bluuebunny/crossref_metadata_2025 huggingface dataset:
Validation of Large Language Models to Identify Dementia Cases in Electronic Health Records
Authors: Yang Richard , Wang Liqin
Published: January 2025

Background

Dementia diagnosis presents global healthcare challenges due to its elusive nature and inconsistent documentation in Electronic Health Records (EHRs). Approaches relying on diagnostic codes and rules may overlook undiagnosed cases or mistakenly identify others, as these codes are frequently used for purposes beyond disease diagnosis. This highlights the need for more sophisticated diagnostic tools. The advent of artificial intelligence (AI) and large language models (LLMs), with their advanced natural language understanding, promises more accurate detection. This study evaluates LLMs’ performance in identifying dementia cases using aggregated EHR data.

Method

The study utilized the EHR from Mass General Brigham (MGB) to identify potential dementia patients through keywords and codes indicating cognitive decline. From this pool, 200 patients underwent independent chart reviews by two experts, with discrepancies resolved by a third. We employed two LLMs, GPT‐3.5 and GPT‐4, and two data preparation approaches for dementia detection: daily medical record aggregation and patient record aggregation. The first approach concatenated daily records related to cognitive decline and analyzed the data chronologically with zero‐shot prompting using both LLMs. Conversely, the second approach concatenated entire patient medical records related to cognitive decline and applied GPT‐4 with few‐shot prompting. For comparison, we included a baseline that requires two separate dementia ICD diagnoses in different years, at least 30 days apart. We assessed each approach using accuracy, positive predictive value (PPV), sensitivity, specificity, and F1 score.

Result

The patient record aggregation plus few‐shot prompting strategy with GPT‐4 had the best performance, achieving an accuracy of 0.86 and an F1 score of 0.80. In the daily medical record aggregation approach, GPT‐4’s zero‐shot prompting outperformed GPT‐3.5, with F1 scores of 0.78 and 0.57, respectively. The baseline rule‐based approach scored a good F1 of 0.74 but showed lower sensitivity, suggesting underdiagnosis with traditional methods.

Conclusion

This study demonstrates that LLMs can significantly enhance dementia diagnosis using EHRs. Our findings reveal that the aggregated patient record and few‐shot prompting strategy with GPT‐4 outperforms traditional methods, offering a more comprehensive and accurate evaluation of dementia.
Lower resting‐state phasic LC activity is associated with cortical tau deposition and Aβ‐related cognitive decline in preclinical Alzheimer’s Disease
Authors: Prokopiou Prokopis C. , Schultz Aaron P , Rentz Dorene M , Sperling Reisa A , Johnson Keith A , Jacobs Heidi I.L.
Published: January 2025

Background

The locus coeruleus (LC) is one of the earliest regions accumulating tau pathology in Alzheimer’s Disease (AD). As the disease progresses, tau in the LC has been linked to increasing cortical tau and amyloid‐beta (Aβ) pathologies and cognitive decline. Previous animal research suggested that novelty‐like phasic LC activity protects against AD‐related cognitive decline. In this work, we investigate whether in‐vivo resting‐state phasic LC activity is associated with AD pathology and cognitive decline in preclinical AD.

Method

Ninety‐two participants (56 Female, mean age at baseline = 74.99±9.0 years) from the Harvard Aging Brain Study underwent longitudinal cognitive testing (mean follow‐up = 5.37±1.88 years), PiB(Aβ)‐PET, FTP(tau)‐PET, and 3T resting‐state BOLD‐fMRI scans (TR/TE = 800/37 ms, voxel = 2 mm3) performed within 1.5 years of each other (mean time difference = 0.96±0.0 years; Table 1). Spontaneous phasic LC activity events were extracted directly from the LC BOLD‐fMRI time‐series using deconvolution and positively‐constrained LASSO regression. The proportion of LC activity explained by the detected events was quantified using the R‐squared coefficient of determination. Vertex‐wise linear regression analyses adjusted for age, sex, and multiple comparisons (pcl<0.05) were used to detect significant associations between LC phasic activity and cortical tau. Longitudinal linear mixed‐model analyses adjusted for age, sex, and years of education were used to evaluate the relationship between LC phasic activity and cognitive decline (composite, see Fig. 2 caption) at different levels of cortical Aβ.

Result

Representative spontaneous LC phasic events and their associated BOLD‐fMRI signal fluctuations are illustrated in Fig. 1A‐B, respectively. Lower resting‐state phasic LC activity was associated with greater bilateral inferior‐temporal tau deposition (Fig. 1C), also confirmed by a region of interest analysis (Fig. 1D; p = 0.03). No relationship between phasic LC activity and Aβ was observed. Furthermore, lower LC phasic activity was associated with steeper cognitive (Fig. 2; p = 0.02) decline, particularly at elevated Aβ levels.

Conclusion

This preliminary work demonstrates that lower levels of spontaneous phasic LC activity are related to elevated cortical tau pathology and steeper downstream AD‐related cognitive decline. These results could inform the design of targeted interventions to support optimal LC phasic activity, promoting resilience. Further research is needed to elucidate these relationships further by utilizing longitudinal data on AD pathology and cognitive function across different subdomains.
Survey on knowledge of Uruguayan neurologist about the FINGER intervention
Authors: Contreras Valeria , Charamelo Ana , Dansilio Sergio
Published: January 2025

Background

The Latin American Initiative for Lifestyle Intervention to Prevent Cognitive Decline (LatAm‐FINGERS) is based on the study FINGER (Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability) in which participate 12 Latin American countries. Is the first non‐pharmacological multicenter randomized clinical trial to prevent cognitive impairment in Latin America (LA), and investigates the feasibility of a multi‐domain lifestyle intervention and the efficacy of the intervention in LA.

