Aidan , George Rebecca J St , Roccati Eddy , Bartlett Larissa , Lawler Katherine , Noyce Alastair J , Tran Son , King Anna E , Vickers James C , Bai Quan , Alty Jane E
Published: January 2025

Background

Finding low‐cost, accessible methods to detect people at risk of preclinical Alzheimer’s disease (AD) is a research priority for neuroprotective drug development and clinical trials. Sub‐clinical asymptomatic decline in episodic memory is a proxy measure of preclinical AD and there is emerging evidence that analysis of motor patterns using laboratory apparatus may detect this stage. There has been little investigation of whether self‐administrated simple hand motor tests using personal computers in an unsupervised environment can detect preclinical AD. This study evaluated how home‐based reaction time tests predict cognitive performance in a sample of cognitively asymptomatic older adults.

Method

894 community participants (66.2 +/‐ 7.46 years old, 71.0 % female) who self‐reported an absence of cognitive symptoms were recruited from the ISLAND cohort study. In an unsupervised environment such as their home, they completed a simple reaction time test and a five‐choice reaction time test from the TAS Test website, and validated online cognitive tests (CANTAB) of episodic memory, working memory and executive function. Reaction time was measured in milliseconds. Test failure was defined as a delay of > 2000 milliseconds. We fitted hurdle linear mixed models to examine associations between reaction time, and test failure, with cognitive performance, adjusted for choice (simple or 5‐choice).

Result

Higher episodic and working memory errors, and worse executive function scores were associated with test failure (episodic memory log‐odds = 0.135, p < 0.001, working memory log‐odds = 0.130, p = 0.002, and executive function log‐odds= 0.132, p < 0.001). There was no significant association between cognitive test scores and reaction time on successful trials (episodic memory p = 0.438, working memory and executive function models would not converge).

Conclusion

Test failure in brief self‐administered online reaction time tests were associated with cognitive test performance across three domains, in a cognitively asymptomatic older cohort. This provides a potential low‐cost and brief home‐based method for risk stratification of enriched cohorts for further assessment.