bluuebunny/crossref_metadata_2025 huggingface dataset:
APOE genotype, cognition and dementia: mediation of ε2 and ε4 effects by structural brain imaging markers in a population‐based study
Authors: Claus Jacqueline Josephine , Rosbergen Mathijs T. , Vernooij Meike W. , Wolters Frank J. , Ikram Arfan
Published: January 2025

Background

Insight into APOE‐mediated pathways is important to unravel pathophysiology and identify therapeutic targets against late‐life cognitive decline and dementia. However, ante‐mortem studies on the mediated effect of APOE on cognition and dementia through different disease markers on structural brain imaging remain scarce, in particular for APOE‐ε2.

Method

We included all dementia‐free participants from the population‐based Rotterdam Study, who routinely underwent cognitive assessment and brain MRI between 2005‐2009, and were followed‐up for incident dementia until 1‐1‐2020. We standardized hippocampal volume (HV) and volume of white matter hyperintensities (WMH), and performed causal mediation analyses to quantify the mediation effects (i.e., natural direct effect, natural indirect effect and percentage mediated) of APOE ε4 and ε2 carriership on cognition operationalized as g‐factor and incident dementia, with ε3/ε3‐carriers as a reference group. We adjusted all models for potential mediator‐outcome confounders (i.e., demographics, education, cardiovascular factors) and for intracranial volume.

Result

Among 5,510 participants (mean age: 65.0[±10.9] years, 55.0% women), 3,244 were ε3/ε3‐homozygotes, 709 ε2‐carriers, and 1,557 ε4‐carriers. During a median 11 years follow‐up, 349 participants developed dementia, of whom 148/1,557 ε4‐carriers (9.5%), 172/3,244 ε3/ε3‐carriers (5.3%) and 29/709 ε2‐carriers (4.1%). APOE‐genotype was not significantly associated with hippocampal volume (Figure 1), whereas those carrying APOE ε2 or ε4 tended to have a slightly higher volume of white matter hyperintensities (Figure 2). In total, 4% of the effect of ε4, and 7% of the ε2‐effect on cognition were mediated by HV. The percentage of the effect on cognition mediated through WMH was 18% for ε4 and 0% for ε2. For incident dementia, there was little to no evidence of mediation by either HV (ε4: 3%; ε3: 0%) or WMH (ε4: 1%; ε3: 0%), which was consistent in sensitivity analyses stratified by duration of follow‐up and by age (≥75 years).

Conclusion

In this population‐based cohort study, we found that one fifth of the effect of APOE‐ε4 on cognition was mediated by WMH, compared to only 4% by lower HV. For dementia, however, we found no significant mediation effects of both HV and MWH, suggesting the involvement of alternative pathways through which APOE exerts its effect on dementia.
Mapping local and distal effects of different neuropathologies on amygdala volume
Authors: Annettesdotter Amanda , Selezneva Katja , Denning Amanda E , Wuestefeld Anika , Ravikumar Sadhana , Ittyerah Ranjit , Levorse Lisa M , Bedard Madigan , Chung Eunice , Robinson John L. , Schuck Theresa , Lee Eddie B , Lim Sydney A , Trotman Winifred , Bahena Alejandra , Irwin David J , Jimenez Maria del Mar Arroyo , Vela Alicia , Buendia Esther , Martin Maria Mercedes Iniguez de Onzono , Rabal Maria del Pilar Marcos , Munoz Monica , Spotorno Nicola , Hansson Oskar , Insausti Ricardo , Yushkevich Paul A. , Wisse Laura E.M.
Published: January 2025

Background

The amygdala is a hotspot for neuropathologies; however, it is unclear 1) which neuropathologies lead to amygdala neurodegeneration, 2) what specific amygdala subnuclei are affected, and 3) if the neuropathologies related to amygdala volume are local (inside the amygdala), or distal (in other regions). We investigate the relationships between different neuropathologies (tau, amyloid‐β [Aβ], α‐synuclein [α‐syn], and transactive response DNA‐binding protein 43 [TDP‐43]) and amygdala volumes.

Method

We analyzed postmortem data from 73 individuals with and without neurodegenerative diseases (age: 77±11 [45–101] years; 26 [36%] females; 51 [70%] cognitively impaired). Volumes of the whole amygdala and three amygdala subregions (lateral, B/Ab [basal/accessory basal], Co/Me/Ce [cortical/medial/central] nuclei: for n=24 individuals) were manually segmented on 0.2x0.2x0.2 mm3 postmortem magnetic resonance images (Figure 1). We used semiquantitative scores (0–3) of Aβ, tau, α‐syn, and TDP‐43 in the amygdala, the dentate gyrus (DG), the Cornu Ammonis 1 and subiculum (CA1/SUB), the entorhinal cortex (ERC), and averaged between the medial temporal lobe (MTL) regions (excluding the amygdala). Partial Spearman correlations were performed to investigate the relationships between neuropathologies and amygdala volumes, adjusting for age, sex, and other pathologies.

Results

Higher ratings of amygdala TDP‐43, MTL TDP‐43, and MTL tau were associated with smaller whole amygdala volume (Figure 2A–B, Figure 3A). However, MTL TDP‐43 was no longer significant when adjusting for amygdala TDP‐43 (Figure 3B). As MTL tau was associated with amygdala volume, we looked into which MTL subregions could be responsible for this association. Here, tau in DG, CA1/SUB, and ERC were all negatively associated with whole amygdala volume (Figure 2B). For exploratory subregional analyses, amygdala α‐syn was initially associated with B/Ab volume (Figure 2C, Figure 3C), but this correlation did not survive FDR‐correction.

