bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigating the synaptic trafficking of AD Biomarker Neuronal Pentraxin 2: Implications for Interneuron and Cholinergic Circuit Dysfunction in Alzheimer’s Disease
Authors: Roh Seung‐Eon , Swartzlander Mira , Cheong Kathryn , Worley Paul F
Published: January 2025

Background

Deficits in interneuron and cholinergic circuits are noted in AD pathology, yet the precise mechanisms of their contribution to cognitive decline in the disease remain elusive. Neuronal Pentraxin 2 (NPTX2), a sensitive marker for synaptic activity and AD progression, is an immediate early gene expressed by pyramidal neurons that functions at excitatory synapses on Parvalbumin interneurons (PV‐IN) to cluster AMPA receptors and strengthen circuit inhibition. NPTX2 is later shed from some synapses into the cerebrospinal fluid (CSF), where reduced NPTX2 levels inversely correlate with hippocampal volume and cognitive performance in individuals with AD/MCI. Recent studies employing NPTX2‐SEP (Super‐Ecliptic pHluorin) as a marker of its synaptic trafficking have suggested that the diurnal oscillation of NPTX2 trafficking is important for circuit refinement, which is crucial for ensemble formation and memory updating.

Method

We aim to investigate the mechanisms of NPTX2 synaptic trafficking by utilizing two‐photon imaging of NPTX2‐SEP in the somatosensory cortex while chemo‐ and optogenetically manipulating PV‐IN and cholinergic circuits, specifically the basal forebrain (BF) and cortical intrinsic cholinergic neurons.

Result

We found that reducing PV‐IN activity leads to rapid shedding of NPTX2, whereas increasing PV‐IN activity results in elevated accumulation of NPTX2 at excitatory synapses on PV‐IN. This suggests that PV‐IN activity is a critical determinant for NPTX2 synaptic exocytosis and shedding and supports a model akin to spike‐timing‐dependent plasticity, wherein synapses are strengthened with correlated pre‐ and postsynaptic activity and weakened when presynaptic activity is not associated with postsynaptic activity. Direct activation of BF cholinergic neurons had minimal effect on NPTX2‐SEP. However, consistent with the observation that activation of nicotinic and muscarinic ACh receptors (AChR) can respectively increase and decrease cortical PV‐IN activity, chemogenetic activation of BF cholinergic neurons with mAChR blocker induced NPTX2 shedding, while nicotine also moderately induced its shedding. Additionally, chemo‐ and optogenetic activation of cortical intrinsic cholinergic interneurons reduced PV‐IN activity and induced NPTX2 shedding.

Conclusion

These results underscore the significant roles of the ACh‐PV pathway in regulating NPTX2 synaptic trafficking and implicate deficits in NPTX2 shedding and circuit refinement due to the failure of the ACh‐PV pathway as a mechanism for cognitive decline in AD.
Neuropsychiatric symptoms and associated structural neuroimaging correlates in Mild Cognitive Impairment
Authors: Leung Cheryl Cheuk Yan Y
Published: January 2025

Background

Neuropsychiatric symptoms (NPS) are behavioural and psychological manifestations frequently present in dementia and mild cognitive impairment (MCI). NPS are known to be associated with adverse health, cognitive and functional outcomes and increasing needs for hospitalisation and institutionalisation. It is understood that MCI may be an intermediate stage between healthy and dementia states. Therefore, NPS‐related brain alterations found at this prodromal phase may provide insights into the pathophysiology of the symptoms and act as potential biomarkers for future prognosis.

Method

By conducting a single‐centre cross‐sectional study of thirty MCI patients from South London and Maudsley NHS services, participants have undergone demographic and clinical interviews, cognitive and neuropsychiatric assessments using the Clinical Dementia Rating, Standardised Mini‐Mental State Examination, and the Neuropsychiatric Inventory ‐ Clinician Rating Scale, as well as 3 Tesla MRI scans. Cognitive, clinical and demographic data for MCI participants with and without specific NPS symptoms have been compared and using a whole brain analysis approach neuroanatomical regions showing correlations between grey matter (GM) volume and NPS symptom severity scores have been identified.

Result

There is some evidence that higher delusion and hallucination severity scores correlate with reduced GM volume in crus I/II of the cerebellum bilaterally, potentially indicating Dementia with Lewy Bodies (DLB) pathology. Furthermore, it has been found that higher aggression severity scores are significantly correlated with greater GM volumes in the calcarine and pallidum regions, and higher irritability severity scores are significantly correlated with greater GM volumes in bilateral anterior cingulate cortex (ACC) and right middle frontal gyrus. An unexpected finding is that the majority of the GM regions of interest (ROIs) appear to have positive correlation with NPS severity scores.

Conclusion

Structural magnetic resonance imaging (MRI)‐based neuroanatomical correlates for a variety of NPS symptoms were found, even as early as the MCI stage of dementia. The unexpected positive correlation between NPS severity and GM for many NPI‐C domains points to possible GM hypertrophy or relative GM sparing associated with NPS. Such volumetric changes may form a distinct recognisable pattern, with potential to increase the specificity of structural MRI biomarkers in predicting future clinical outcomes in MCI.
Cognitive Frailty as a Distinct Construct: Differential Risk Factors and Reversibility
Authors: Tay Laura , Tay Ee Ling , Mah Shimin , Ng YeeSien
Published: January 2025

Background

Cognitive frailty (CF) has been proposed as a state of reduced cognitive reserve that is intermediate between age‐related cognitive changes and neurodegenerative diseases. We aim to examine (i) whether cognitive frailty presents with risk factors distinct from isolated phenotypes of physical frailty and cognitive impairment, (ii) reversibility of cognitive frailty subtypes.

