bluuebunny/crossref_metadata_2025 huggingface dataset:
Early basal ganglia imaging abnormalities in pre‐symptomatic and early symptomatic novel APP duplication carriers
Authors: Paz Rotem , Bergmann Eyal , Eran Ayelet , Rozen Yael , Golan Sapir , Merhav Goni , Hoffmann Chen , Domachevsky Liran , Beeri Michal S , Kalfon Limor , Falik‐Zaccai Tzipora , Aharon‐Peretz Judith , Kahn Itamar , Lesman‐Segev Orit H. , Ravona‐Springer Ramit
Published: January 2025

Background

We aim to describe the imaging findings in pre‐symptomatic and early‐symptomatic individuals carrying a recently described novel APP duplication rearrangement causing early‐onset AD (EOAD).

Method

We studied individuals from one pedigree that carry APP duplication and CH 5 mutation gain that had structural and resting state functional (rs‐f) brain MRI. Non‐carrier family members were assessed as controls. Volumetric analysis was performed using Freesurfer and normalized to total intracranial volume. Fazekas scores for white matter hyperintensities (WMH) and microbleed count were performed visually by two neuroradiologists. rs‐fMRI seed to whole brain analysis was used to create functional connectivity maps of the default mode network (DMN). F18‐Flutemetamol amyloid‐PET was available for two of the mutation carriers. Amyloid deposition was quantified using SUVR with the pons as reference region and compared to SUVR of young adults and amyloid‐positive older adults (Ab+OA).

Result

Fourteen mutation carriers (mean age 29.8[19‐39], 8 (57%) F, median education 12Y[11‐14Y], mean MMSE 28[23‐30]), and nine non‐carrier family members were included (36.8Y[19‐56Y], 5 (55%)F, 12Y[12‐19], 29[27‐30]). Volumetric analysis revealed an increase in amygdala volume (log) (estimate = 0.01, p = 0.03) and a (non‐statistically significant) trend toward decrease in the putamen, globus pallidus, and pons volume with age in mutation carriers (Figure 1A). WMHs and microbleeds were found in some mutation carriers from the age of 28Y (Figure 1B). rs‐fMRI showed a trend toward a disconnection between the anterior and the posterior component of the DMN in the APP‐dup carriers >30Y (n = 6) compared with non‐carrier (n = 8; U = 10, p = 0.08). Moreover, increased connectivity was found between the anterior component of the DMN and the striatum compared to carriers <30Y (n = 8, U = 9, p = 0.06) and to non‐carriers (U = 9, p = 0.06) (Figure 2). Cortical amyloid deposition was high but within the range of Ab+OA, and extremely high, above the level of deposition in Ab+OA in the putamen, caudate, and thalamus (Figure 3).

Conclusion

We found early basal ganglia abnormalities in presymptomatic and early symptomatic novel APP duplication mutation carriers, including high amyloid deposition, DMN disconnection, increased connectivity between anterior DMN and striatum, and volumetric alterations. These findings point to the basal ganglia as a region of early pathology that requires further research.
Mapping the spatial immunometabolic responses of microglia in response to Alzheimer’s pathology
Authors: Saito Kai , Goulding Danielle S. , Dimas Sophia H , Patel Ela , Snipes Andy , Nelson Peter T , Macauley Shannon L , Morganti Josh M.
Published: January 2025

Background

Single cell RNA sequencing has defined multiple transcription states of microglia in the context of AD neuropathology. Growing appreciating for several of these disease‐associated phenotypes are linked with acquisition of altered metabolism, conceptually known as immunometabolism. Despite increasing knowledge in microglial heterogeneity, relatively little is known regarding the spatial distribution of these phenotypes in the context of pathology proximity.

Method

Using 10X Genomics Xenium system, we developed a fully custom 400+ gene panel consisting of probes for deep phenotyping of microglial heterogeneity, in tandem with canonical and rate‐limiting genes associated with multiple cellular metabolic pathways, as well as genes that canonically define neuronal subsets, astrocytes, endothelia, oligodendrocytes, pericytes, and infiltrating immune classes, etc. This panel was employed across three AD‐recapitulating mouse models (n = 2/3 per genotype): PS19 (12 months old), APP/PS1 (12 months old), and 5xFAD (22 months old), and their age‐matched ‘WT’ littermate controls. In parallel, we performed the identical experiments using custom Xenium probe set in age and sex matched human autopsy tissue from the dorsolateral PFC gray matter from cases (n = 2/bin) with low (Braak I/II), middle (Braak III/IV) and high (Braak V/VI) pathological burden.