Conclusions

These preliminary results indicate that TDP‐43 has a local effect on whole amygdala volume, whereas tau seems to affect amygdala volume distantly through other MTL regions, with the largest effect seen in DG tau, followed by CA1/SUB and ERC. Subregional analyses will be updated once a larger sample is available, as well as further analyses on non‐MTL regions.
Mechanistic Insights of Gamma Sensory Stimulation: CSF Proteomic Analyses Reveal Changes in Myelin and Synaptic Proteins
Authors: Shpokayte Monika , Pandey Kiran , Singer Annabelle C , Doung Duc , Lah James J. , Levey Allan I. , Seyfried Nicholas T , Malchano Zach , Kern Ralph , Hajos Mihaly
Published: January 2025

Background

Preclinical investigations in Alzheimer’s disease (AD) have highlighted the efficacy of gamma sensory stimulation in mitigating AD‐related pathologies. Cognito Therapeutics, Inc. (Cambridge, MA) has designed the Sensory Stimulation System for safe at‐home usage, to induce EEG‐confirmed gamma oscillations as a potential treatment for AD. In the present study, unbiased proteomic analysis of patient derived CSF samples was conducted to characterize the underlying mechanism of action and assess treatment effects of gamma sensory stimulation in AD.

Method

The FLICKER study (NCT03543878) recruited ten participants with MCI due to AD from the Emory Goizueta Alzheimer's Disease Research Center. The trial employed a delayed‐start study design with 4‐ or 8‐week daily gamma sensory stimulation. Cerebrospinal fluid (CSF) was collected at baseline, 4‐ and 8‐weeks and the proteome was analyzed (Emtherapro, Atlanta, GA) using tandem‐mass tag spectrometry. The CSF proteome of participants was mapped to previously established brain‐derived co‐expression modules (Johnson et al. 2022) of AD. Concordant and Discordant proteins were analyzed using Emtherpro’s internal AD proteome database.

Result

A total of 2,785 CSF proteins were detected across all CSF samples. Differential expression analysis of proteins from baseline (N=5) vs. (N=5, 8 weeks) revealed 110 proteins that met the significance threshold. 60 proteins upregulated and 50 proteins downregulated as result of treatment. Treatment significantly impacted CSF proteins associated with AD‐related brain modules, including synapses, myelination, post‐synaptic density, and neurotransmitter regulation. Two key myelin‐related proteins that showed significant treatment time‐dependent changes over 8‐weeks of treatment were PLP1, a major structural component of myelin, and EV12A, a cell surface receptor primarily found on myelinating oligodendrocytes and precursor cells. Changes are also seen in cell surface receptors and molecules such as TENM3, EPHA7, and DSCAM which are involved in neuronal network failure, neurogenesis, and neuronal plasticity, respectively. Lastly, γSynuclein, a protein linked to neurofilament network integrity and memory dysfunction, exhibited significant decreases over 8 weeks.

Conclusion

This study shows that sensory stimulation induces broad biomarker support, highlighting its impact on myelin changes, synaptic regulation, and network function. These findings contribute to our understanding of the underlying mechanisms of gamma sensory stimulation in the context of AD.
Association between polygenic risk for Alzheimer’s disease and brain structure in children and adults
Authors: He Xiao‐Yu , Wu Bang‐Sheng , Yu Jin‐Tai
Published: January 2025

Background

Alzheimer’s disease (AD), a complex and polygenic disease with a considerable hereditary component (60–80%), is a progressive neurodegenerative disorder characterized by concealed onset, and individuals often have significant cognitive impairment and histopathological changes in the brain before overt clinical diagnosis. However, the correlations between genetic risk for Alzheimer’s disease (AD) with comprehensive brain regions at a regional scale are still not well understood. We aim to explore whether these associations vary across different age stages.

Method

This study used large existing genome‐wide association datasets to calculate polygenic risk score (PRS) for AD in two populations from the UK Biobank (N ∼ 23 000) and Adolescent Brain Cognitive Development Study (N ∼ 4660) who had multimodal macrostructural and microstructural magnetic resonance imaging (MRI) metrics. We used linear mixed‐effect models to assess the strength of the association between AD PRS and multiple MRI metrics of regional brain structures at different stages of life.

Result

Compared to those with lower PRSs, adolescents with higher PRSs had thinner cortex in the caudal anterior cingulate and supramarginal. In the middle‐aged and elderly population, AD PRS had correlations with regional structure shrink primarily located in the cingulate, prefrontal cortex, hippocampus, thalamus, amygdala, and striatum, whereas the brain expansion was concentrated near the occipital lobe. Furthermore, both adults and adolescents with higher PRSs exhibited widespread white matter microstructural changes, indicated by decreased fractional anisotropy (FA) or increased mean diffusivity (MD).