Methods

Participants were older adults aged >60 years from a community frailty screening programme. Physical frailty was assessed using Fried phenotype. Cognitive status was assessed based on response to a single question on memory symptoms and performance of the modified Chinese version of Mini‐Mental State Examination (CMMSE). All participants completed assessments for social vulnerability, mood, comorbidities, functional performance, sensory problems (hearing, vision), nutritional status, and sarcopenia. Each participant was classified into one of the diagnostic groups: reversible cognitive frailty (rCF) defined as subjective cognitive decline with prefrailty/ frailty; potentially reversible cognitive frailty (pCF) defined by mild cognitive impairment co‐existing with prefrailty/ frailty; (iii) isolated prefrailty/ frailty (PF); isolated cognitive impairment (CI); robust‐cognitively intact. Participants were followed at 1 year for frailty and cognitive status.

Results

Among 961 participants, 351 (36.2%) were robust‐cognitively intact, 112 (11.7%) had rCF, 56 (5.8%) had pCF, 279 (29.0%) had isolated PF, and 163 (17.0%) had isolated CI. Depression increased risk for both CF subtypes (rCF: RRR 17.59; pCF: RRR 7.97; p<0.001), isolated PF [RRR 4.72 (2.76, 4.31)], and isolated CI [RRR 4.85 (2.11, 11.12)]. Sarcopenia was significantly associated with CF (rCF: RRR 15.12; pCF: RRR 14.20; both p<0.001) and isolated PF [RRR 16.13 (5.61, 46.40)]. Visual impairment was significantly associated with rCF [RRR 2.40 (1.26, 4.59)] and isolated CI [RRR 2.01 (1.16, 3.45)], while hearing impairment was associated with isolated PF [RRR 1.75 (1.00, 3.76)]. Education was protective against CF and isolated CI, while participation in social/ community activities was protective against PF only. At 1‐year, 25% of rCF and 12.5% of pCF reverted to being robust‐cognitively intact.

Conclusion

Depression is a common risk factor across cognitive frailty subtypes and isolated phenotypes of physical frailty and cognitive impairment. Sarcopenia may contribute to cognitive frailty through physical frailty.
Differential network‐based propagation of cortical thinning in atrophy subtypes in non‐demented individuals
Authors: Lorenzini Luigi
Published: January 2025

THIS IS A RESUBMISSION OF A PREVIOUSLY SUBMITTED ABSTRACT ALREADY ACCEPTED, NEEDED FOR FELLOWSHIP APPROVAL

Background

Different patterns of atrophy exist in the dementia stage of AD. However, little is known about the heterogeneity of atrophy patterns and the mechanisms that drive subsequent propagation of the disease in the preclinical stages.

Method

From the AMYPAD‐PNHS cohort, we included a total of 1323 non‐demented individuals, including 1094 amyloid‐negative, and 229 amyloid‐positive participants (Table 1). Gray matter thickness in 100 regions of interest was measured using FreeSurfer. Global cortical amyloid burden was derived from amyloid PET scans in Centiloids (CL).

Individuals were assigned to atrophy subtypes based on cortical thickness measures using Non‐Negative Matrix Factorization (Figure 1). Multinomial regression models were used to study differences between subtypes in age, sex, global CL and APOE E4 carriership. Linear regression models were used to investigate the effect of time on atrophy within each subtype. Coordinated deformation models (Figure 1, Shafiei et al. 2023) were used to estimate network‐based thickness changes in each region, by multiplying the effect of time in connected regions by the strengths of their connections. Connectivity strength was based on templates of functional, structural and morphometric similarity networks, and allowed us to evaluate differential mechanisms. Significance was tested using a permutation approach.

Results

Three significant subtypes of regional GM atrophy were identified:‘limbic predominant’, ‘typical AD’, and ‘diffuse cortical’ (Figure 2). Individuals assigned to the limbic predominant subtype were significantly older, while the typical AD subtype had more APOE E4 carriers compared to the others (all p<0.001). Both limbic predominant and typical AD subtypes had higher CL compared to the diffuse cortical atrophy subtype (all p<0.001). Significant longitudinal thickness changes per subtype are shown in Figure 2. In the typical AD subtype, all network architectures constrained longitudinal GM changes (p<0.001), while in the diffuse atrophy subtype, propagation was mostly determined by morphometric similarity (p<0.005). No significant prediction model was found for the limbic predominant subtype.

Conclusion

We show that atrophy subtypes can already be detected in non‐demented individuals. Progression of atrophy within subtypes is determined by network‐based mechanisms.
Cognitive clusters in sporadic early‐onset Alzheimer’s disease patients from the LEADS study
Authors: Logan Paige E. , Lane Kathleen A. , Gao Sujuan , Eloyan Ani , Taurone Alexander , Thangarajah Maryanne , Touroutoglou Alexandra , Vemuri Prashanthi , Dage Jeffrey L. , Nudelman Kelly N. , Carrillo Maria C. , Dickerson Bradford C. , Rabinovici Gil D. , Apostolova Liana G. , Hammers Dustin B. ,   LEADS Consortium
Published: January 2025

Background

Early‐onset Alzheimer’s disease (EOAD) occurs before age 65 and has more diverse disease presentations than late‐onset AD. To improve our understanding of phenotypic heterogeneity among EOAD individuals, we analyzed cognitive scores using data‐driven statistical analysis.

Method

Baseline cognitive data from 286 sporadic EOAD individuals from the Longitudinal EOAD study (LEADS) were transformed to z‐scores using data from 95 cognitively normal (CN) individuals. Cognitive composites were generated for domains of memory, language, speed/attention, visuospatial, and executive function. Residuals from linear regression models on Z‐scores adjusted for age, sex, and education were obtained. Cluster analysis using the Ward method on the cognitive domain residuals was performed and scree plot using the pseudo T‐squared determined the optimal number of clusters for the EOAD sample. We also compared gray matter density (GMD) of each EOAD cluster to CN participants using voxel‐wise multiple linear regressions.