Result

We demonstrate unique intrinsic relationships of microglial heterogeneity as a function of AD‐associated pathological burden in our mouse models. ‘DAM’‐like microglia displace anatomically‐restricted homeostatic‐associated heterogeneity in as a function of pathology accumulation. In the PS19 model, we demonstrate significant susceptibility of the hippocampal formation to acquire DAM‐like and Interferon‐assocatied microglial phenotypes, whereas in both the APP/PS1 and 5xFAD broader anatomical accumulation was apparent in cortical, hippocampal, and thalamic regions. Using machine learning, we demonstrate that proximity to ThioS+ pathology drives distinctive metabolic shifts in microglial populations, with preferential signatures enriching upon both glycolytic as well as cholesterol metabolism alterations. Further, several of the indices observed in our mouse models were conserved in the human tissue.

Conclusion

Microglial heterogeneity is governed by anatomical locale as well as a function of proximity to AD‐related pathology, highlighting areas of susceptibility, which is correlated with shifts in transcriptional profiles linked with both glycolytic and cholesterol metabolism.
Integration of GWAS and cerebrospinal fluid proteogenomics identifies proteins for AD and shared dysregulated mechanisms in other neurological traits
Authors: Western Daniel , Yang Chengran , Timsina Jigyasha , Gorijala Priyanka , Liu Menghan , Ruiz Agustin , Marquié Marta , Boada Mercè , de Rojas Itziar , Rutledge Jarod , Oh Hamilton Se‐Hwee , Wilson Edward N. , Guen Yann Le , Greicius Michael D , Wyss‐Coray Tony , Alvarez Ignacio , Aguilar Miquel , Pastor Pau , Robins Chloe , Pulford David J. , Sung Yun Ju , Cruchaga Carlos
Published: January 2025

Background

Cerebrospinal fluid (CSF) is a valuable resource for the study and diagnosis of neurological diseases, but few studies have comprehensively characterized the genetic determinants of CSF protein levels that may contribute to the development of disease. These quantitative trait loci (QTL) have proven vital to identifying candidate genes for disease treatment and monitoring. Here, we utilize our largest‐to‐date CSF protein QTL atlas to prioritize potentially causal proteins for 14 neurological traits and examine the unique and overlapping disease mechanisms observed using CSF proteins.

Method

We generated the largest CSF proteogenomic dataset (3,506 samples, 6,361 proteins) to date. We performed proteome‐wide association study (PWAS), colocalization, and Mendelian Randomization (MR) to identify potentially causal proteins for 14 neurodegenerative and psychiatric diseases or disorders. We then performed pathway analysis to identify dysregulated mechanisms underlying disease and used RHOGE to assess the overlap of proteogenomic profiles between diseases. We are repeating these analyses using blood plasma to assess overlap with a more accessible tissue.

Result

Across the 14 diseases, we identified 171 protein‐disease associations in CSF through at least two of PWAS, COLOC, and MR. For Alzheimer’s disease (AD), we identified 38 proteins enriched in immune‐relevant pathways (TREM2, CD33, IL34) and lysosomal function (GRN, CLN5, TMEM106B). Many proteins were found for schizophrenia (38), multiple sclerosis (27), and bipolar disorder (22), among others. We identified negative genetic correlations between PD and neuroticism and between anorexia nervosa and most other psychiatric traits. We observed limited overlap between CSF and plasma pQTLs (1,225/4,767 colocalize; 25.7%) with a moderate correlation in pQTL effect size (R = 0.576). Disease‐specific analyses in plasma are ongoing.

Conclusion

We have identified numerous novel associations for neurological diseases that may represent therapeutic or biomarker targets in disease. We highlighted substantial differences in proteogenomic regulation between CSF and plasma, demonstrating the importance of investigating novel tissues in genetic studies. Through the integration of analyses from both tissues (ongoing), we will uncover disease‐relevant changes specific to neurological tissues or shared between tissues that may allow for diagnosis or prioritization of individuals for treatment based solely on proteomics generated from accessible tissues.
GRK2 activity promotes Aβ generation by altering GPR3 signaling and intracellular trafficking
Authors: Lu William , Guimaraes Thais Rafael , Huang Yunhong , Todd Nicholas , Thathiah Amantha
Published: January 2025

Background

G protein‐coupled receptors (GPCRs) are associated with multiple stages of the pathophysiology of Alzheimer’s disease (AD). Biased GPCR signaling preferentially activates G protein‐ or β‐arrestin‐mediated signaling pathways and presents opportunities to develop more selective and safer therapeutics but remains largely unexplored in AD. Recently, we developed a G protein‐biased GPR3 AD mouse model, which does not recruit β‐arrestin 2, that displays reduced amyloid‐β (Aβ) pathology without adverse cognitive effects associated with elimination of both G protein and β‐arrestin signaling.

Method

We investigated how G protein‐biased GPR3 signaling ameliorates Aβ accumulation in HEK293 cells stably expressing the full‐length amyloid precursor protein (HEK‐APP) using biochemical and immunocytochemical methods. To investigate the involvement of GPCR kinases (GRKs) in GPR3‐ mediated Aβ generation, we employed a CRISPR/Cas9 genome editing strategy to generate Grk2‐deficient HEK293 cells along with complementary pharmacological inhibition of GRK2 in HEK‐APP and human neurons.