Conclusion

In conclusion, our results suggest genetic loading for AD may influence brain structures in a highly dynamic manner, with dramatically different patterns at different ages. This age‐specific change is consistent with the classical pattern of brain impairment observed in AD patients.
Evaluating Large Language Models (LLMs) in Information Extraction: A Case Study of Extracting Cognitive Exam Dates and Scores
Authors: Zhang Hao , Jethani Neil , Jones Simon , Genes Nicholas , Major Vincent J , Jaffe Ian S , Cardillo Anthony B , Heilenbach Noah , Ali Nadia Fazal , Bonanni Luke J , Clayburn Andrew , Khera Zain , Sadler Erica C , Prasad Jaideep , Schlacter Jamie , Liu Kevin , Silva Benjamin , Montgomery Sophie , Kim Eric J , Lester Jacob , Hill Theodore M , Hill Theodore M , Avoricani Alba , Chervonski Ethan , Davydov James , Small William , Chakravartty Eesha , Grover Himanshu , Dodson John , Brody Abraham A. , Aphinyanaphongs Yindalon , Masurkar Arjun V. , Razavian Narges
Published: January 2025

Background

Large language models (LLMs) provide powerful natural language processing capabilities in medical and clinical tasks. Evaluating LLM performance is crucial due to potential false results. In this study, we assessed ChatGPT and Llama2, two state‐of‐the‐art LLMs, in extracting information from clinical notes, focusing on cognitive tests, specifically the Mini Mental State Exam (MMSE) and Cognitive Dementia Rating (CDR).

Method

We compiled a dataset consisting of 765 clinical notes mentioning MMSE and CDR. 22 medically trained experts provided the ground truth. ChatGPT (GPT‐4, version “2023‐03‐15‐preview”) and Llama2 (“Llama‐2‐70b‐chat”) were used to extract MMSE and CDR instances with corresponding dates. Inference was successful for 742 notes. We used 20 notes for fine‐tuning and training the reviewers. The remaining 722 were assigned to reviewers, with 309 assigned to two reviewers simultaneously. Precision, sensitivity, true/false negative rates, and accuracy were calculated. For double‐reviewed notes, we qualitatively assessed the errors.

Result

The patient and note characteristics can be found in Table 1. For MMSE information extraction, ChatGPT (vs. Llama2) achieved accuracy of 83% (vs. 66.4%), sensitivity of 89.7% (vs. 69.9%), true‐negative rates of 96% (vs 60.0%), and precision of 82.7% (vs 62.2%). For CDR the results were lower overall, with accuracy of 87.1% (vs. 74.5%), sensitivity of 84.3% (vs. 39.7%), true‐negative rates of 99.8% (98.4%), and precision of 48.3% (vs. 16.1%). We qualitatively evaluated the MMSE errors of ChatGPT and Llama2 on double‐reviewed notes. Llama2 errors included 27 cases of total hallucination, 19 cases where other scores were reported instead of MMSE, 25 missed scores, and 23 cases where the wrong date was reported for the right score. In comparison, ChatGPT’s errors included only 3 cases of total hallucination, 17 cases of wrong test reported instead of MMSE, and 19 cases of reporting a wrong date.

Conclusion

ChatGPT exhibited high accuracy in extracting MMSE scores and dates, with better performance compared to Llama2. The use of LLMs could benefit dementia research and clinical care, by identifying eligible patients for treatments initialization or clinical trial enrollments. Rigorous evaluation of LLMs is crucial to understanding their capabilities and limitations.
Examining early cerebral amyloid beta and tau accumulation in association with cognition in a predominantly middle‐aged cohort
Authors: Gonzales Mitzi M. , O’Donnell Adrienne , Ghosh Saptaparni , Thibault Emma G , Tanner Jeremy A. , Satizabal Claudia L , Decarli Charles , Fakhri Georges El , Johnson Keith A , Beiser Alexa S , Seshadri Sudha , Pase Matthew P.
Published: January 2025

Background

In older adults, greater amyloid (Aβ) and tau positron emission tomography (PET) binding is associated with cognitive decline and dementia. However, the association of early amyloid and tau PET accumulation with cognition at midlife remains unclear. The goal of the current study was to evaluate the associations of Aβ and tau PET with cognition in a predominately middle‐aged community‐based cohort, as well as to examine the factors that may modify these associations.

Method

Participants from the observational Framingham Heart Study completed cognitive assessments and underwent 11C‐Pittsburgh Compound B (PiB) Aβ and 18F‐Flortaucipir tau PET imaging. Associations of standardized quantitative measures of Aβ (global composite) and tau (five early regions of interest) PET retention with cognition were evaluated using linear regression models. Interactions with age, apolipoprotein ε4 status, and education were examined and stratified analyses were performed where interactions were significant. All statistical tests were two‐sided and were FDR‐corrected to account for multiple comparisons

Result

The sample included 423 participants (mean age 57±10 years, 50% female, Table 1). There were no significant associations between Aβ or tau and cognition in the overall sample after correcting for multiple comparisons (Table 2). Stratified analyses indicated a significant association between higher fusiform gyrus tau and poorer visuospatial function in those younger than 55 years (b=‐0.27, 95% CI ‐0.46 to ‐0.07, p=0.007) and associations between higher inferior and middle temporal tau with poorer visuospatial function in those without a college degree (inferior temporal b=‐0.25, 95% CI ‐0.02 to 0.41, p=0.01, middle temporal b=‐0.25, 95% CI ‐0.22 to 0.0, p=0.02).

Conclusion

The continuous range of amyloid beta and tau accumulation at midlife was not cross‐sectionally associated with cognition. However, the findings suggest that higher tau accumulation at younger ages or in the context of lower cognitive reserve may increase vulnerability for poorer cognition as early as midlife.
Novel MRI method enables in vivo quantification of pre‐atrophic neurodegeneration in a mouse model of Alzheimer’s Disease
Authors: Tomaszewski Michal R , Sukstansky Alexander L , Haley Hyking D , Meng Xiangjun , Miller Corin O , Yablonskiy Dmitriy A.
Published: January 2025

Background

Robust methods are needed for preclinical evaluation of novel Alzheimer Disease (AD) therapies to accelerate drug discovery. Quantitative Gradient Recalled Echo (qGRE) MRI shows significant promise to provide insight into neurodegeneration in AD prior to atrophy development in humans, with qGRE R2t* metric (tissue‐specific subcomponent of R2*) highlighting areas of low neuronal density (doi:10.3233/JAD‐210503). In this study a novel qGRE method is shown to non‐invasively measure the longitudinal neuronal loss in the hippocampus of a mouse model of AD tauopathy Tg4510.