Results

Three clusters of cognitive performance were identified from the EOAD sample. Disease duration was not significantly different across clusters. Using a z‐score of ‐1.5 SD as the impairment threshold, all clusters were impaired across most domains (Table 1). Cluster‐3 was more impaired than cluster‐2 in all domains (Table 2; all p<.0001), and in all domains except episodic memory compared to cluster‐1 (all p<.01). Cluster‐1 (n = 71; 85.9% amnestic) was most impaired in executive function, visuospatial, and speed/attention. Cluster‐2 (n = 133; 88.7% amnestic) was most impaired in episodic memory. Cluster‐3 (n = 82; 69.5% amnestic) was most impaired in executive function, visuospatial, and speed/attention (Table 1). 3D‐comparisons showed all EOAD clusters had reduced GMD compared to CN. Cluster‐1 and cluster‐3 both showed widespread atrophy, with cluster‐3 being more severe. Cluster‐2 showed the most atrophy in the temporal and parietal lobes (Figure 1).

Conclusion

We identified heterogeneity in cognitive patterns among sporadic EOAD individuals. Cluster‐3 appeared to reflect widespread impairment, and cluster‐2 represented an amnestic‐only presentation. Despite comparable disease duration, some EOAD patients progress faster, while some are more resilient. 3D‐comparisons showed neurodegenerative changes affecting brain regions responsible for respective impaired cognitive functions in each cluster (e.g., cluster‐2 is primarily amnestic‐impaired and has temporoparietal atrophy). Future work should explore amyloid‐PET and tau‐PET burden.
Machine Learning‐Driven Analysis of COVID‐19 Vaccination Effects on Alzheimer’s Disease Progression: A Retrospective Cohort Study
Authors: Fajar Rifaldy , Prihantini Prihantini , Elfiany Elfiany , Putri Sahnaz V
Published: January 2025

Background

Recent evidence suggests a potential link between systemic inflammation induced by viral infections like COVID‐19 and the exacerbation of neurodegenerative processes in Alzheimer’s disease (AD). This study aims to explore the novel idea that COVID‐19 vaccines may offer neuroprotective effects against the progression of AD, leveraging machine learning techniques to analyze multimodal data sets.

Method

We conducted a retrospective cohort study involving 10,000 participants aged 65 and older, with an initial diagnosis of early‐stage AD, from five distinct geographic locations. Participants were divided into two groups: those who received a COVID‐19 vaccine (n = 5,000) and those who did not (n = 5,000), matched for age, sex, comorbidity, and baseline cognitive function. We utilized a combination of machine learning models, including deep learning neural networks and gradient boosting machines, to analyze longitudinal data encompassing genomic profiles, clinical assessments, and neuroimaging data collected over a two‐year period. The primary outcome was the rate of cognitive decline, measured semi‐annually using the Mini‐Mental State Examination (MMSE) and the Alzheimer’s Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog).

Result

The vaccinated group showed a statistically significant slower rate of cognitive decline compared to the unvaccinated group. Specifically, the annual MMSE score deterioration was 1.2 points less in the vaccinated group (95% CI: 0.8‐1.6, p<0.001). Additionally, the ADAS‐Cog progression rate was reduced by 30% (95% CI: 25%‐35%, p<0.001). The machine learning models identified a significant interaction between vaccine‐induced immune response markers and a slower progression of AD‐related neurodegenerative changes in neuroimaging data.

Conclusion

Our findings suggest that COVID‐19 vaccination has a neuroprotective effect in early‐stage Alzheimer’s disease, likely due to reduced systemic and neuroinflammation. This study reveals the potential therapeutic benefits of vaccination in older adults at risk of Alzheimer’s and urges further research to understand the biological mechanisms and long‐term outcomes.
Direct ABCA7 high‐risk allele modulates medial temporal lobe dynamic network flexibility among cognitively healthy older African Americans
Authors: Arnasalam Alyssa , Sheikh Mustafa , Budak Miray , Piaszczynska Wiktoria , Oyono Arcande , Perez José Mojica , Fausto Bernadette A. , Gluck Mark A.
Published: January 2025

Background

The medial temporal lobe (MTL) is the earliest region to display atrophy in Alzheimer’s disease (AD)1. Apolipoprotein E (APOE‐ε4) and ABCA7‐80 (rs115550680), two genes involved in lipid metabolism, are the strongest heritable contributors to AD in African Americans2. However, the longitudinal influence of these genes on MTL dynamic network flexibility, a novel neuroimaging marker of preclinical AD, is unknown. This study investigated the influence of APOE‐ε4 and ABCA7‐80 high‐risk alleles on MTL dynamic network flexibility longitudinally among cognitively healthy older African Americans.

Method

135 participants (Age≥60, Meanbaseline age = 68.07, SDbaseline age = 7.31, Meaneducation = 13.56, SDeducation = 2.99) from the longitudinal study, Pathways to Healthy Aging in African Americans conducted at Rutgers University–Newark, completed saliva collection for genotyping and ≥1 neuroimaging visits across 4 years. Associations between APOE‐ε4 and ABCA7‐80 on MTL dynamic network flexibility across time were assessed using linear mixed models.