Result

We first validated that biased GPR3 signaling reduces Aβ generation in HEK‐APP cells. To gain mechanistic insight into how biased GPR3 affects Aβ generation, we determined that biased GPR3 displays reduced binding to APP relative to wild‐type GPR3. We then determined that Grk2 deficiency leads to reduced β‐arrestin 2 recruitment to GPR3 and decreased Aβ generation in HEK‐APP cells. Similar to the effect of Grk2 deficiency, pharmacological inhibition of GRK2 activity with CMPD101 also leads to a reduction in Aβ generation in both HEK‐APP cells and familial AD neurons. Further studies indicate that GRK2 modulates the localization of GPR3 and APP to the Golgi apparatus, early endosomes and endoplasmic reticulum. Interestingly, GRK2 inhibition also leads to increased levels of APP phosphorylation at threonine 668.

Conclusion

These results suggest a role for GRK2 in regulating the intracellular trafficking and localization of G protein‐biased GPR3 and APP, which may directly affect Aβ generation. Future studies will further elucidate how GRK2 activity impacts GPR3‐mediated Aβ generation and could illuminate novel targets for the development of AD therapies.
Clinical Use of Lecanemab at an Academic Medical Center
Authors: Honig Lawrence S. , Kim Jee Min , Gonzalez Wendy P. , DiMuro Vanessa , Jagannathan Radhika , Marder Karen , Noble James M. , Bell Karen L. , Mayeux Richard
Published: January 2025

For Alzheimer’s disease (AD), there are currently two FDA‐approved agents developed as disease‐modifying treatments. Approval of lecanemab (Leqembi®) in 2023, via accelerated approval mechanism, followed by traditional approval accompanied by medical coverage decision by the Center for Medicare Services, has resulted in increasing use of this anti‐amyloid monoclonal antibody, demonstrated in 18‐month long clinical trials to slow Alzheimer’s disease. Despite a broad package insert (with only contraindication product severe hypersensitivity), nationwide prescriptions have been reportedly affected by concerns regarding drug eligibility, monitoring, and whether real‐world experience would mirror clinical trial data. In our practice, prescription of the medication has been contingent upon: (a) diagnosis of AD, (b) early stage of AD, (c) amyloid confirmation by CSF or PET, (d) acceptable ARIA‐H at baseline MRI, and (e) non‐mandatory apolipoprotein‐E genotyping. Here we present data on the first 85 patients prescribed lecanemab at our center. Patient age is 73±8 yr (51‐88) and sex 51% women, with 82% accepting apolipoprotein‐E4 testing (42% non‐carriers, 44% heterozygotes, and 14% homozygotes). Barriers associated with our above eligibility criteria (a) through (e) have been minimal. Similarly, barriers have generally not been large for MRI monitoring and infusion center availability; but during this first year of drug availability there have been challenges in coverage by insurers/payors other than standard original Medicare. Patients/families have had strong interest in this drug, with apparent good understanding and acceptance of risks of ARIA‐E and ARIA‐H. Patients deemed not eligible by their treating practitioners have been declined for the following reasons in descending order of frequency: disease too severe, non‐Alzheimer’s dementia (no amyloid confirmation), logistical (travel/time) considerations, disease too mild (presymptomatic), and excessive ARIA‐H on baseline MRI. Overall, with up to 21 infusions per patient, adverse event rates have been similar to those in clinical trials with 7% ARIA–E (all asymptomatic), and low rates of infusion reactions. Suspension or discontinuation of therapy has occurred in 9% (7% due to ARIA, 1% due to persistent infusion reactions, 2% due to disinterest). Overall findings at our center suggest that experience in clinical use may not be dissimilar to that in the clinical trials.
Brainstem and midbrain structures involved in memory encoding in healthy aging and mild cognitive impairment, a 3T task‐fMRI study
Authors: Penalba‐Sánchez Lucía , Yi Yeo‐Jin , Kurt Elif , Femminella Grazia Daniela , Loane Clare , Duckett Millie , Callaghan Martina F , Weiskopf Nikolaus , Dolan Ray , Howard Robert J , Düzel Emrah , Hämmerer Dorothea
Published: January 2025

Background

Memory decline, which is especially prevalent in Alzheimer’s disease (AD), has been studied via fMRI, primarily focusing on the prefrontal cortex and hippocampus. However, emerging evidence suggests that the brainstem, alongside various midbrain regions, is an initial target for pathological processes like hyperphosphorylated TAU protein accumulation. Among these, the locus coeruleus, a noradrenergic nucleus in the pons, projects to critical midbrain areas supporting memory encoding. Hence, our study aimed to investigate BOLD task activations in AD relevant to memory, while focusing on differences in responses to emotional versus neutral stimuli in the brainstem and midbrain.

Method

Using event‐related fMRI, 53 subjects (28 healthy older adults, 25 with mild cognitive impairment (MCI)) (see table 1) underwent an incidental recognition memory task involving emotional and neutral images. Memory tests followed immediately, and 4 hours after encoding. Group differences in brain activations for remembered versus not remembered images using the study template were examined.