We were interested in knowing what information Uruguayan neurologists have on the subject. In Uruguay, according to official information, in 2021 there were 139 registered neurologists. No surveys have been carried out on the subject in Uruguay.

Objectives: To know what information the Uruguayan neurologists have about the results of the FINGER intervention and the frequency of indication of primary prevention measures to people at risk of cognitive impairment.

Methods

This is a cross sectional, observational and descriptive trial. A survey was designed in the SurveyMonkey application with 13 questions and it was sent to neurologists through social networks. Informed consent was requested.

Results

The survey was answered by 41 neurologists. 38.5% of responders were aware of the results of the FINGER intervention in Finland and 36% have made prevention recommendations taking them into consideration.

40 participants responded regarding primary prevention measures. Of these, 90% stated that they made recommendations to people at risk of cognitive impairment. 30% reported making nutritional suggestions frequently, 95% suggested cognitive stimulation exercises and 92.5% suggested participating in regulated physical activity programs.

47.5% knew about the LatAm FINGERS initiative and 42.5% knew that Uruguay was participating in it. All respondents expressed interest in knowing the results of the LatAm FINGERS initiative when it has concluded.

Conclusions

Most Uruguayan neurologists make recommendations on primary prevention measures for cognitive impairment. There was moderate knowledge about the results of the FINGERS study, but there is a marked interest in learning more about the topic.

It is planned to extend the survey to other medical specialists involved in the care of people at risk of cognitive impairment.
Rapid discovery and optimization of novel brain shuttles and shuttle‐enabled anti‐amyloid therapeutics using multiplexed in vivo biologics design
Authors: Lofgren Shane
Published: January 2025

Background

Drug delivery to the central nervous system has long been hindered by the restrictive properties of the blood‐brain barrier (BBB). Recent advances have highlighted the ability of certain antibody “shuttles'' to traverse the BBB and enhance the delivery of diverse therapeutic payloads. However the true potential of this approach remains underexplored and is limited by traditional in vitro screening platforms that fail to capture the complexities of in vivo biology. Novel technologies that facilitate the development of brain shuttles and shuttle‐enabled neuromedicines could improve the uptake, efficacy, safety, and dosing of broad classes of therapeutics, and transform the treatment of vast numbers of patients with neurological disease.

Method

Here, we introduce a high‐throughput in vivo screening methodology based on Manifold’s mCodeTM technology to evaluate BBB penetration and uptake of over 1000 brain shuttling antibody candidates targeting 10+ different receptors (Figure).

Result

Our approach reveals antibody shuttles with diverse molecular properties and distinct pharmacokinetic profiles in brain, blood, and other peripheral tissues. We leverage this large in vivo dataset using machine learning to further engineer these antibodies for enhanced brain uptake and residence time. Engineering of brain shuttles with anti‐amyloid antibodies against BACE1 and amyloid beta significantly improved the uptake and efficacy of these fusions versus unshuttled controls and comparator shuttled molecules.

Conclusion

Collectively, our work (1) expands the pool of known targets and molecules capable of shuttling therapeutic payloads across the BBB, (2) validates the utility of these molecules toward the design of novel neuromedicines for Alzheimer’s disease, and (3) signifies a paradigm shift in utilizing thoughtfully‐designed, high‐throughput in vivo screening in early stages of drug discovery.
Unmet ADL/IADL Needs among Veterans with Dementia: An Analysis of the HERO CARE Multi‐site Survey
Authors: Desir Marianne E , Munoz Richard A , Hansen Jared , Tang Fei , Dang Stuti
Published: January 2025

Background

Receiving sufficient assistance with ADLs/IADLs can support dementia patients’ physical and psychosocial health, as well as aging in place. The Department of Veterans Affairs has prioritized supporting Veterans in aging at place a home when this is their preference. We aimed in the current study to analyze if there are demographic characteristics and/or comorbidities of Veterans with dementia that are predictive of having unmet ADL/IADL needs.

Method

In 2021‐2022 the caregivers of 741 Veterans with dementia completed round one of the HERO CARE survey, a prospective longitudinal panel design survey administered to caregivers and VHA‐enrolled Veterans across five VHA sites, with oversampling of Veterans with higher predicted risk of long‐term institutionalization. 314 of these surveys had sufficient response data for inclusion in the current analysis. Multiple linear regression was used to regress the outcome of combined total score of unmet ADL/IADL needs (minimum = 0, maximum = 15, mean = 4.86, SD = 4.92) on specific demographic characteristics and comorbidities (using Hierarchical Condition Categories) across five models. The model of best fit was identified by AIC.

Result

Non‐white/non‐Hispanic race‐ethnicity (β = 3.14, se = 0.64) and having Parkinson’s or Huntington’s diseases (β = 2.718, se = 0.870) were associated with having more unmet ADL/IADL needs at the 5% significance level. Having major depressive, bipolar, and/or paranoid disorders (β = ‐ 1.395, se = 0.656) was associated with having less unmet ADL/IADL needs at the 5% significance level. When controlling for the other predictors, having non‐white/non‐Hispanic race‐ethnicity was associated with an average increase of 3.25 unmet ADLs/IADLs, having Parkinson’s or Huntington’s Disease was associated with an average increase of 2.72 unmet ADLs/IADLs and having major depressive, bipolar, and/or paranoid disorders was associated with a 1.40 decrease in unmet ADLs/IADLs.