Result

At baseline, the APOE‐ε4 allele had no significant relationship with MTL Dynamic Network Flexibility (ß = 0.034, p = 0.297), whereas ABCA7‐80 was significantly associated with MTL Dynamic Network Flexibility (ß = ‐0.124, p = 0.003). The ABCA7‐80 x time interaction was significantly associated with MTL Dynamic Network Flexibility (ß = ‐0.074, p = 0.029), while there was no such significant ApoE‐ε4 x time interaction (ßApoE*Instance = ‐0.017, pApoE*Instance = 0.53).

Conclusion

There were baseline and longitudinal differences on MTL dynamic network flexibility between ABCA7‐80 but not APOE‐ε4 risk groups among cognitively healthy older African Americans. ABCA7‐80 may have greater influence than APOE‐ε4 in the early MTL network changes associated with AD risk in older African Americans.
Enhancing Early Detection of Mild Cognitive Impairment Using Preprocessed Connected Speech and Natural Language Processing
Authors: Lu Chingching , Wang Pei‐Ning
Published: January 2025

Background

Early detection is crucial for the timely intervention and management of dementia, potentially slowing its progression. Early stages of dementia might only subtly affect communication, yet connected speech analysis can detect these minor anomalies. Cognitive tests involving connected speech, like the Boston Diagnostic Aphasia Examination’s (BDAE) “cookie‐theft” picture description task, are pivotal in detecting dementia. However, previous research typically treats their responses as a whole.

Method

This study preprocesses connected speech from the “cookie theft” task to facilitate AI‐driven detection improvements. We analyzed narratives from 54 normal subjects, 26 with MCI, and 38 with Alzheimer’s Disease (AD), focusing on nine major concepts to quantify accuracy across groups.

Result

Differences in concept accuracy were significant even among normal individuals. A detailed analysis revealed that concepts 3 and 1 were particularly effective in differentiating between normal individuals and those with cognitive impairments, and between MCI and AD. Concepts 2, 3, and 7 were crucial for distinguishing between normal and MCI subjects. Concepts 4, 5, 8, and 9 showed no discriminatory power.

Conclusion

Advances in technology, particularly in natural language processing (NLP), allow for the automated analysis of connected speech. It can provide quick and reliable assessments. By categorizing and preprocessing speech data before AI analysis, our approach enhances the model’s predictive accuracy for early‐stage dementia detection. It can also help for developing more diagnostic images and cognitive training exercises. Furthermore, it does not require expensive equipment or invasive procedures, making it accessible for widespread use in various settings, including community centers and primary care, and particularly beneficial for regular monitoring.
Patterns in NIA Health Disparities Research Framework Domains and AD‐Plasma Biomarkers
Authors: Vassilaki Maria , Aakre Jeremiah A , Castillo Anna M , Lesnick Timothy G. , Kremers Walter K. , Algeciras‐Schimnich Alicia , Graff‐Radford Jonathan , Knopman David S. , Mosley Thomas H. , Windham B Gwen , Griswold Michael E. , Lowe Val J. , Jack Clifford R. , Petersen Ronald C. , Vemuri Prashanthi
Published: January 2025

Background

The NIA Health Disparities Research (NIA‐HD) Framework organizes factors in four domains (i.e., environmental, sociocultural, behavioral, and biological), which work together over the lifetime to influence health and health disparities.

Method

In previous work, we employed a 2‐stage approach using factor and principal component (PC) analyses to identify patterns of factors in the domains of the NIA‐HD Framework. We found three PCs that identified related groupings from more than one NIA‐HD domain. PC1: retirement status, residence type, multivitamin use, heart disease, Charlson comorbidity index, walking/balance difficulties, and Beck Depression Inventory (BDI)‐II questions – mainly from the somatic dimension; PC2: physical activity/exercise, social and group activities, education, occupation, cardiometabolic risk factors, and self‐rated health; PC3: national and state area deprivation index ranking and BDI‐II questions – mainly in the cognitive dimension. Age and sex‐adjusted linear regression models were used to assess the cross‐sectional association of each PC with AD‐plasma biomarkers measured using the Quanterix Simoa platform in the Mayo Clinic Study of Aging (MCSA) participants. AD‐plasma biomarkers included Aβ 42/40, phosphorylated‐tau 181 (p‐tau181), plasma glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). All analyses were considered statistically significant at a p <0.05.

Result

There were 1300 cognitively unimpaired participants, 50 years old or older, with available plasma biomarkers (mean age (SD) 68.6 (9.5) years; 49.1% were female) at the current study baseline. PC1 and PC3 were associated with higher NfL and p‐tau 181 values (p<0.05). PC1 and PC2 were associated with higher GFAP values (p<0.05). No PCs were associated with the Aβ 42/40 ratio. Findings were mostly similar after additionally adjusting for global cognitive performance and chronic kidney disease.

Conclusion

We found that patterns in a wide range of environmental, sociocultural, behavioral, and biological factors were associated with AD plasma biomarkers. Longitudinal studies are warranted to validate findings and support multi‐faceted approaches to address health disparities and achieve disease delay and prevention.
Developing an anatomically valid segmentation protocol for anterior regions of the medial temporal lobe
Authors: Sadeghpour Niyousha , Lim Sydney A , Wuestefeld Anika , Denning Amanda E , Ittyerah Ranjit , Trotman Winifred , Chung Eunice , Sadaghiani Shokufeh , Prabhakaran Karthik , Bedard Madigan , Ohm Daniel T , Artacho‐Perula Emilio , Martin Maria Mercedes Iniguez de Onzono , Munoz Monica , Romero Francisco Javier Molina , González José Carlos Delgado , Jimenez Maria del Mar Arroyo , Rabal Maria del Pilar Marcos , Sanchez Sandra Cebada , Prieto Carlos de la Rosa , Insausti Ricardo , McMillan Corey T , Grossman Murray , Lee Eddie B , Detre John A. , Trojanowski John Q , Tisdall M. Dylan , Irwin David J , Wolk David A , Yushkevich Paul A. , Wisse Laura E.M.
Published: January 2025

Background

The anterior portion of the MTL is one of the first regions targeted by pathology in sporadic Alzheimer’s disease (AD) indicating the potential for imaging metrics from this region to serve as valuable imaging biomarkers. However, most existing automated approaches for MTL segmentation do not incorporate anterior MTL subregions, and the few that do fail to account for its complex anatomical variability. Leveraging a unique postmortem dataset consisting of histology and structural MRI scans we aimed to develop an anatomically valid segmentation protocol for anterior entorhinal cortex (ERC), Brodmann Area (BA) 35, and BA36 and apply it for automated MTL segmentation of in vivo 3 tesla (T) MRI.