Result

Results revealed a trend for greater activation in the left caudate nucleus in older adults, compared to those with MCI, when subsequently remembered items were compared with not remembered ones (small volume correction (SVC), cluster level pFWE‐corr = 0.08). Similarly, a significant increased activation was observed in the locus coeruleus (SVC, cluster level pFWE‐corr = 0.018). However, after adjusting for group and individual differences in LC integrity and global grey matter volume (GMV), no significant differences persisted, suggesting that structural changes contribute significantly to differences in LC activation between healthy controls and MCI participants (see Figures 1 and 2).

Conclusion

In conclusion, our findings underscore the caudate nucleus’s role in memory encoding for healthy older adults versus those with MCI. A decline in LC function in MCI appears related to a decline in LC integrity. These insights contribute to understanding memory mechanisms in healthy aging versus MCI. Future studies are needed to explore potential neural memory compensatory processes in MCI.
Transcranial electric field stimulation on iron deposition cures multiple pathologies of Aß, tau, microglial inflammation and improves cognitive impairment in Alzheimer’s mouse model
Authors: Kim Jong‐Ki
Published: January 2025

Background

The interplaying neuropathology of amyloid plaque, tau tangles, and microglia‐driven inflammation (tri‐pathology) are related to neuronal and synaptic loss damage in Alzheimer’s damages. Interventions that target Aβ or tau individually have not yielded substantial breakthroughs. Iron plays a pivotal role in tri‐pathology by protein‐bound iron‐oxide deposition in amyloid plaque, tau tangle, and microglia, resulting in redox‐active toxicity or microglial response induction, such as proinflammatory activation, autophagy dysfunction, and ferroptosis.

Methods

Using a single transcranial treatment, we stimulated the iron deposition in the tri‐pathologic iron inclusions. This treatment involved the use of a noncontact capacitive‐electrode alternating electric field (1 Mhz, < 1.5 V/cm) (TEFS) to induce the electro‐Fenton effect from the iron oxide surface of pathologic iron‐inclusion bodies in the brain of an Alzheimer’s disease (AD) mouse model (3xTg). We assessed the therapeutic effect of this phenomenon one month after treatment using histology, western blot analysis, and behavioral tests and compared the results with an untreated control.

Results

Our study revealed that TEFS‐mediated depletion of iron deposition and Aβ plaque prevented tau expression in early‐stage AD. In late‐stage AD, TEFS depleted Aβ plaque and tau tangle and downregulated ferroptosis and microglial‐driven neuroinflammation. Furthermore, TEFS improved impaired cognitive function, restored hippocampal neurogenesis, and altered microglial phenotype in both stages of AD brain.

Conclusion

Our results suggest that TEFS‐driven degradation of insoluble iron deposition cures multiple tri‐pathologies, promotes disease‐modifying properties, and offers a potential molecular‐targeting nonpharmacological treatment option for AD.
Effort‐based decision making and white matter tracts associated with dimensions of apathy in Alzheimer’s and Parkinson’s disease
Authors: Gazes Yunglin , Lee Seonjoo , Jin Zekai , Chen Bryan , Huey Edward D. , Heibronner Sarah , Heron Campbell Le , Vanegas Nora
Published: January 2025

Background

Apathy is marked by diminished motivation and goal‐directed behavior, prevalent in neurodegenerative diseases like Alzheimer’s disease (AD) and Parkinson’s disease (PD). Effort‐based decision‐making paradigms (EBDM), which require choices between tasks of varying effort levels for varying rewards, are effective assessments of goal‐directed behavior. Using a transdiagnostic approach, we are examining the neurodegeneration of networks on apathy and EBDM.

Method

We present preliminary results of a novel transdiagnostic study consisting of AD/amnestic Mild Cognitive Impairment (aMCI) and PD patients: 1) apathy is measured with Dimensional Apathy Scale (DAS), 2) an EBDM paradigm (Apple Gathering Task‐AGt) is used to estimate sensitivity to effort and reward, and microstructural integrity of relevant white matter tracts is estimated using fractional anisotropy [FA] from multi‐shell diffusion MRI. Probabilistic tractography in MRtrix toolbox was used to extract tracts connecting frontal‐subcortical regions. Using hierarchical Bayesian modeling and Drift Diffusion Model, we examined the associations among the apathy scale, behavioral performance, and brain health, covaried for age, MMSE, and UPDRS (PDs only).

Result

Table 1 shows participant characteristics and group differences in study measures. Overall, AD/aMCI patients showed greater apathy and worse clinical scores for cognition (MMSE and MoCA) than PD patients. On AGt, AD/aMCI patients demonstrated longer latency and lower effort sensitivity. AD/aMCI patients showed lower baseline drift rate with higher scores for the behavioral‐cognitive dimension of DAS (95% credible interval [CrI]: ‐1.6 to ‐0.16, Figure 1). PDs showed less effort sensitivity with higher executive dimension of DAS (95% CrI: ‐2.8 to ‐0.23). In AD/aMCI, higher FA for the tract connecting right dorsal lateral prefrontal cortex to the striatum was associated with lower emotional apathy (95% CrI: ‐0.774, ‐0.048, Figure 2). In PDs, higher FA of Striatum‐Anterior Insula Cortex tract was associated with lower apathy in the executive dimension (95% CrI: ‐0.83, ‐0.161, Figure 2 upper left).