Method

Tg4510 (n=15) and wild type (WT, n=7) mice underwent MRI (7T field strength) at 3, 5, 6, 7 months old (WT at 3 and 5mo only). Mice were isoflurane‐anesthetized to minimize BOLD contribution to R2* signal. 3D Multi‐GRE sequence was used to generate R2* maps. Light‐sheet microscopy of the brains stained with NeuN and MBP was used to visualize neuronal nuclei and myelin content respectively.

Result

Significant decrease in NeuN staining between 3mo and 6mo was observed in the hippocampus of Tg4510, indicating a decrease of over 30% in neuronal density (p<0.001, Figure 1), validating the mouse model. Longitudinal analysis showed clear changes in R2* values in the Tg4510 hippocampus undergoing neurodegeneration between 3 and 5 months old (Figure 2). Histogram analysis revealed patterns of increase in low R2* value (Dark Matter, DM), and broadening of R2* distribution. These were quantified as significant increase in both DM Volume Fraction (DMVF) and R2* Standard Deviation (SD) in Tg4510 mice (Figure 3, p=0.004/p=0.016 DMVF/SD) but not in WT controls (p>0.25). Further monotonical increase was also observed in both metrics in time. A significant negative correlation was observed between myelin content and the DMVF (p=0.01, r=‐0.76) in the hippocampus, suggesting sensitivity of the technique to the loss of myelinated axons.

Conclusion

In this study a method is proposed for using R2* relaxometry as a direct biomarker of the neuronal loss. Low R2* volume fraction (DM) and the heterogeneity of R2* both show high sensitivity for capturing longitudinal neurodegeneration. The presented technique, together with accompanying histological validation can be readily applied in preclinical models of neurodegeneration for pharmacodynamics and mechanism of action assessment.
The Association Between Neuroticism and Global Cognition is Mediated by Negative Affect: Findings from the I‐CONECT Study with Socially Isolated Older Old
Authors: Yu Kexin , Wu Chao‐Yi , Gatchel Jennifer R. , Dodge Hiroko H
Published: January 2025

Background

Personality traits are long‐standing characteristics of behavior and emotion. Personality might influence cognitive health in later life by affecting responses to stressful events and engagement in cognitively stimulating activities, such as interpersonal interaction. The current study examined associations between personality traits and cognition in late life, and potential mediation by positive and negative emotion, depression, and social connectedness.

Method

We used baseline data from the Internet‐Based Conversational Engagement Clinical Trial (I‐CONECT) study. The I‐CONECT study recruited socially isolated older adults who were 75+ and were either cognitively unimpaired (CU) or had mild cognitive impairment (MCI). Big‐5 personality traits (neuroticism, extraversion, agreeableness, conscientiousness, and openness) were measured with the NEO‐FFI Personality Inventory. Global cognition was assessed with the Montreal Cognitive Assessment (MoCA); depressive symptoms with the 15‐item Geriatric Depression Scale, social connectedness with the 6‐item Lubben Social Network Scale (LSNS‐6), and emotional characteristics (negative affect, social satisfaction, and psychological wellbeing domains) with the NIH Toolbox‐emotion battery (NIHT‐EB). We ran general linear models to identify which Big‐5 personality traits were related to the MoCA score and to establish relationships between the Big‐5 personality trait and proposed mediators. Then, we ran mediation analyses. All analyses controlled for age, sex, and education. Sensitivity analysis included MCI status as a covariate.

Result

The analytical sample included 146 participants (female 69.2%, mean age 81.1 years, mean education 15.2 years, MCI 56.2%). Out of the five personality traits, only Neuroticism was related to MoCA (Path c, β = ‐0.08, p = 0.05). The mediation analysis showed that negative affect mediated the association between Neuroticism and MoCA (coefficients in Figure 1). Controlling for MCI did not change the model results. All the other mediators, including GDS‐15, LSNS‐6, and social satisfaction and psychological wellbeing did not mediate the relationship.

Conclusion

The neuroticism trait in socially isolated older adults was associated with worse global cognition, and this relationship was mediated by symptoms of negative affect. Results suggest that the NIHTB‐EB may capture symptoms of negative affect distinct from the GDS‐15. Behavioral health interventions aimed at delaying cognitive decline could consider addressing negative affect for individuals with high neuroticism traits.
Independent and interactive contributions of cerebrovascular disease, neuroinflammation, and tau pathophysiology to Alzheimer’s disease‐related diagnostic conversion in adults with Down syndrome
Authors: Edwards Natalie C. , Lao Patrick J. , Alshikho Mohamad J. , Rizvi Batool , Aguilar Lisi Flores , Petersen Melissa , O'Bryant Sid E. , Tudorascu Dana , Handen Benjamin L , Gutierrez Jose , Wilcock Donna M. , Head Elizabeth , Brickman Adam M.
Published: January 2025

Background

By age 40 years, adults with Down syndrome (DS) develop Alzheimer’s disease (AD) pathology and progress to dementia in their 60s. Despite minimal systemic vascular risk factors, individuals with DS have MRI evidence of cerebrovascular injury that progresses with AD severity, suggesting an intrinsic vascular component to DS‐AD that may interact with neuroinflammatory processes to promote tau pathology and cognitive decline. In the current study we examined whether cerebrovascular disease (CVD) burden and inflammation/astrocytosis independently and interactively were associated with incident diagnosis among adults with DS.