Method

We included 20 cases between 61 to 97 years of age (50% females) with and without neurodegenerative diseases (11 vs. 9 cases) to ensure broad generalizability of the developed protocol. Postmortem digitized MTL Nissl‐stained coronal histology serial sections from these cases were registered to same‐subject 0.2×0.2×0.2‐mm3 9.4T postmortem MRI and annotated by an expert neuroanatomist. To develop the segmentation protocol, we determined the location of the histological borders of interest in relation to anatomical landmarks observable on in vivo MRI. The protocol was first applied manually to 29 3T in vivo MRI scans and then used to train an automatic segmentation method T1‐ASHS (Automatic Segmentation of Hippocampal Subfields). Intra‐rater reliability of a manual rater and five‐fold cross‐validation accuracy of T1‐ASHS were assessed with the Dice Similarity Index (DSI).

Result

Segmentation rules for the borders of ERC, BA35 and BA36 based on systematic analysis of inter‐landmark distances on histological sections are shown in Figure 1. Intra‐rater reliability for the manual rater applying these rules to 15 in vivo 3T MRI scans was high (Table‐1; Figure‐2). Comparing manual segmentations with the automated ones generated by T1‐ASHS showed moderate reliability, reflecting the challenging anatomy of this region. However, segmentation accuracy for the whole MTL including the newly added region was comparable to the previously reported accuracy for MTL without this region (Table‐1).

Conclusion

Future work will examine trhe utility of morphometric measures of anterior MTL regions enabled by this protocol for early AD.
Neurotransmitter‐related functional connectivity alterations associated with cognitive decline in people with mild cognitive impairment and mild Alzheimer’s disease
Authors: Venneri Annalena , Manca Riccardo
Published: January 2025

Background

Early alterations in the ventral tegmental area, a major brainstem dopaminergic nucleus, may be a marker of Alzheimer’ disease (AD). However, how dopamine (DA) may influence neurofunctional and cognitive decline due to AD remains elusive. The aim of this study was to investigate alterations in resting‐state functional connectivity (FC) associated with DA distribution in the brain along the AD continuum.

Materials

Eighty‐six older adults with mild cognitive impairment (MCI), 58 with mild dementia due to AD and 76 cognitively unimpaired (CU) participants of the multicentre VPH‐DARE@IT project were included. Participants underwent comprehensive clinical, neuropsychological and MRI assessments

Methods

Functional MRI data were pre‐processed by using the REACT pipeline to obtain FC maps informed by DA receptor and transporter PET/SPECT atlas for the whole brain and for the nigrostriatal and mesocorticolimbic pathways. Whole‐brain FC maps informed by acetylcholine (ACh) were also extracted for comparison. A cognitive composite score (Cog‐CS) was calculated as the average of neuropsychological test z‐scores. Between‐group differences in neurotransmitter‐informed FC were assessed using ANCOVA models in SMP12. Moreover, the association between FC maps and both Cog‐CS and episodic memory scores was investigated in the whole sample. Age, education, sex, total intracranial volume and recruitment site were included as covariates.

Results

The AD group showed mesocorticolimbic DA‐related FC decline in the bilateral precuneus, and increase in the thalamus, while the MCI group showed nigrostriatal FC decline in the left superior temporal gyrus. ACh‐related FC decline was observed in both MCI and AD, compared with CU, in fronto‐parietal and temporal areas. The Cog‐CS was positively associated with ACh‐related FC only in posterior cingulate, temporal and cerebellar areas. Episodic memory performance was correlated positively with ACh‐ and DA‐related FC in occipito‐parietal areas and negatively with DA‐related FC in thalamic and fronto‐temporal areas.

Conclusions

FC alterations associated with both Ach and DA may be sensitive to cognitive decline due to AD. These findings, first of this kind, may offer useful insights to test recently proposed hypotheses on the involvement of these neuromodulatory systems in driving AD‐related neuropathological changes as well as to investigate the mechanisms of action of novel treatments.
Exploring the Mediating Role of Social Participation in Reducing Caregiver Burdens in Dementia Care
Authors: Bae Suyeong , Hong Ickpyo
Published: January 2025

Background

The increasing global incidence of dementia is accompanied by rising burdens for caregivers, who face physical and emotional challenges such as depression and pain. Existing research primarily explores the negative impacts of caregiving on quality of life, health, and finances, alongside the benefits of social support and specific programs. However, such approaches might be relatively passive. Our study aims to examine the mediation effect of social participation between caregivers and their burdens. We expect the study finding could be used as an active strategy that significantly alleviates caregiver burdens.

Method

We used the data of caregivers and recipients from the 2022 National Health and Aging Trends Study and National Study of Caregiving IV. The dependent variables were self‐reported questionnaires that assess physical and emotional burdens. Social participation was used as a mediator, and the independent variable was whether the caregiver cared for recipients with dementia or not. Structural equation modeling was utilized to investigate the mediating role of social participation in the relationship between caregivers and the physical and emotional burdens they experience.