Conclusion

The Veterans Affairs Healthcare System (VAHS) may have characteristics that support the provision of ADL/IADL assistance for patients who have dementia in conjunction with major depressive, bipolar and/or paranoid disorders. Increased attention to ADL/IADL supports among VAHS patients who have dementia and non‐white/non‐Hispanic race/ethnicity and/or Parkinson’s or Huntington’s diseases may support Veteran health, wellbeing, and aging in place.
Ancestry‐specific effects of APOE on AD endophenotypes and modifiable risk factors
Authors: Boeriu Ana I , Fulton‐Howard Brian , Phillips Nicole , Barber Robert , O'Bryant Sid E. , Yaffe Kristine , Andrews Shea J
Published: January 2025

Background

APOE is highly pleiotropic, with the e4 allele the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD) and associated with other cardiometabolic traits. The APOE*e4 allele demonstrates ancestry‐specific differences in the risk for AD. Here, we investigated whether similar ancestry‐specific effects are observed across other AD endophenotypes and modifiable risk factors for AD.

Method

Participants were 2505 non‐Hispanic Whites, Hispanics, and African Americans with genetic data from the Health and Aging Brain Study ‐ Health Disparities cohort (Table 1). Genetic ancestry was determined through principal component analysis, by projecting participants onto the 1000 Genomes reference panel. Global ancestry proportions were estimated using ADMIXTURE. The association of APOE*e4+ and *e2+ alleles with cognitive performance, plasma biomarkers, neuroimaging, and clinical comorbidities was investigated using regression models stratified by European (EUR), Amerindian (AMR), and African (AFR) ancestry. Covariates included age, gender, education; and intracranial volume for neuroimaging endophenotypes. Ancestry‐specific effects were determined by evaluating the equality in regression coefficients from the ancestry‐stratified models.

Result

Genetic ancestry assignments were highly concordant with self‐reported race: 1071 EUR, 1003 AMR, and 431 AFR participants (Table 1). APOE*e4 was associated with lower BMI, poorer cognitive performance, increased risk of cognitive impairment and dyslipidemia, reduced cortical thickness and hippocampal volume, and plasma biomarkers levels ‐ higher pTau181, lower Ab42, and Ab42/Ab40 ratios (Figure 1). APOE*e2 was associated with reduced dyslipidemia risk (Figure 2). Notably, ancestry‐specific effects were observed, with APOE*e4 associated with lower Ab42/Ab40 in EUR compared to AMR. Additionally, APOE*e2 shows ancestry‐specific effects for Ab42/Ab40, pTau181, and Ab40. In particular, AFR have a lower Ab42/Ab40 compared to both EUR and AMR. EUR have lower levels of pTau181 compared to both AFR and AMR. AFR have higher Ab40 compared to EUR and AMR.

Conclusion

Our findings demonstrate that the impact of APOE on AD endophenotypes varies across ancestries, notably with amyloid and tau plasma biomarkers, and dyslipidemia. This underscores the critical need to consider genetic ancestry in assessing the effect of APOE on AD endophenotypes.
Use of a blood‐based amyloid test for screening in INVOKE‐2: a phase 2 randomized, double‐blind, placebo‐controlled study evaluating AL002 in early Alzheimer’s disease
Authors: Burgess Brady , Nguyen Tuan , Simmons Adam , Gupta Ruchi , Chow Tiffany , Romano Gary
Published: January 2025

Background

The PrecivityAD® blood‐test (C2N Diagnostics) predicts cerebral amyloidosis due to Alzheimer’s Disease (AD). PrecivityAD® incorporates plasma Aβ42/40, age and apoE proteotype into an algorithm that generates an amyloid probability score (APS) corresponding to the likelihood of a positive amyloid PET scan, defined as ≥25 centiloid (CL). A prototype PrecivityAD algorithm validated against amyloid PET status scored by visual read (VR) was used to improve screening efficiency in INVOKE‐2, a phase 2 randomized, double‐blind, placebo‐controlled trial evaluating TREM2‐activating antibody AL002 in early AD.

Methods

VR‐validated PrecivityAD (VR‐PrecivityAD) used refined thresholds defined as low (VR‐APS = 0‐31), intermediate (32‐57) or high (58‐100) likelihood of amyloid positivity. CL‐validated PrecivityAD (CL‐PrecivityAD) results were scored using established thresholds for low (CL‐APS = 0‐35), intermediate (36‐57) or high (58‐100) likelihood of amyloid positivity. INVOKE‐2 screening subjects meeting inclusion criteria for Clinical Dementia Rating Global Score (CDR‐GS), Mini‐Mental State Examination (MMSE), and Repeatable Battery for the Assessment of Neuropsychological Status Delayed Memory Index (RBANS‐DMI) (CDR‐GS = 0.5‐1, MMSE≥20, RBANS‐DMI≥95) were required to have a positive VR‐PrecivityAD blood‐test (intermediate or high VR‐APS result) prior to a confirmatory amyloid PET VR or CSF test to establish eligibility. Positive predictive value (PPV) was defined as number of individuals with confirmed positive blood‐tests as a percentage of all positive blood‐tests.

Results

Positive VR‐PrecivityAD results were reported for 51% of individuals (362/710) with a PPV of 87% overall, 91% for high or 82% for intermediate results (Table). Comparison of VR‐APS against CL‐APS results indicated the INVOKE‐2 positivity threshold (VR‐APS≥32) was equivalent to an effective CL‐APS threshold of ∼25, lower than the established CL‐PrecivityAD threshold (CL‐APS≥36). In this comparison 58% of individuals would have scored negative on CL‐PrecivityAD compared to 49% observed with VR‐PrecivityAD. Importantly, 80% (52/65) of discordant individuals with positive VR‐PrecvityAD and negative CL‐PrecivityAD results had a subsequent positive confirmatory test (Table).