Conclusion

Our results demonstrate distinctions in apathetic symptoms and behavioral performance for AD/aMCI and PD patients, and also in the role of different fronto‐subcortical white matter tracts in dimensions of apathetic symptoms. Future analysis in a larger cohort will directly test the suggested mediation effects of regional white matter quality on apathy measures.
Mortality Trends in Alzheimer’s Disease in Mississippi, 2011‐2021
Authors: Jones Elizabeth A.K.
Published: January 2025

Background

Alzheimer’s disease is the sixth most common cause of death in the United States (U.S.), with one in three adults 65 years of age and older dying of the disease each year. Deaths from Alzheimer’s have more than doubled between 2000 and 2019, killing more adults than both breast cancer and prostate cancer. In 2021, Alzheimer’s disease resulted in 36 deaths per 100,000 in the U.S. In Mississippi, deaths from Alzheimer’s have almost doubled between 2011 and 2021, resulting in 52.9 deaths per 100,000. Women have a higher mortality rate from Alzheimer’s than men. Alzheimer’s is a progressive disease that develops through seven stages. There are effective strategies to prevent the onset of Alzheimer’s.

Method

This paper reviews the risk factors, mortality trends, etiology, and prognosis of Alzheimer’s in Mississippi with a focus on prevention.

Result

The southern diet with foods high in sugar and sodium, along with sedentary and poor lifestyle choices, increases mortality risk from Alzheimer’s disease for women in Mississippi, specifically due to women over 65 having higher rates of obesity and hypertension.

Conclusion

Understanding the epidemiology and risk factors of Alzheimer’s in Mississippi will help inform communities, policies, and programs to prevent disease occurrence.
Structural and functional frontal‐executive dysfunction in patients with isolated REM sleep behaviour disorder
Authors: Mitolo Micaela , Baldelli Luca , Sighinolfi Giovanni , Sambati Luisa , Manners David Neil , Lodi Raffaele , Provini Federica , Tonon Caterina
Published: January 2025

Background

Isolated REM Sleep Behavior Disorder (iRBD) is a well‐recognized prodromal state of an underlying α‐synucleinopathy, occurring several years before an overt neurodegenerative disorder becomes fully manifest. iRBD has been related to poorer cognitive performance and higher frequency of mild cognitive impairment (MCI). The aim of this study was to explore in detail, with structural and functional MRI, frontal‐executive dysfunction in iRBD patients and to evaluate its association with cognitive performance.

Method

Thirty‐two iRBD patients (24 males; age, mean±SD = 67.9±7.1 years) and thirty age‐matched healthy controls were recruited and underwent an extensive neuropsychological assessment and multiparametric MR acquisition. The MR protocol (3T) included T1‐w volumetric (isotropic 1mm3), diffusion weighted imaging (b = 2000 s/mm2, 64 directions) and resting‐state (TR = 0.735s, 10 minutes) acquisitions. Brain volumetry analysis was conducted using FreeSurfer. TBSS was applied to evaluate white matter microstructural alterations. Resting state networks were investigated with ICA. Correlations between MR parameters and neuropsychological variables were explored with Spearman’s test.

Result

iRBD patients, when compared with healthy controls, showed worse performance on tests related to attentive‐executive, memory, and visuospatial functions (i.e., cancellation test p = 0.041, similarities p = 0.015, 15‐words recall p = 0.004, and simple drawing copy p = 0.007); they also showed volume reduction in left rostral anterior cingulate (p = 0.005). TBSS highlighted increased anterior corpus callosum and forceps minor Radial Diffusivity in iRBD patients (p <0.05). Significant correlations were found between this alteration and executive dysfunctions (i.e. Stroop test, r = 0.46, p = 0.009). Moreover, fMRI data showed ‘Executive control’ network alteration in iRBD patients within cortical (i.e. superior and middle frontal gyrus, opercular cortex, paracingulate and precentral gyrus) and subcortical structures (i.e. putamen and caudate); these data correlated with worse performance in executive‐attentive tests (i.e., cancellation time, r = ‐0.45, p = 0.018 and frontal assessment battery, r = 0.44, p = 0.023).

Conclusion

This study showed that structural and functional frontal‐executive alterations in iRBD patients are associated with attentive‐executive functioning, findings that are similar to those observed in some synucleinopathies. Further studies with bigger samples and follow‐ups are needed to confirm these results, and to monitor the trajectory of these alterations longitudinally.