Result

The final sample was 1,836 caregivers, and they consisted of 595 males (32.41%) and 1241 females (67.59%). The model fit value indicated that the model fits the data (chi‐square value = 322.795, df = 60, p‐value = 0.000; RMSEA = 0.049; CFI = 0.938; TLI = 0.919; SRMR = 0.043). The caregivers who care for recipients with dementia were negatively associated with social participation (standardized coefficient = −0.114, p‐value <.0001). Social participation was negatively associated with the physical and emotional burden (standardized coefficient = −0.230, p‐value <.0001; standardized coefficient = −0.208, p‐value <.0001, respectively). There were no significant direct paths between caregivers who care for recipients with dementia and physical burden, emotional burden each other.

Conclusion

The study findings can help recognize the role of social participation in the caregivers who care for recipients with dementia by understanding the positive effect of social participation. In addition, the findings suggest that social participation can reduce the physical and emotional burden of caregivers who care for recipients with dementia.
Deferoxamine treatment decreases amyloid fibrils and lowers iron mediated oxidative damage in ApoEFAD mice
Authors: Thorwald Max A , Godoy‐Lugo Jose A , Christensen Amy , Pike Christian J. , Forman Henry Jay , Finch Caleb E
Published: January 2025

Background

Iron is implicated in Alzheimer’s disease (AD) and is bound to β‐amyloid (Ab) plaques. AD brains have increased 4‐hydroxynonenal (HNE) adducts, a lipid decomposition product bound to proteins originating from iron mediated lipid peroxidation. Increased brain iron may result from cerebral microbleeds which by nature are rich sources of iron. In EFAD aging, microbleeds arise before amyloid plaque formation, suggesting a role for microbleeds in plaque formation. We hypothesize that treatment with the iron chelator Deferoxamine (DFO) would reduce brain iron and attenuate oxidative damage from these microbleeds.

Method

6‐month female EFAD mice were treated with DFO (10mg/kg/day) by diet (2 weeks; n = 9) or intraperitoneal injection (1 week; n = 11) and compared to untreated (n = 8). Cerebral cortex was assayed for soluble Aβ peptides, insoluble Aβ fibrils, and HNE by dot blot. Antioxidants were measured by Western blot or GPx assay (Cayman Chemical).

Result

DFO in diet or by IP decreased insoluble fibrillar amyloid by 50% with corresponding 2‐fold increases in soluble Aβ monomers Aβ40 and ‐42. DFO reduced HNE levels by 50%; nitrotyrosine, a non‐iron dependent oxidation marker, remained unchanged. Protection from lipid oxidation is mediated by GPx4 or GSTA4, which DFO increased by 50%. These measures were complimented with 25% increases in total GPx activity by DFO.

Conclusion

DFO solubilized fibrillar Aβ and increased Aβ monomers. Furthermore, DFO increased antioxidants critical to the protection against microbleed‐induced oxidative damage. These findings are substantiated by the decrease in HNE. Future studies will examine combination therapy with Aβ monoclonal antibodies which may liberate bound iron from Aβ plaques.
D13 caspase‐6‐cleaved tau, a new biomarker to complement Alzheimer’s disease diagnosis
Authors: Rizzi Liara , Rojas Julio C. , Ambrose Andrew J. , Balthazar Marcio Luiz Figueredo , Arkin Michelle R. , Grinberg Lea T.
Published: January 2025

Background

Caspase‐cleaved tau can critically be involved in the pathogenesis and progression of Alzheimer’s disease (AD), due to its ability to promote both misfolding and neurodegeneration, which ultimately leads to progressive cognitive impairment. Neuropathological studies show that caspase‐cleaved tau species are abundant in AD brain neurons, yet show only a modest degree of co‐occurrence with phospho‐tau. This suggests that caspase‐cleaved tau is an overlooked form of tau pathology that is related to the vulnerability and pathogenesis of AD.

Method

We developed a homebrew Simoa immunoassay for detecting N‐terminal D13 caspase‐6‐cleaved tau in the cerebrospinal fluid (CSF). For developing the assay, we used a neo‐epitope monoclonal antibody developed and validated by our group and used in previously published histological work. After optimization, we tested this assay in a pilot study with a discovery cohort comprising CSF samples from 20 subjects with mild to moderate dementia and positive for AD biomarkers and 20 well‐characterized healthy controls (HC).

Result

The signal translated in the mean average enzymes per bead was significantly higher in Alzheimer’s disease cases compared to healthy controls (0.01640 vs. 0.01189, ρ < 0.001). There were no significant differences in demographics such as age (ρ = 0.072) or gender (ρ = 0.723) between the two groups.

Conclusion

We introduce the initial D13 caspase‐6‐cleaved tau biomarker immunoassay for quantitatively assessing caspase‐cleaved tau pathology in CSF. This assay offers the chance to identify pathological tau that conventional p‐tau assays may overlook, potentially enhancing the assessment of clinical trials. We are currently expanding the study cohort and correlating the findings with metrics from p‐tau biomarkers.
Impact of Aerobic Cycling on Affective Symptoms and Quality of Life in Persons Experiencing Subjective Cognitive Decline
Authors: Watry Rebecca Ann‐Maria , Hadidi Niloufar , Kreitzer Mary Jo , Bhimani Rozina , Yu Fang , Salisbury Dereck L.
Published: January 2025

Background

Transition to subjective cognitive decline (SCD), and dementia is often accompanied by increased affective symptoms (i.e., anxiety and depression), which increase the risk of Alzheimer’s dementia and decreased quality of life (QoL). The hazard ratio of SCD with affective symptoms is significantly worse in comparison to SCD only. A paucity of research investigates the impact of treatments, including aerobic exercise, on SCD, affective symptoms, and QoL. The purpose was to examine the preliminary efficacy of moderate‐intensity cycling exercise versus control on SCD, affective symptoms, and overall QoL, including QoL domains.