Method

This study included 149 participants from the Alzheimer Biomarkers Consortium – Down Syndrome (baseline mean age[SD]=44.6[9] years) with available baseline MRI, plasma biomarker data, and at least two time‐points of clinical consensus diagnosis data (i.e., cognitively stable, mild cognitive impairment [MCI], and clinical AD) who were classified as cognitively stable or MCI at baseline. Logistic regression models assessed if baseline small vessel CVD, operationalized as white matter hyperintensity (WMH) volume, and plasma glial fibrillary acidic protein (GFAP), Aβ42/Aβ40, p‐tau217, and neurofilament light (NfL) concentrations are associated with conversion from a milder diagnosis to a more severe clinical diagnosis. Mediation models examined relationships between biomarkers and diagnostic conversion. All models adjusted for study site, sex/gender, latency between visit dates, and age group (below or above/equal to the median age of the sample).

Result

Diagnostic conversion occurred in 26% of the sample. Higher baseline WMH volume (OR 1.08 [1.01, 1.81]), GFAP (OR 1.006 [1.003, 1.01]), and p‐tau217 (OR 20.56 [5.01, 112.43]), but not NfL nor Aβ42/Aβ40 concentrations were associated with higher odds of conversion to more severe cognitive impairment. GFAP concentration mediated the relationship between WMH and diagnostic conversion (ACME 0.05 [0.01, 0.1], p=0.006). P‐tau217 concentration mediated the relationship between GFAP and diagnostic conversion (ACME 0.13 [0.05, 0.23], p=0.004).

Conclusion

Our findings suggest that among individuals with DS, CVD promotes AD‐related clinical progression by increasing astrocytosis which, in turn, promotes tau pathophysiology and downstream MCI and AD incidence. The results implicate CVD and its interface with inflammation as a core feature of AD in DS.
Effect of Smart Ambient Bright Light (SABL) in Nursing Home Residents with Dementia: A Pilot Study
Authors: Jao Ying‐Ling , Wang Julian , Liao Yo‐Jen K , Berish Diane , Boltz Marie , Calkins Margaret
Published: January 2025

Background

Neurobehavioral distress significantly impacts people with dementia. Lighting interventions have shown positive effects in this population, yet most did not accommodate natural daylight. This study developed an innovative, bright light system, the smart ambient bright light (SABL), that provides auto‐controlled, consistent indoor lighting and accommodates natural daylight. This study evaluated the effect of the SABL on neurobehavioral symptoms and affect in nursing home (NH) residents with dementia.

Method

This crossover, cluster randomized control trial recruited residents with dementia and agitation from two NHs in Pennsylvania. The study had five phases: baseline, intervention, post‐intervention/washout, control, and post‐control/washout. The intervention and control phases were four weeks each, and the intervention sequence was randomly assigned. The SABL was installed in residents’ bedrooms and common areas. Neurobehavioral symptoms and affect were measured at baseline and biweekly. The Neuropsychic Inventory (NPI) was calculated as a total score and four subscales: psychosis hyperactivity, mood, and frontal. Repeated measures analysis of variance were conducted.

Result

27 NH residents completed the study. Participants averaged 87.4 years and were primarily female (74.1%). After controlling for age, dementia stage, and gender, participants’ scores on NPI total (p = 0.007), hyperactivity (p = 0.04), mood (p = 0.03), and psychosis (p = 0.02) were statistically significantly lower during the intervention period as compared to the control period. Participants’ affect did not show a significant difference. No intervention‐related adverse effects were reported. Moreover, NH staff reported favorably that they would like the SABL to be used in their facility with an average rating of 4.1 on a 1‐5 rating scale.

Conclusion

Overall, results suggest that the SABL is well‐accepted and has a positive impact on most neurobehavioral symptoms in NH residents with dementia. Future studies may replicate the study in a larger, more diverse population, examine the intervention fidelity, and establish implementation strategies in NHs.
Decreased entropy of functional MRI signals in individuals with mild cognitive impairment compared to cognitively normal controls
Authors: Neumann Dara L , Tozlu Ceren , Razlighi Qolamreza R , Luchsinger José A. , Stern Yaakov , Devanand Davangere , Kuceyeski Amy
Published: January 2025

Background

Mild cognitive impairment (MCI) is a clinical cognitive deficit that is not severe enough to meet the threshold for Alzheimer's Disease (AD); however, MCI patients have an increased risk of developing AD. Therefore, a diagnosis of MCI may represent a critical turning point in the trajectory of developing AD. Establishing neurological signatures of MCI using network control theory (NCT) may allow more informed diagnosis, and an understanding of its underlying mechanisms could pave the way for novel treatments.

Method

Functional MRI (fMRI) metrics were collected in MCI patients (n = 57, mean age = 66.68) and healthy controls (HC) (n = 500, mean age = 72.25). The average structural connectivity matrix was obtained using age‐matched controls from the Human Connectome Project‐Aging dataset. Commonly recurring brain states were identified via k‐means clustering of activation matrices over 200 regions using the Schafer atlas. NCT was used to compute the transition energy (TE): the minimum energy required to transition between each pair of brain states. The entropy of each region’s activity was calculated using SampEn, and was then correlated with TE using Pearson’s correlation. Pairwise/global (average of all brain state pairs) TE and global entropy (average of all regions) were compared between MCI and HC using ANCOVA with age and sex as covariates.