Conclusions

The prototype VR‐PrecivityAD blood‐test was highly predictive of amyloid positivity, confirmed by VR‐PET or CSF, among INVOKE‐2 screening subjects. Use of a lower VR‐APS threshold was associated with fewer false negatives without a meaningful increase in false positives when compared to the standard CL‐PrecivityAD threshold in the INVOKE‐2 screening population.
Single step capture and assessment of multiple plasma extracellular vesicle biomarkers in Alzheimer’s disease detection
Authors: Lewis Jean M , Harris Dorathy Ann , Kosmatka Janell , Balcer Heath I , Dhani Harmeet , Hinestrosa Juan Pablo , Billings Paul R , Rissman Robert A.
Published: January 2025

Background

Blood tests for Alzheimer’s disease (AD) that measure biomarkers could be useful as minimally‐invasive ways to give patients more and earlier access to screening. While some AD biomarkers can be detected in plasma, they need to be more sensitive to make plasma AD tests more effective. Extracellular vesicles (EVs) in plasma carry AD‐related biomarkers from the brain and could offer a concentrated source of brain‐related biomarkers, but it is hard to isolate and analyze plasma EVs for clinical use.

Method

We present a simplified method for isolating EVs directly from plasma using an alternating current electrokinetic (ACE) microchip. No sample pre‐treatment steps were needed. Protein biomarkers on the EVs were detected by adding fluorescent antibodies to the plasma samples before capture by the chip. This allowed measurement of EV biomarker levels directly on the chip.

Result

AD or non‐AD control plasma was measured for ten different AD‐related biomarkers. EV‐associated NCAM1, pTau231, α‐synuclein, and TDP‐43 levels were able to distinguish a group of 10 AD, 10 MCI, and 10 non‐AD subjects. pTau231 was different between AD and non‐AD (p = 0.0300) and α‐synuclein differentiated AD from MCI (p = 0.0148).

Conclusion

This study shows how ACE microfluidic chip technology can help differentiate AD and MCI patients from non‐AD controls with clinical relevance. This work also highlights the important diagnostic role of plasma EV biomarkers in neurodegenerative disease.
Advancing Inclusivity for African American and Hispanic Populations in Alzheimer’s Disease Trials: Understanding Screen Failures from the Aducanumab Confirmatory Trial
Authors: Showell Shardae , Murphy Jennifer , Dent Gersham , Dawson Katherine
Published: January 2025

Background

Given the high prevalence of Alzheimer’s disease (AD) and historic underrepresentation of African Americans and Hispanics in AD clinical trials, there is a critical need to advance understanding of inclusive clinical trial considerations. ENVISION was a confirmatory study designed to validate clinical efficacy of aducanumab, which included specific goals for African American and Hispanic population enrollment in the United States. In our pursuit, we found a 90% screen failure rate among African Americans and Hispanics compared to 75% in non‐Hispanic whites. In this analysis, the documented reasons for screen failure among African American and Hispanic participants were evaluated. These data are shared to foster a dialogue that encourages the development of more inclusive trial design in future AD studies.

Method

ENVISION (NCT05310071) was a multicenter, randomized, double‐blind, placebo‐controlled, phase 3b/4 confirmatory study of aducanumab in participants with mild cognitive impairment (MCI) and mild dementia AD. Data from the ENVISION screen failure population of African Americans (N = 75) and Hispanics (N = 110) within the United States were analyzed, and reasons for screening failure based on inclusion‐exclusion criteria and health characteristics are reported.

Result

Not meeting the inclusion requirement for MCI or mild AD according to NIA‐AA criteria was the most common reason for screen failure at 55% and 58%, for African Americans and Hispanics respectively. The remaining causes of screen failures include unconfirmed amyloid beta pathology (African Americans, Hispanics: 7%, 14%), brain MRI exclusionary findings (1%, 6%), and the lack of an identified care partner (3%,1%). However unspecified reasons in the opinion of the investigator represent 19% of African Americans and 8% of Hispanics. Assessment of baseline physical health characteristics known to be AD risk factors revealed a higher incidence of elevated levels of hemoglobin A1c and blood pressure among the screen failed population of African Americans and Hispanics compared to randomized participants.

Conclusion

The screen failed population of African Americans and Hispanics represent a group of individuals that are eager to participate in AD clinical trials, but unable to. This hypothesis generating analysis provides insight for new avenues of future exploration in clinical trial design for better inclusion of underrepresented populations.
Brain‐Wide Cellular‐Resolution Measurement of Antibody Therapeutic Biodistribution
Authors: Redd Chase , Guanzon Nathaniel , Gallegos Yessenia , Weiss Jacob , Jensen Camilla Stampe , Vergo Sandra B. , Wheeler Damian G.
Published: January 2025

Background

To look deep inside tissues, traditional histological methods cut specimens into thin slices. Providing access to the intricate anatomy of intact organs, tissue clearing offers neuroscientists unbiased and complete views of brain anatomy and function. One area where these methods have particular utility is in the development of CNS therapeutics where they can be used to examine the regional distribution of the therapeutics in the brain as well as brain‐wide target engagement and phenotypic efficacy. We have developed a pipeline that provides unbiased and complete cellular resolution measurements of brain‐wide therapeutic biodistribution in pre‐clinical rodent brains.

Methods

With our optimized iDISCO‐based clearing method and our Mesoscale Imaging System for ZEISS Lightsheet microscopes, we can image cellular‐resolution immunoreactivity across entire mouse brains in <20 min. Here we examined whether our technology can detect antibody therapeutics crossing the blood‐brain barrier (BBB). To do this, we took advantage of a bispecific antibody engineered to bind to the Alzheimer’s Disease target, BACE1, as well as the transferrin receptor (TfR1), which helps shuttle the antibody across the brain endothelium and into the brain parenchyma.