Methods

The Exergames Study randomized community‐dwelling older adults with SCD (n = 38) to 12 weeks (36 sessions) of exergames, cycling only, and stretching control groups using a 2:1:1 allocation ratio. For this secondary data analysis, the exergames and cycling groups were combined (n = 30). SCD symptoms, affective symptoms, and QoL were assessed by the SCD‐Q, GAS‐10, GDS‐SF, and WHOQOL‐BREF. Between‐group change was evaluated by ANCOVA, and relationships between changes in QoL were calculated with multiple linear regression, adjusting for baseline values.

Results

Enrollment was from November 2019 ‐ December 2021. The mean age was 74.6 (7.4) years old and 69% were female (Table 1). There were no significant between‐group changes (Table 2). Large and moderate between‐group effect sizes were seen in favor of the stretching group for WHOQOL‐BREF Social domain (between group change = 1.90 [1.19], ηp2 = 0.19); GAS‐10 (between group change = ‐5.36 [0.29], ηp2 = 0.11); and WHOQOL‐BREF Physical Domain (between group change = 4.56 [4.40], ηp2 = 0.10). Increased affective symptom scores by one item corresponded with a decrease in predictive QoL scores (anxiety‐physical health ‐0.52 [0.25], p = 0.05; depressive‐overall ‐3.01 [1.10], p = 0.01; depressive‐psychological ‐1.19 [0.36], p < 0.01; Table 3).

Conclusion

Although non‐significant, between‐group changes favored the control group. Changes in affective symptoms predicted changes in QoL. The participation attention received by this secluded population of older adults and COVID‐19 losses likely impacted results. Further research with larger groups (that does not span a pandemic) is necessary to elucidate the full impacts of aerobic cycling on SCD symptoms, affective symptoms, and QoL.
SAA‐Determined α‐Synuclein in Early AD ADNI Participants: Contribution to cognitive trajectories from a sex differences perspective
Authors: Milà‐Alomà Marta , Hausle Zachary , Schaap Tamar M
Published: January 2025

Background

α‐synuclein (αSyn) aggregates are a common co‐pathology in Alzheimer’s disease (AD) and can be identified in CSF with high reliability using the Seed Amplification Assay (SAA). While AD prevalence and impact on cognition are higher in women, the opposite pattern is found for α‐synucleinopathies. Our objective was to study the independent and joint contributions of αSyn, Aß and p‐tau on cognitive trajectories in early AD individuals from a sex differences perspective.

Method

We studied 529 ADNI participants (39.1% women) meeting criteria for early AD (CSF Aß+, MMSE 20‐28, and CDR 0.5 or 1.0) with baseline Aß42, p‐tau181 and αSyn determinations in CSF, and longitudinal cognition (mean follow‐up time of 5.4 years). We used logistic regressions to compare baseline cognition and biomarker levels between SAA groups in each sex. Additional models were adjusted by p‐tau181/Aß42 ratio to determine whether the impact of SAA‐positivity (SAA+) on baseline cognition was independent from the degree of AD pathology. Sex‐stratified linear mixed‐effect models were run to evaluate the contributions of baseline αSyn, Aß and p‐tau to cognitive trajectories over time. Additional models included the interaction term with sex. Age, APOEe4 and education were added as covariates in all models.

Result

No sex differences were found in SAA+ prevalence. At baseline, p‐tau181 positivity was higher in women, particularly among SAA‐. Neither Aß burden nor cognitive scores differed by sex. SAA‐positivity at baseline was associated with higher Aß burden, particularly in men. SAA‐positivity associated with lower baseline cognitive performance in all tested cognitive domains specifically in men, and the effect was maintained after adjusting for p‐tau181/Aß42 (Table 1). Baseline SAA‐positivity also had an independent contribution to longitudinal cognitive trajectories specifically in men, with significant interactions between sex, SAA status and time in global cognition and in memory (Table 2, Figure 1).

Conclusion

There are no sex differences in the prevalence of αSyn pathology in individuals with early AD. However, baseline αSyn, Aß and p‐tau181 independently associate with cognitive decline in men, but not in women. Further research is warranted to elucidate sex‐specific contributions of pathologies to cognitive decline and implications for clinical trials targeting the early AD population.
Plasma NfL, P‐Tau181 and and P‐Tau181/Aβ42 Ratio are associated with incident mild behavioural impairment in dementia‐free individuals
Authors: Liao Yingqi , Chong Joyce R , Kan Cheuk Ni , Zhao Xuhao , Chai Yuek Ling , Lai Mitchell Kim Peng , Chen Christopher , Xu Xin
Published: January 2025

Background

Mild behavioural impairment (MBI) is associated with accelerated cognitive decline and conversion to dementia. However, the relationship between Alzheimer’s disease (AD)‐related pathological mechanisms and MBI remains unclear. This study aimed to examine whether baseline plasma neurofilament light chain (NfL), phosphorylated tau‐181 (P‐Tau181) and the P‐Tau181‐to‐Amyloid beta 42 (P‐Tau181/Aβ42) ratio are associated with incident MBI in an Asian cohort of dementia‐free individuals.