Acknowledgement: This study was supported by the Italian Ministry of Health (#GR‐2019‐12369242).
Plasma proteome profile of Lewy body pathology‐positive individuals
Authors: Gomes Bárbara Fernandes , Benedet Andrea L. , Padovani Alessandro , Tolassi Chiara , Zanusso Gianluigi , Bongianni Matilde , Moda Fabio , Blennow Kaj , Zetterberg Henrik , Pilotto Andrea , Rosa‐Neto Pedro , Ashton Nicholas J.
Published: January 2025

Background

Lewy bodies (LB), the main hallmark of Parkinson’s disease (PD), are a frequent co‐pathology in Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). The varying extents of LB pathology in these disorders can influence disease progression and severity. Consequently, understanding LB impact on the proteomic profile of these diseases is crucial, potentially leading to identifyng novel blood biomarkers related to this pathology which are urgently needed. The aim of this project was to assess novel NULISAseq™ α‐synuclein (αSyn) biomarkers in blood. Considering the prevalence of monomeric αSyn in blood, we investigated whether other plasma proteins identified via NULISAseq™ or protein models could serve as surrogates for LB pathology determined by real‐time quake‐inducing conversion seed amplification assay (SAA).

Method

The proteomic profile of two independent cohorts was assessed using the NULISAseq™ CNS Disease Panel (Alamar Biosciences). A pilot cohort included amyloid‐β (Aβ)‐positive and SAA‐negative AD patients (n = 30) and Aβ‐negative SAA‐positive patients (DLB, n = 22; PD, n = 2). The TRIAD cohort included young (n = 32), cognitively unimpaired Aβ‐positive and Aβ‐negative (CU+, n = 111; CU‐, n = 26) individuals, Aβ‐positive and Aβ‐negative mild cognitive impairment (MCI+, n = 40; MCI‐, n = 39), as well as AD dementia (ADD, n = 38) and non‐AD (n = 27) patients. LB pathology was confirmed in both cohorts by the same SAA method.

Result

In the pilot cohort, no differences in plasma αSyn (SNCA, pSyn129, Oligo‐Syn) levels were observed. However, plasma phosphorylated tau‐217 (pTau‐217, logFoldChange (FC) = ‐1.00, p.adj<0.001), enolase‐2 (ENO2, logFC = ‐2.03, p.adj = 0.02), Fms Related Receptor Tyrosine Kinase 1 (FLT1, logFC = 0.54, p.adj = 0.04), and amyloid‐β42 (Aβ42, logFC = 1.09, p.adj = 0.04) were differentially expressed in SAA‐negative vs SAA‐positive patients. Furthermore, the ratio of pTau‐217/FLT1 exhibited the best separation between the SAA‐positive and SAA‐negative groups (AUC = 0.90, 95% CI 0.82‐0.98). The TRIAD cohort was used to validate these results, from which data is to be shown.

Conclusion

The proteomic profile of LB‐positive is distinct from LB‐negative individuals, with four biomarkers differentially expressed in plasma. We also determined that a combination of these biomarkers may be useful to discriminate SAA‐positive from SAA‐negative individuals. Plasma αSyn levels did not reflect CSF SAA outcome, possibly due to peripheral αSyn expression not reflecting brain pathology.
Heart rate variability and cardiorespiratory fitness associated with biological brain aging in a healthy adult lifespan sample
Authors: Gazes Yunglin , Mackay‐Brandt Anna , Colcombe Stan
Published: January 2025

Background

Measures of cardiovascular health have long been associated with brain health. For example, aerobic capacity (VO2max) is associated with preservation of functional and structural brain integrity in later life. Recent work has highlighted the utility of relative brain age (RBA; the age‐corrected difference between a brain’s chronological and estimated biological ages) to examine the rate of biological brain aging. However, the impact of cardiovascular factors on RBA remains underexplored. Here, we examine estimates of biological brain aging (via RBA) in the context of two key measures of cardiovascular health: aerobic fitness (VO2max), and heart rate variability (HRV) ‐ a measure of autonomic regulation associated with cognitive control, emotional regulation, and risk of neurological conditions, including dementia.

Method

Data were obtained from ‘Mapping Interindividual Variation in the Aging Connectome’, an open‐science, community‐ascertained neuroimaging study with deep health and behavioral phenotyping. We examined a subset of 164 participants aged 38‐71 with imaging and heart rate data. HRV (std of beat‐to‐beat intervals) was computed from photoplethysmography collected during the neuroimaging procedure. RBA was derived from a machine learning method (Joint and Individual Variation Explained; JIVE) trained using structural features extracted from T1‐weighted MRI data. VO2max was estimated using a modified Balke submaximal testing procedure. RBA, HRV, and VO2max associations were examined using ordinary least squares, controlling for age and sex.

Result

As expected, higher VO2max was associated with younger RBA (Figure 1: t(77) = ‐2.11, p = 0.038) and lower mean HR (t(58) = ‐2.49, p = 0.015). Interestingly, higher HRV (Figure 2: t(161) = ‐1.98, p = 0.049) also predicted younger RBA.