Results

We demonstrated that our methods can detect IV‐dosed BACE1/TfR1 bispecific antibody throughout the brain. In mice dosed with a monospecific control antibody that does not bind TfR1, immunoreactivity was at background levels, similar to that seen in mice not dosed with any antibody. The bispecific therapeutic antibody was detected in the parenchyma and enriched in brain regions with high BACE1 expression, indicating that the antibody crosses the BBB and engages the target. However, there are high levels of bispecific antibody bound to TfR1 in the vasculature where is does not have access to drug targets. To quantify the effective parenchymal levels of the bispecific antibody, we have extended out AI‐powered quantification pipeline to segment the staining in the vasculature and measure only the therapeutically relevant bispecific antibody signal in the brain parenchyma.

Conclusion

These data provide a clear demonstration of the utility of tissue clearing methods for quantitative brain‐wide monitoring of Alzheimer’s Disease therapeutic antibody biodistribution.
Development of Orally Available, Brain Penetrant Compound That Reduces Tau Pathology
Authors: Wolozin Benjamin , Ash Peter E.A. , Berson Amit , Stykel Morgan G , Murphy Caroline , Fredette Nick , Larsen Glenn
Published: January 2025

Background

Increasing data indicates that the pathophysiology of microtubule associated protein tau is mediated by its interactions with RNA and RNA binding proteins via stress granules (SGs) and the translational stress response. Aquinnah now reports identifying small molecule compounds that inhibit tau/TIA1 SGs in neuronal cell lines and show strong in vivo efficacy in a classic mouse model of tauopathy.

Method

Compounds identified using high content imaging screening in SH‐SY5Y neuroblastoma cells, inducibly over‐expressing tau::GFP and TIA1::mKate2, following exposure to stressor. Validation was performed with rat hippocampal primary neurons and 3D human iPSC neuron/astrocyte assembloids. In vivo efficacy studies were conducted in 8 & 9‐month old P301S tau mice that were treated daily for 1 month. Pathological tau, misfolded (MC‐1) and phosphorylated (AT8 pS202/T205, pT181), was quantified in treated P301S tau mice by AlphaLISA and immunohistochemistry.

Result

We identified a compound series that reduced tau pathology both in vitro and in vivo. The lead target acts in the proteostasis pathway, being present in both neurons and immune cells. Strong reductions of tau pathology were observed in primary rat neurons and 3D human iPSC assembloids. Treatment of 9‐month P301S tau mice QD orally for 28 days also showed strong reduction of tau pathology, with results characterized and quantified with AlphaLISAs and immunohistochemistry. Quantification of each marker measured by AlphaLISA showed reductions of: MC‐1, 70% (P = 0.0031), pS202/T205 tau (AT8) 65% (P = 0.0018) and pT181 tau, 60% (P = 0.0005). Histopathology and a clinical chemistry panel indicated no adverse effects from 28‐days of QD treatment.

Conclusion

Aquinnah has identified an orally bioavailable, brain penetrant compound that is able to strongly reduce tau pathology in a mouse model of tauopathy with late stage disease. These results show strong promise as a potential therapeutic agent for treatment of Alzheimer’s disease and related disorders.
Phase 3 Clinical Protocol: Placebo‐Controlled, Double‐Blind, Parallel‐Group to Study Safety and Efficacy of NA‐831 in Combination with Lecanemab in Subjects with Early Alzheimer’s Disease
Authors: Tran Lloyd , Tran Zung Vu , Vu Fern
Published: January 2025

Background

Lecanemab has been approved by the FDA for patients with early Alzheimer’s disease (AD). NA‐831 is an experimental drug that has showed a proof of safety and efficacy in Phase 2 clinical trial for patients with early Alzheimer’s disease.

AD patients are treated with a number of comedications not only to address cognitive impairment (standard‐of‐care) but also other comorbidities. It has been shown that amyloid reduction at best leads to modest changes in clinical deterioration and that there is room for additional therapeutics to improve patient quality of life. In addition, amyloid‐related imaging abnormalities side‐effects need to be considered opening the possibilities of dose‐sparing with new combinations.

Method

The phase 3 study consists of a Core and Open Label Extension (OLE) Phase will be conducted to evaluate the efficacy and safety of combination therapy of NA‐ 831 and lecanemab with patients with Early Alzheimer’s Disease (EAD). The Core is an 18‐month treatment, multi‐centers, double blind, placebo controlled parallel group study.

Enrollment: 600 participants. Ages: 50 to 90 Years. All sexes are eligible for study.

Core Study:

Participants will be divided in 3 groups, randomly assigned in a 1:1 ratio to receive a drug or a combination of two drugs or placebo.

Group 1: will receive one 30 mg of NA‐831 capsule orally once a day or placebo,

Group 2: will receive and intravenous lecanemab (10 mg per kilogram of body weight every 2 weeks) or placebo.

Group 3: will receive one 30 mg of NA‐831 capsule orally once a day and intravenous lecanemab (5 mg per kilogram of body weight every 2 weeks) or placebo.

Open Label Extension Phase: Participants completing the core study will receive one 30 milligram (mg) NA‐31 capsule orally once a day, and intravenous lecanemab (5 mg per kilogram of body weight every 2 weeks)

Result

Results will be announced upon the completion of the Phase 3.