Method

Dementia‐free participants were recruited from the community and memory clinics and underwent cognitive, neuropsychiatric and clinical assessments annually and brain MRI scans biennially at baseline and over a maximum of 5 years in an ongoing longitudinal study. Plasma NfL, P‐Tau181 and Aβ42 were measured using Single molecule array (Simoa) assays. Baseline MBI was defined as the presence of NPS at baseline and Y1 using the Neuropsychiatric Inventory, while incident MBI was defined as the development of new NPS persisting over any two consecutive years of follow‐up. The associations between baseline plasma biomarkers and incident MBI were examined using generalized estimating equation modelling. Additionally, competition risk survival analyses based on the Fine‐Gray model were performed to account for the competing risk of incident dementia. All models were adjusted for age, gender, education, clinical diagnosis (i.e. No cognitive impairment (NCI) vs. Cognitively impaired‐No dementia (CIND)) and the presence of cerebrovascular diseases (CeVD) at baseline.

Result

Three hundred and five participants with complete NPI data and plasma biomarkers were included (age 72.1 ± 7.8 years, 52.5% female). Among the 248 without baseline MBI, 25.3% (n = 55) developed incident MBI. Elevated levels of plasma NfL (OR[95%CI] = 5.72(2.00, 16.36), p = 0.001) and P‐Tau181/Aβ42 ratio (OR[95%CI] = 3.54(1.03, 12.21), p = 0.05) were individually associated with incident MBI. Furthermore, when accounting for the presence of incident dementia and CeVD and plasma NfL, high levels of plasma P‐Tau181 were independently associated with an increased likelihood of incident MBI (HR[95% CI] = 2.44 (1.01, 5.86), p = 0.047).

Conclusion

The relationship of plasma P‐Tau181, P‐Tau181/Aβ42 ratio and NfL with incident MBI suggests an association between AD‐pathology and neurodegeneration with late‐life behavioural changes. Therefore, combining clinical assessments with AD‐related plasma biomarkers may improve the early identification of at‐risk individuals for behavioural disturbances in dementia.
Investing in Healthy Brain Aging: Why Africa Must Reform Social Pension Programs
Authors: Mostert Cyprian M
Published: January 2025

Background

African social pension schemes have irregularities. We discuss these irregularities and highlight potential reforms that may be introduced to improve healthy brain aging.

Method

This analysis is based on comprehensive data from reputable sources such as the World Bank, the World Health Organisation, the United Nations, and the Organisation for Economic Co‐operation and Development. The use of such reliable data ensures the accuracy and validity of our findings.

Result

We demonstrate that the current social pension scheme eligibility criteria are not designed to enforce healthy brain aging. Healthy life expectancy, which captures the number of years a person can expect to live in good health, is lower than the age for social pension eligibility criteria. For example, women’s life expectancy at birth in sub‐Saharan Africa was 66 years in 2017. However, healthy life expectancy was only 56 years, meaning that women spent four years in poor health before earning a social pension at 60 years and die 6 years later. For men, life expectancy at birth was 61 years in 2017, and healthy life expectancy was 53 years, which means men in sub‐Saharan Africa spend 12 years of their lives in poor health before earning a social pension at 65 years. Majority of these men die before earning the pension.

Conclusion

Our analysis underscores the urgent need for pension reforms in Africa. We propose that pension payouts should commence from the onset of poor health in elderly citizens. The current system of delayed payouts is counterproductive to the goal of promoting healthy brain aging.
GPR3‐biased signaling is involved in microglial activation in a preclinical Alzheimer’s disease mouse model
Authors: Espinosa Diego Rolando Hernandez , Guimaraes Thais Rafael , Huang Yunhong , Thathiah Amantha
Published: January 2025

Background

Microglia play a crucial role in clearing amyloid‐beta (Aβ) plaques, one of the primary pathological hallmarks of AD. We previously showed that G protein‐biased signaling by the G protein‐coupled receptor GPR3 reduces soluble Aβ levels and leads to an increase in Aβ plaque compaction and a reduction in Aβ plaque area in the preclinical AppNL‐G‐F
AD mouse model. These results suggest a protective microglial response that may limit Aβ plaque formation in G protein‐biased GPR3 AD mice. However, the precise mechanism by which biased GPR3 signaling in microglia restricts the growth of Aβ plaques remains unknown.

Method

We utilized a CRISPR/Cas9 genome editing strategy to mutate six serine/threonine residues in the GPR3 C‐terminus to phosphorylation‐deficient alanine residues to generate a G protein‐biased GPR3 mouse model. We also introduced a hemagglutinin (HA) tag in the N‐terminus of GPR3 to determine the expression and localization of the GPR3 protein in vivo. We crossed the AppNL‐G‐F AD mouse model with our GPR3HA/HA and G protein‐biased GPR3HA/Ala mice. We then performed bulk RNAseq on cortical brain samples from AppNL‐G‐F, GPR3HA/HA (AD KI), and AppNL‐G‐F, G protein‐biased GPR3 (Biased AD KI) mice. To characterize the microglia phenotype, we are conducting Flow cytometry (FC) of Biased AD KI relative to AD KI brains at 6, 12, and 18 months of age (early‐, mid‐, and late‐stage pathology).

Result

The bulk RNAseq data reveal that microglial activation in Biased AD KI mice is consistent with a disease‐associated microglia (DAM) profile. The DAM profile includes upregulation of phagocytosis‐ and endolysosomal‐related genes, such as Trem2, Lyz2, Itgax, Cst7, Clec7a, and Cd68. Specifically, we observe an upregulation of Trem2 and Tyrobp (DAP12), congruent with our observed increase in the total area occupied by microglia, Aβ plaque coverage area, and Aβ plaque compaction in Biased AD KI mice. Preliminary FC analysis also indicates differential expression of DAM markers in microglia isolated from our Biased AD KI mice.

Conclusion

Our findings provide compelling evidence for the involvement of biased GPR3 signaling in regulating microglial function and the response to the accumulation of Aβ pathology in AD.