Conclusion

Our findings were conceptually consistent with previous work demonstrating that higher VO2max is associated with greater brain integrity, extending these findings to biological brain aging (RBA). Interestingly, the HRV findings suggest that autonomic integrity may also play a role in slowing apparent brain aging. In combination, these findings suggest that HRV may provide a similar but more accessible window into the physiological factors that influence brain health than VO2max testing. Future work examining the association between autonomic integrity metrics and brain health longitudinally or during interventions may prove fruitful.
Hypertension‐Induced Accelerating Brain Oxygen Extraction Fraction Precedes Age‐Related White Matter Dysfunction in Asymptomatic Cognitive Decline
Authors: Yan Yifan , Zhao Xuhao , Zhang Yaping , Li Wanxin , Lin Zhiying , Zhou Yi , Fang Shenghao , Huang Jingkai , Song Peige , Lin Zixuan , Xu Xin
Published: January 2025

Background

Oxygen extraction fraction (OEF) reflects the equilibrium between brain oxygen delivery and consumption, potentially serving as an early Alzheimer’s disease (AD) biomarker. Previous investigations were mainly conducted in cognitive impairment and AD population. However, the potential neuropathway connecting cardiometabolic condition, OEF, and dementia‐related brain structural changes, especially in early cognitive decline, is unclear. This study investigated the associations of OEF with white matter dysfunction (WMD) among cognitively normal older adults and explored OEF’s mediating role between early cardiometabolic conditions and WMD.

Method

Eligible cognitively intact older participants (aged above 50 years without cognitive impairment on a comprehensive cognitive battery) were recruited from communities in China and completed the demographic, medical investigations and MRI scans. OEF was measured using T2‐relaxation‐under‐spin‐tagging (TRUST). WMD was assessed by two certified neuroradiologists from T2‐flair images to obtain a Fazekas score. Subjective cognitive decline (SCD) was assessed. Cardiometabolic conditions, including hypertension, diabetes mellitus, hyperlipidemia, stroke, and heart disease were assessed through medical history and/or lab measurements. General linear regression models and formal mediation analysis were performed. Sensitivity analysis was performed among participants without any cardiovascular diseases (stroke and/or heart disease).

Result

Among a total of 267 individuals (mean age 68.4±8.8 years, 183(68.5%)female, 118(44.2%) SCD), OEF ranged from 28.6% to 53.5% (IQR = 5.3). After adjustment for demographics (age, sex, education), lifestyle factors (smoke, BMI, and physical inactivity), medical history, and SCD status, increasing OEF was associated with worsen Fazekas scores (β = 0.02, 95%CI = (0.01,0.04)). Both hypertension (β = 1.90, 95%CI = (0.53,3.27)) and stroke (β = ‐2.54, 95%CI = (‐4.42,‐0.67)) were independently associated with OEF. Mediation analysis demonstrated that higher OEF mediated the effects of hypertension on Fazekas scores (mediation effect = 0.04, 95%CI = (0.01,0.09)). The mediation proportion was up to 13.0% (p = 0.02). Robust mediation effect was found among participants without any cardiovascular diseases.

Conclusion

Abnormal brain oxygen delivery is associated with WMD at the early stage of cognitive impairment. Our study elucidates the potentially casual influence of OEF on the pathway between hypertension and WMD. OEF could be utilizable as a fast and convenient measurement in predicting early brain structural disturbances implicated in cognitive impairment and dementia.
Structural MRI‐Based AD Score using Bayesian VAEs
Authors: Nemali Aditya , Moyano Jose Bernal , Yakupov Renat , Schütze Hartmut , Spottke Annika , Ramirez Alfredo , Schneider Anja , Metzger Coraline D. , Laske Christoph , Bittner Daniel , Heneka Michael T. , Peters Oliver , Speck Oliver , Glanz Wenzel , Wagner Michael , Jessen Frank , Düzel Emrah , Ziegler Gabriel
Published: January 2025

Background

Alzheimer’s Disease (AD), a progressively worsening neurodegenerative disorder, impacts millions globally. Understanding its progression is crucial for developing effective interventions and management strategies. However, high variability in disease progression amongst individuals and the complexity of neuroimaging data pose significant challenges. Current diagnostic methods often fail to capture the nuanced progression, leading to delayed interventions, and lack uncertainty estimates, necessary for reliable decision‐making (Schaar et al., 2022). To address these issues, we here propose a Structural MRI‐Based AD Score (SMAS) using a Bayesian supervised Variational Autoencoder (Bayesian sVAE). The approach captures distinct morphometrical brain patterns associated to cognitive impairment across stages of AD. The score and model has potential to support personalized treatment plans and improve the efficacy of diagnostic tools.