Result

The brain states identified via k‐means clustering were high and low amplitude activity in the visual, somatomotor, and limbic networks (Figure 1). While there were no significant differences in pairwise or global TE between MCI and HC (Figures 2‐3), MCI had significantly lower global entropy than HC. ANCOVA revealed that increased age is associated with increased entropy. Pearson correlation showed a significant inverse relationship between global TE and entropy across individuals (r = −0.13) (Figure 3).

Conclusion

Entropy of brain activity measured with fMRI is a promising neuroimaging biomarker of MCI, which is often underdiagnosed or diagnosed with delay. Future work will investigate regional entropy reduction patterns between MCI and AD patients to establish the use of these metrics in disease progression, and to get a more detailed picture of brain activity changes in individuals with these diagnoses.
Biological Factors Influencing [18F]MK6240 and [18F]FTP Correlation in Target Regions
Authors: Tissot Cécile , Tsai Hsin‐Yeh , Therriault Joseph , Tudorascu Dana , Rahmouni Nesrine , Servaes Stijn , Stevenson Jenna , Lussier Firoza Z , Pezzoli Stefania , Ziontz Jacob , Gordon Brian A. , Pascual Belen , Lowe Val J. , soleimani‐meigooni David N. , Oh Hwamee , Klunk William E , Rosa‐Neto Pedro , Jagust William J. , Pascoal Tharick Ali , Baker Suzanne L.
Published: January 2025

Background

The association between [18F]Flortaucipir (FTP) and [18F]MK6240, two commonly used tau‐PET tracers in Alzheimer’s disease (AD), varies due to distinct binding properties and off‐target signal regions. Our study aims to elucidate the biological factors influencing this association and evaluate the applicability of a common equation across different on‐target regions.

Method

113 individuals from the HEAD dataset (11 young, 58 cognitively unimpaired elderly, and 44 cognitively impaired) underwent [18F]MK6240, [18F]FTP and Aβ‐PET scans. Images were processed using the inferior cerebellar grey (CG) as the reference region, with subjects categorized by Aβ status. Stepwise linear fitting identified off‐target (OFF) regions impacting tracer associations within the whole cortex, Braak and temporal‐meta regions of interest (ROIs). OFF regions included were a composite mask (pallidum, putamen, caudate ‐ PPC) to address collinearity in subcortical nuclei, as well as the region with the greatest partial volume effects (PVE) on the ROI (meninges, choroid plexus, and the hotspot medial to entorhinal cortices (EC)). Akaike information criteria (AIC) analyses tested linear models with various off‐target regions.

Result

PPC and PVE regions influenced tracer association in on‐target regions. PPC binding is associated with age. PPC and meninges retention, along with Aβ status interaction, demonstrated the best model fit for the whole cortex (Figure 1). Weighting factors derived from the whole cortex model were applied to Braak regions and temporal meta‐ROI. Braak III‐VI and temporal‐meta ROI showed optimal models including OFF regions and Aβ status interaction (Figure 2). Forcing the whole equation gave optimal results. For Braak I (EC), adding the OFF covariates only was the best model. For Braak II (hippocampus), the best model included OFF regions and the interaction with Aβ status (Figure 2). Forcing the whole cortex equation onto Braak I and Braak II yielded suboptimal fits.

Conclusion

Harmonizing tau‐PET tracers involves considering significant covariates. Integrating meningeal and age‐related off‐target regions enhances [18F]MK6240 and [18F]FTP association in on‐target regions, further improved by Aβ status inclusion. While the whole cortex model may not suit early ROI, it proves effective for Braak III and beyond. Creating an equation for tracer translation necessitates incorporating meningeal and subnuclei off‐target retention.
Exploring biological response profiles to amyloid antibodies in clinical practice using Quantitative Systems Pharmacology
Authors: Grant Athena , Short Shaina M , Geerts Hugo
Published: January 2025

Background

With the approval of several anti‐amyloid antibodies and a robust pipeline of new amyloid‐based therapies, attention turns towards questions related to real‐world clinical practice. Here we explore the impact of several biological pathways on the amyloid biomarker response of AD patients using a Quantitative Systems Pharmacology (QSP) approach with the ultimate objective to find measurable biomarkers for responder identification.

Method

Using a well‐validated QSP biophysically realistic model of amyloid aggregation, we performed sensitivity analysis to identify key drivers of amyloid biomarkers both in a longitudinal observational context and after treatment with specific amyloid antibodies. One Factor at a Time (OFAT), Pareto plots and Big Data classification algorithms in large virtual patient trials were used.

Result

Not unexpectedly, in observational studies the major driver of amyloid aggregation (age of decrease in CSF Ab42 and maximal SUVR readout) included parameters of the amyloid aggregation, notably the exponential weighting factor of the aggregate order on the backward (monomer dissociation) rate constants. Smaller contributions of the forward rate constants, synthesis of APP and microglia‐mediated clearance of amyloid species were found.

The same parameter was the major driver of SUVR response in trials with donanemab (dona) versus aducanumab (adu) and lecanemab (leca) with opposite effects on oligomers and protofibrils reduction. In contrast, parameters associated with secondary nucleation and flow from interstitial fluid (ISF) into cerebrospinal fluid (CSF) were driving ARIA‐E lability with opposing directions between adu versus dona and leca versus dona. The contribution of the different processes to the biomarker responses of the three antibodies were smaller in non‐APOE4 patients, except for the ARIA‐E liability where they were more pronounced.