Conclusion

The Phase 3 clinical trial will be conducted more than 30 sites in the US and several countries. The details of the Phase 3 methodology and protocol will be presented and discussed.
Tau Magnitude and eXent–Tau‐MaX: Capturing tau spread and local accumulation provides a robust metric of tau burden
Authors: Brown Christopher , Das Sandhitsu R. , Cousins Katheryn A Q , Tropea Thomas F. , Chen‐Plotkin Alice , Lee Eddie B , Nasrallah Ilya M. , Detre John A. , Yushkevich Paul A. , Shaw Leslie M. , Wolk David A
Published: January 2025

Background

Measures of tau burden have typically relied upon measures of magnitude, such as mean standardized uptake value ratio (SUVR), or extent, such as number of tau positive regions. However, heterogenous patterns of tau spread and accumulation present challenges to using these measures in isolation to quantify tau burden. Therefore, we hypothesized that a combined measure of tau magnitude and extent (Tau‐MaX) would outperform either measure in isolation.

Method

Baseline 18F‐flortaucipir PET scans from 916 participants from ADNI (n = 741) and Penn Aging Brain Cohort (ABC, n = 175) were used for this study. SUVRs, using an inferior cerebellar reference region, were converted to Tau Pathology Indices (TPI) based on mixed‐Gaussian models (Figure 1). Regions with TPI > 0 (reflecting tau positivity) were weighted by region size and summed to form a measure of Tau Magnitude and eXtent (Tau‐MaX, Figure 1). This process was carried out globally and within two common meta‐ROIs: meta‐temporal and Braak 5/6. For each of these three meta‐ROIs, we compared diagnostic group differences, association with Centiloid values from amyloid PET, correlation with Fujirebio Lumipulse p‐tau217 measures, and delayed recall performance using Tau‐MaX, mean SUVR, or extent of tau positivity. Comparison between associations was performed using Hittner’s Z.

Results

Group differences and results from regression analyses are shown in Table 1. There was a stepwise increase in all measures across diagnostic groups, although extent measures were more sensitive for detecting differences between CN Aβ+ and CN Aβ‐ individuals. Similarly, extent measures were more closely associated with Centiloid values in Aβ+ individuals in the meta‐temporal and Braak ROIs, but Tau‐MaX was more sensitive globally. Tau‐MaX had a stronger relationship with plasma p‐tau217 compared to either SUVR or extent. Finally, Global Tau‐Max and meta‐temporal Tau‐Max and SUVR were the best predictors of delayed recall performance.

Conclusion

Tau‐MaX provides a robust metric of tau burden by incorporating both magnitude and extent. Further, the region agnostic approach may be particularly useful in more heterogenous cohorts that do not follow canonical Braak patterns of spread and accumulation. Longitudinal analyses of these measures will help identify their utility as markers of therapeutic response.
Influence of tau on non‐traditional memory scores in early‐onset Alzheimer’s disease
Authors: Kostadinova Ralitsa V. , Bushnell Justin , Hammers Dustin B. , Apostolova Liana G. , Clark David G.
Published: January 2025

Background

A common neuropsychological test for assessing episodic memory is the Rey Auditory Verbal Learning Test (RAVLT), a sequence of 8 word‐list learning and recall tasks (five learning trials, immediate recall of an intrusion list, short‐delay and long‐delay recall). There is extensive research correlating patterns of RAVLT performance with clinical dementia syndromes, but little work relating these patterns to biomarkers in early‐onset dementia. Here, we analyze the relationship between patterns of tau deposition and RAVLT performance in early‐onset populations.

Method

We transcribed RAVLT recordings from 249 subjects in the Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS). We calculated three composite scores from scores on the individual RAVLT tasks: learning ratio, raw learning score, and recency ratio. We then performed principle components analysis (PCA) on tau measurements in 108 regions of interest, identifying five components accounting for 90.9% of the variance. We entered RAVLT composite scores as dependent variables in a series of linear regression models. The PCA components, along with diagnostic syndrome and nuisance variables (age, sex, education), were entered as independent variables.

Result

Principal component 1 loaded positively in all ROIs in both hemispheres, with weaker loadings in the motor strip, occipital region, and subcortical nuclei. Principal component 5 loaded positively on left > right temporal lobes and white matter. These two were significant predictors of both learning ratio and raw learning score, showing that an increase in tau affects the performance of these RAVLT metrics. Loadings for principal component 4 were more complex, but in general were positive in the right > left hemisphere, including parietal lobes and superior temporal gyri, with negative loadings elsewhere in the temporal lobes. This component was a significant predictor of recency ratio. In all cases, regression coefficients were negative, indicating that tau within ROIs with positive loadings was negatively correlated with the memory score in question.

Conclusion

RAVLT measures are sensitive to the effects of tau deposition in early‐onset Alzheimer’s disease. Further work is needed to evaluate these scores as predictors of specific forms of pathology in early‐onset dementia.
Neural flexibility as a promising biomarker for Alzheimer’s Disease
Authors: Varangis Eleanna , Liu Jun , Miao Yiqi , Zhu Xi , Stern Yaakov , Lee Seonjoo
Published: January 2025

Background

Neural flexibility (NF) during tasks was associated with cognitive aging, while that during rest was not associated with aging and cognition in a healthy aging population. However, NF has not been studied in AD. We aim to evaluate whether AD is associated with alterations in NF and probe its predictive utility for AD conversion.

Method

The study included 862 older adults with valid resting‐state fMRI data: 461 who are cognitively normal (CN, 53.5%), 294 with Mild cognitive impairment (MCI, 34.1%), and 107 with Alzheimer’s Disease (AD, 12.4%) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The MRI images were processed using fMRIPrep, and the mean time series of each node was extracted according to the Power Atlas parcellation scheme. We performed dynamic community detection based on generalized Louvain methods. We defined the NF of a node as the number of times that a node changed its community assignment across the sliding windows, normalized by the total number of possible changes and computed global NF (GNF) and network‐level NF. We performed linear mixed models on NF to explore the effect of AD group indicators on NF controlling for the age at scan, gender, education level, and the random intercept of site. We then evaluated the dementia transition of neural flexibility using survival analysis. In the non‐demented participants at baseline, we performed Cox‐proportional hazard regression analysis with each NF.

Results

NF is significantly higher in AD group than the CN group on global, CON, MRN, SMN‐H, SMN‐M, VAN, and VIS networks (Figure 1); neural flexibility is significantly higher in the MCI group than the CN group in the VIS network (Figure 1). Among n = 670 non‐demented participants at baseline, n = 53 (8.6%) participants converted to dementia during the follow‐ups. Higher neural flexibility in VIS was positively associated with AD transition (HR = 1.323, 95%CI 1.002 to 1.747, p = 0.049, per 1 standard deviation in NF, Figure 2), controlling for age, gender, and education.

Conclusion

We found that NF during resting was higher in AD patients and predicted dementia transition. Thus, NF can be a valuable biomarker of AD, and more validation and mechanistic studies need to be performed.
Amyloid Biomarker Discordance in Patients Evaluated for Anti‐Amyloid Therapy
Authors: Ramanan Vijay K. , Graff‐Radford Jonathan , Bornhorst Joshua A , Johnson Derek R. , Cogswell Petrice M , Burkett Brian J , Lowe Val J. , Stricker Nikki H. , Botha Hugo , Jones David T. , McCarter Stuart J , Neth Bryan J. , Jack Clifford R. , Knopman David S. , Petersen Ronald C. , Algeciras‐Schimnich Alicia
Published: January 2025

Background

Evidence for abnormal amyloid‐β (Aβ) plaque accumulation is necessary prior to initiating anti‐amyloid therapy in early symptomatic Alzheimer’s disease (AD). While the clinical trials for lecanemab and related drugs utilized positron emission tomography (PET) to demonstrate brain amyloidosis, current appropriate use recommendations for clinical practice consider PET or cerebrospinal fluid (CSF) biomarkers as satisfactory for this purpose. Here, we present four clinical cases where CSF biomarker results were discordant from amyloid PET, with the potential to result in erroneous treatment targeting.

Method

Patients were seen at a tertiary care subspecialty clinic in consideration for lecanemab therapy. All patients had office examination, neuropsychological assessment, structural magnetic resonance imaging (MRI), amyloid PET (with either 11C‐Pittsburgh compound B or 18F‐florbetapir), CSF AD biomarkers (Roche Elecsys p‐tau181/Aβ42 and Fujirebio Lumipulse Aβ42/Aβ40 ratios), and apolipoprotein E (APOE) allele testing. Amyloid PET interpretations were made by consensus visual review from experienced readers.

Result

All four patients had clinical diagnoses of mild cognitive impairment or mild dementia (Table 1). Two patients had positive CSF p‐tau181/Aβ42 and Aβ42/40 ratios with negative amyloid PET (indicating sparse to no neuritic plaques). Case 1 displayed aphasia (characterized by anomia and deep dysgraphia) and imaging findings possibly compatible with semantic dementia. Case 2 displayed a gait abnormality and imaging signs of abnormal CSF dynamics. Two other patients had negative CSF p‐tau181/Aβ42 measures with positive amyloid PET (indicating moderate to frequent neuritic plaques). In those instances, the clinical syndrome and imaging studies were strongly supportive of AD and the CSF Aβ42/40 ratio was “likely positive” (Table 1). For one patient (Case 4), tau PET and Lumipulse plasma p‐tau217 concentration were both positive.

Conclusion

Clinicians prescribing anti‐amyloid therapies should be aware of the possibility for CSF biomarkers to be discordant from amyloid PET status in select scenarios. These cases highlight the value of considering PET imaging in the presence of clinically atypical features, concern for mixed etiology, or strong clinical suspicion for AD despite negative CSF biomarkers. Larger series are needed to identify broader patterns contributing to biomarker discordance by assay, modality (PET versus CSF/plasma measures), and medical/neurologic comorbidities.
Air pollution diesel particles decrease synaptosomal post‐synaptic but not pre‐synaptic proteins in mouse cortex
Authors: Godoy‐Lugo Jose A , Thorwald Max A , Sioutas Constantinos , Mack William J , Finch Caleb E
Published: January 2025

Background

Chronic air pollution exposure increases accelerates cognitive aging and AD risk. Synapse loss in AD correlates with decreased cognitive ability. In rodents, inhaled air pollutants decreased glutamatergic synapses, decreasing excitatory postsynaptic currents (EPSCs), while increasing total levels of AMPA and NMDA receptor protein. To further resolve air pollution effects in these synaptic components, we examined synaptosomal proteins from mice exposed to diesel exhaust particles (DEP).

Method

C57BL/6 mice were exposed to re‐aerosolized DEP (n = 12, 100 µg/m3; NIST 2975) or filtered air (FA, n = 12) for 5 h/day for 8 weeks. Synaptosomes were isolated by centrifugation from cerebral cortex and proteins analyzed by immunoblots.

Result

DEP exposure decreased synaptosomal PSD95 by ‐30% and Homer1, and SAP97 by ‐20%. Also decreasing NMDA receptor subunits GluN1 and GluN2A by ‐20%. In contrast, DEP did not alter pre‐synaptic vesicle proteins SNAP‐25, SYN1, SYT1, and SYP.