Conclusion

This approach can be used with the pharmacology of different therapies (including novel amyloid antibodies, gamma‐secretase modulators and oligomerisation inhibitors), to identify pathways characterizing individual patient responses.
What makes ‘hard decisions’ hard? Decision‐making in dyads of people living with Alzheimer’s disease and their care partners
Authors: Largent Emily A. , Erickson Claire M. , Gupta Anjali , Kleid Melanie , Harkins Kristin , Stites Shana D. , Peterson Andrew H. , Karlawish Jason , Clapp Justin
Published: January 2025

Background

People living with Alzheimer’s disease and related dementias confront numerous decisions that affect their wellbeing, as well as that of their family members. Research demonstrates the importance of family involvement in such decision making, yet there is a lack of knowledge about how patients and families work together to make decisions and how families can best provide decisional support.

Methods

Semi‐structured interviews were conducted separately with 15 patients diagnosed with mild cognitive impairment (MCI) or mild dementia, identified through a National Institute on Aging‐funded Alzheimer’s Disease Research Center, and 14 care partners. As part of a study of decisional support, interviewees were asked to describe a hard decision they had faced. Data analysis was guided by a constructivist grounded theory approach and consisted of iterative rounds of coding with checks for intercoder reliability.

Results

Patients and care partners most frequently identified the patient no longer driving as a hard decision; other hard decisions included changing the patient’s living arrangements or surrendering responsibility for their finances. Though interviewed separately, dyad members frequently identified the same hard decision. Hard decisions were characterized by tension between the patient’s independence or identity and the safety of the patient or others; the tension was nearly always resolved in favor of safety, particularly safety of others. Despite characterizing these as “decisions,” patients often felt they had no meaningful choice and implied that the outcome was inevitable. Consistent with these findings, both patients and care partners typically indicated that care partners initiated these decisions and denied engaging in substantive deliberation before enacting changes. Patients and care partners described hard decisions as emotionally difficult because they were confronted with the progression of the patient’s disease. Even as they acknowledged the importance of safety, patients grieved their loss of independence and diminished sense of self. Care partners expressed empathy for the patient’s losses and grieved alterations to the relationship.

Conclusions

Hard decisions are associated with undesirable outcomes more than with difficult decision‐making processes. When disease progression necessitates change, patients and care partners grieve even as they acknowledge change is appropriate. They may benefit from others acknowledging this grief.
MicroRNA‐502‐3p, a novel regulator of GABA function in Alzheimer’s disease
Authors: Sharma Bhupender , Torres Melissa , Rodriguez Sheryl , Kumar Subodh
Published: January 2025

Background

In various neurological disorders, including Alzheimer’s disease (AD) and AD‐related dementia, there is a notable reduction in gamma‐aminobutyric acid (GABA)ergic neurons, which represent the most abundant inhibitory neurons in the human brain. This study explores molecular association between miR‐502‐3p and the function of GABAergic neurons in AD.

Method

The investigation commenced by examining the status of GABA receptor proteins and miR‐502‐3p in postmortem AD brains. Subsequent in‐vitro experiments were conducted using the mouse hippocampal neuronal (HT22) cells, transfected with miR‐502‐3p agomiRs and antagomiRs. In‐silico analysis, performed to select miR‐502‐3p potential targets. Thereafter targeting of the GABRα1 gene by miR‐502‐3p were confirmed through a different technique, including QRT‐PCR, western blotting and ELISA, cell viability, miRNA in‐situ hybridization, immunoblotting, and immunostaining techniques were used to confirm the effect of miR‐502‐3p overexpression on the GABRα1 level and GABRα1 proteins.

Result

Reduced levels of GABA receptor subunits correlating with Braak stages were identified in AD postmortem brain samples compared to control. We found upregulated miR‐502‐3p expression in AD postmortem brain samples, correlating with Braak stages. In‐silico analysis, revealed multiple binding sites of miR‐502‐3p at GABRα1 mRNA. The targeting of the GABRα1 gene by miR‐502‐3p were confirmed through luciferase assay, QRT‐PCR, western blotting and ELISA for GABRα1. Elevated miR‐502‐3p levels showed toxic effects on HT22 cells and reduced cell viability. Furthermore, miRNA in‐situ hybridization, immunoblotting, immunostaining and whole cell patch‐clamp analysis confirmed that miR‐502‐3p overexpression (miR‐502‐3p agomiRs) suppressed GABRα1 mRNA and protein levels. Conversely, suppression of miR‐502‐3p (miR‐502‐3p antagomiRs) resulted in the restoration of GABRα1 levels, an increase in GABA current, and an overall enhancement of GABA function. Additionally, enhanced levels of proteins associated with AD were found with miR‐502‐3p overexpression and reduced with miR‐502‐3p suppression.

Conclusion

The study uncovered an inverse correlation between miR‐502‐3p levels and GABA subunit proteins. Notably, inhibition of miR‐502‐3p demonstrated a protective effect on GABA function. Collectively, these findings suggest that miR‐502‐3p could serve as a promising therapeutic target for enhancing GABAergic neuron function in neurological disorders, including AD and AD‐related dementia.
Preparing home health clinicians to educate caregivers of persons living with dementia
Authors: Albrecht Tammi , Endicott Sarah , Kehl‐Floberg Kristen E , Schroeder Molly , Sayavedra Noelia , Mahoney Jane , Carlsson Cynthia M. , Walaszek Art
Published: January 2025

Background

The majority of persons living with moderate to severe dementia live in their homes despite the challenges of increasing care needs as dementia progresses. Caregivers are not prepared to understand and manage common medical concerns, such as incontinence, dehydration, and impaired mobility. Health care clinicians need training and tools to better prepare caregivers for these responsibilities. The goal of this program was to address this need by developing an educational program for home health clinicians who treat and support persons living with moderate to severe dementia in their homes.

Methods

Participants included registered nurses, physical therapists, occupational therapists, speech therapists, and social workers from two home health agencies. Trainings were held throughout a two‐year period. Outcomes measured included clinician knowledge, attitudes, and self‐efficacy gathered via surveys at baseline, immediately after training, and six‐months post‐training. Outcomes measured also included caregiver burden, caregiver self‐efficacy, and use of medical services and community resources gathered via surveys at baseline and six‐months post‐training.

Results

Twenty‐one clinicians were trained; 19 completed the baseline survey and 11 completed the post‐training survey. The clinicians implemented the caregiver training with 29 caregivers; 24 completed the baseline survey and 11 completed the six‐month post‐training survey. Clinicians demonstrated improvements in knowledge and self‐efficacy post‐training. Clinicians experienced significant improvements in attitudes as measured by the Dementia Attitudes Scale post‐training, especially in comfort and familiarity with caring for persons living with dementia. Caregivers reported similar levels of caregiver burden and self‐efficiency at baseline and six‐months post‐training. Caregivers reported overall satisfaction with the training they received from home health clinicians.

Conclusion

Persons living with dementia and their caregivers are impacted by changes in cognition, function, and physical health as dementia progresses. Home health clinicians are well‐positioned to help address these needs. The training provided to clinicians led to improvement in attitudes and confidence in the care of persons with dementia. Family caregivers reported a high level of satisfaction with the training; however, a small sample size and the effects of the COVID‐19 pandemic affected the ability to identify changes in caregiver burden, caregiver self‐efficacy, and use of medical and social services.
Role of ApoE polymorphism in Dementia
Authors: Agarwal Rachna , Kushwaha Suman , Tripathi Chandra Bhushan
Published: January 2025

Background

ApoE polymorphism especially APOE ε4 play a central role in AD pathophysiology through Aβ‐dependent and Aβ‐independent neuropathogenic pathway in the Alzheimer’s disease.

Method

A cross‐sectional study was performed on non diseased and diseased subjects with stroke from outpatient services of Neurology department of Institute of Human Behavior & Allied Sciences (IHBAS), New Delhi (India). Subjects diagnosed with various dementias including Alzheimer’s disease, non AD dementias and dementia with Behavior & Psychological symptoms were taken. APOE genotyping was done in all subjects by ARMS‐PCR method.

Result

The most common allele APOE ε3ε3 was observed across all dementia groups (AD, non AD dementia. Dementia with BPSD & forgetfulness, whereas ε2ε4 was least commonly observed. Multivariable logistic regression analysis showed that the presence of APOE ε4 genotyping is significantly increasing the risk of AD three times more as compared to other alleles (Adjusted Odds Ratio: 3.07, 95% CI: 1.39 ‐ 6.78). The age and gender did not emerge out as significant contributors in AD. In group of AD with BPSD, the most common Behavior & Psychological symptoms observed was paranoid & delusional ideation.

Conclusion

APOE ε4 is a risk factor for Alzheimer's disease.
Parsing disease heterogeneity using normative modelling and Generative Adversarial Networks (GANs)
Authors: Chintapalli Sai Spandana , Govindarajan Sindhuja Tirumalai , Shou Haochang , Huang Hao , Davatzikos Christos
Published: January 2025

Background

Structural and functional heterogeneity in the brains of patients with Alzheimer's disease (AD) leads to diagnostic and prognostic uncertainty and confounds clinical treatment planning. Normative modelling, where individual‐level deviations in brain measures from a reference sample are computed to infer personalized effects of disease, allows parsing of disease heterogeneity. In this study, GAN based normative modelling technique quantifies individual level neuroanatomical abnormality thereby facilitating measurement of personalized disease related effects in AD patients.

Method

We adapt the pix2pix GAN to translate a subject with disease to a corresponding subject without disease. We train this model using a dataset comprising of healthy controls and synthetically simulated patients. Healthy controls (n=6000) are selected from the ISTAGING consortium. Our neuroanatomical brain measures are the 10 region of interest (ROI) volumes (covering left and right frontal, parietal, occipital, temporal lobes as well as deep brain structures) computed using a multi‐atlas segmentation technique. To simulate patients, for each healthy control we introduce 10‐30% atrophy or expansion in a random combination of ROIs while preserving clinical covariate effects. The model learns to synthesize patient‐specific controls by removing disease‐related variations from patient’s brain measures (Figure 1). Deviation of the patient from the synthesized disease‐free control acts as an image‐based biomarker that is sensitive to disease effects and severity. For performance assessment, we select 200 controls (CN) and 200 AD participants (PT) from the OASIS dataset and compute their deviations across the 10 ROI volumes using the model pretrained on the ISTAGING dataset. Logistic regression is used to assess the overall discriminative power of the derived deviations in AD classification.

Result

Larger deviations in PT compared to CN suggest disease related abnormality in brain measures (Figure 2.a). Additionally, GAN’s deviations provide a considerable gain over raw ROI volumes in AD classification as quantified using the 5‐fold AUC scores (Figure 2.b).

Conclusion

GAN‐based normative modelling technique introduced here is a useful tool to parse heterogeneity in brain measures at an individual level. We see that self‐supervised training of the model using pseudo‐synthetically simulated patient data that is agnostic to disease patterns can help detect real disease related effects.