Conclusion

Mechanisms behind early synapse disfunction after exposure to air pollution may relate to greater decreases in post‐synaptic than the pre‐synaptic proteins we assayed at the synapse. Future studies will evaluate the hippocampus, which has shown selective impact in CA1 neurons EPSCs, and the role of air pollution‐induced oxidative damage at synapse cites.
Altered Brain Effective Connectivity in MCI during Object‐Location Associations: an fMRI Study
Authors: Sun Boxin , Deng Jinxian , Scheel Norman , Bhaumik Arijit K , Ren Jian , Hampstead Benjamin M. , Li Tongtong
Published: January 2025

Background

Existing work suggests that Alzheimer’s disease (AD) pathology can affect the direction and intensity of information signaling in functional brain regions. This study aims to explore how mild cognitive impairment (MCI) can affect the brain effective connectivity.

Method

We used an event‐related functional magnetic resonance imaging (fMRI) paradigm to compare patients with aMCI and healthy controls with normal cognition (NC) as they encoded 90 ecologically‐relevant object‐location associations (OLAs). Two additional OLAs, repeated a total of 45 times, served as control stimuli. Memory for these OLAs was assessed following a 1‐hour delay. The groups were well matched on demographics and brain volumetrics. A total of 44 right‐handed participants (19 NC, 25 aMCI, age mean: 71.5) completed this study.

We evaluated the effective connectivity between all the possible functional brain region pairs using causalized convergent cross mapping (cCCM), which measures the intensity of directional information transfer between the brain regions.

Result

The region pairs where the effective connectivity (in terms of cCCM values) of NC and MCI exhibit the largest, statistically significant differences (p‐value < 0.05) are shown in Figure 1, and the result for the visuospatial network alone is shown in Figure 2. Our analysis shows that during the encoding of ecologically relevant object‐location associations, MCI demonstrated statistically significant reduction in effective connectivity (p‐value < 0.05) across some regions, but also showed increased effective connectivity across other regions.

Conclusion

The increased effective connectivity of MCI in some regions indicates the presence of detours in information transfer due to the weakening of connectivity in other regions and may reflect the compensatory mechanism of the brain.
Reproducibility of Centiloid Values in Real‐World Amyloid PET Data: Comparison of the Imaging Dementia‐Evidence for Amyloid Scanning (IDEAS) to Four Large Research Datasets
Authors: Blazhenets Ganna , Zeltzer Ehud , Lagarde Julien , Landau Susan M. , Koeppe Robert A. , Carrillo Maria C. , Dickerson Bradford C. , Apostolova Liana G. , Jagust William J. , Rabinovici Gil D. , Joie Renaud La ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Published: January 2025

Background

The Centiloid framework was developed to harmonize amyloid‐PET quantification across radiotracers and processing pipelines to facilitate data sharing and merging; it is now widely used across research and clinical trials. As we just completed the quantification of 10,361 amyloid‐PET scans from the largest “real‐world” study of amyloid‐PET (IDEAS) and are about to release the data, we aimed to compare the distribution of IDEAS Centiloid values with other available datasets.

Method

In IDEAS, amyloid scans were acquired across 343 facilities and centrally processed at UCSF using a PET‐only pipeline. We also had access to PET data from our own UCSF Alzheimer’s Disease Research Center and the LEADS study. Using the GAAIN platform, we identified two other cohorts with available Centiloids: ADNI and MCSA. For each cohort, we collected Centiloids, demographic, and basic clinical data. Gaussian mixture models (GMM) were fitted to Centiloid values for each cohort, and data‐driven Centiloid cutoffs were calculated as mean + 2SD of the first Gaussian. Finally, we compared Centiloids to PET visual reads (when available) and determined the Centiloid cutoff value maximizing correspondence between visual read and binarized Centiloids based on Cohen’s kappa.

Result

The 5 cohorts were heterogeneous in terms of sample characteristics and radiotracers (Table 1). In all cohorts, a two‐Gaussian model was considered the best fit for the data based on the integrated completed likelihood criteria (Figure 1). The first Gaussian peaks were close to zero, with mild variability across studies (from ‐5 in IDEAS to 10 CL in MSCA). The second peak was more heterogeneous across cohorts (from 67 to 102 CL) with a rightward shift in cohorts enriched with clinically impaired patients. Mean Centiloid values in visually negative and positive scans generally matched well with results derived from GMM (Figure 2). Across all cohorts, GMM‐based Centiloid cutoffs tended to be slightly lower (18‐26) compared to those based on visual inspection (25‐31).

Conclusion

The availability of Centiloids across cohorts enables a direct comparison of amyloid‐PET results in otherwise different studies. Despite some variability across cohorts and analysis methods, Centiloid cutoffs align well with thresholds from the existing literature.
Metallaphotoredox Enabled Single Carbon Atom Insertion into Alkenes for Allene Synthesis
Authors: Liu Gang , Shi Zhaoxin , Guo Chuning , Gu Danyu , Wang Zhaobin
Published: January 2025

Efficient methods for synthesizing allenes from readily available starting materials pose a persistent challenge in organic chemistry. In this work, we present a novel two‐stage protocol for allene synthesis involving the single‐atom insertion into alkenes, facilitated by synergistic photoredox and cobalt catalysis. Diverging from conventional methods such as the Doering‐LaFlamme reaction, this photochemical rearrangement approach operates efficiently under mild conditions in a radical‐based manner. The protocol exhibits a broad substrate scope and demonstrates applicability in the late‐stage diversification of alkene‐containing natural products and bioactive molecules. Preliminary mechanistic studies and density functional theory (DFT) calculations offer insights into the reaction pathway, indicating a radical mechanism involving fleeting cyclopropyl carbene intermediates followed by rapid ring opening to form allenes.