Method

We used 415 and 200 longitudinal MRI scans from DELCODE (Jessen et al., 2018;) and ADNI (Salvatore et al., 2018), respectively. We focused on features computed from T1‐w images using CAT12 longitudinal pipeline (Gaser et al., 2022). The Bayesian sVAE model (Fig. 1) consists of an encoder network that learns to map brain features into a lower‐dimensional embedding space. Moreover, a predictive block predicts memory performance based on the latent mapping, and a decoder block that reconstructs the original input images from the latent space. We trained the sVAE on baseline DELCODE cohort with the expectation that the model will capture brain signatures characterizing aging and progression towards AD. We then assessed its generalization ability on follow‐up data and on ADNI.

Result

The Bayesian sVAE model, trained on sMRI features, shows potential for a parsimonous anatomy‐based characterization of individual disease progression. The model’s capacity to differentiate among various clinical groups using a single score (SMAS), and its correlations with key clinical and demographic variables, suggest its potential for identifying structural brain related to progression (Fig. 2). Using longitudinal test data, the model‐based latent scores indicated expected group differences and changes (Fig. 3).

Conclusion

The Bayesian sVAE model has shown promise in continuously monitoring atrophy over stages of AD progression. We provide indications for generalizability to unseen data (ADNI), suggesting robustness across different imaging protocols and scanners, and considerable stability over repeated measures.
Implementation and validation of an electroencephalography dual‐task paradigm for detection of preclinical Alzheimer’s Disease
Authors: Rada Juliana Moreno , Saldarriaga Luisa María Zapata , Guevara Eduardo Montoya , Cuartas Santiago Gonzalez , Ramírez María José Hidalgo , Cano Paula Andrea Cataño , Alvarez Sara Garces , Flores Nicolás Vargas , Lopera Juan Esteban Pineda , Estrada Santiago Rivera , Mosquera Andrés Felipe Asprilla , Mancilla Juan Pablo Restrepo , Niño David Fernando Aguillón , Arroyave Juan Rafael Orozco , Quintero Carlos Andrés Tobón , Gómez John Fredy Ochoa
Published: January 2025

Background

Dementia has a worldwide prevalence of 55 million people, with 60 to 70% of cases attributed to Alzheimer’s Disease (AD). In Antioquia, Colombia, exists a group of families with early‐onset AD associated to PSEN1‐E280A, a genetic variant with an autosomal dominant inheritance pattern and a penetrance over 99%, which enables the study of individuals across different disease stages. Electroencephalography (EEG) is a non‐invasive, portable, and low‐cost technique that allows the study of electrophysiological changes associated with neurodegeneration. When used in conjunction with dual‐task paradigms, EEG could serve as a clinical marker for evaluating brain functional reserve according to three theoretical models: the ability to share cognitive resources between tasks, the cross‐talk dependent on the content of processed information, and the bottleneck model. Therefore, the combined use of EEG and dual‐task represents a potential novel and adaptable alternative in clinical settings for detecting preclinical stages of AD.

Method

The study population comprises cognitively healthy individuals who are carriers of the PSEN1‐E280A variant and control subjects without mobility limitations or impairments in verbal or written communication skills. The experimental protocol involves a motor task (single‐task) of elbow flexion‐extension and a motor‐cognitive task (dual‐task) that integrates the single‐task with six cognitive tasks. Data on upper extremity function (UEF) were collected using a tri‐axial wearable gyroscope and accelerometer sensor, while EEG recordings were obtained with the Open BCI CYTON BIOSENSING BOARD device, using the channels FP1, FP2, C3, C4, P7, P8, O1, O2.

Result

10 healthy non‐carrier individuals have been evaluated to describe the behavior of the metrics in control subjects. The UEF measured by angular velocity curves illustrates a lower amplitude and flat points during the dual‐task compared to the single‐task, indicating that cognitive activity impacted motor performance. The EEG recordings showed a higher power spectral density during dual‐task compared to single‐task.

Conclusion

The obtained results represent the motor performance between single and dual‐task modalities, which possibly represent a change in the dynamics of brain functioning as observed in the EEG signals.
Portable, Low‐field MRI for Alzheimer’s Disease
Authors: Kimberly W. Taylor
Published: January 2025

Background

Low‐field magnetic resonance imaging (LF‐MRI) may facilitate point‐of‐care assessment of patients with Alzheimer’s Disease (AD) that can increase accessibility. However, image quality may be limited by lower signal‐to‐noise ratio (SNR). We developed a machine learning pipeline to quantify brain morphometry and white matter hyperintensities (WMH) using LF‐MRI, validated the volumes against conventional high‐field (HF) counterparts, and compared the volumes with aged controls.

Methods

Patients with a diagnosis of mild cognitive impairment (MCI) or dementia due to AD (n = 45, age 73±8 years) were prospectively enrolled in the MGH Memory Division outpatient clinic. A separate cohort of controls (n = 23, age 64±8 years) were enrolled from the Yale Emergency Department and used for comparison. All patients underwent LF‐MRI acquisition on a 0.064T MRI which included T2 FLAIR and T1w sequences. We processed images through FreeSurfer‐based pipelines using LF SynthSR and SynthSeg for quantification of brain volumes and WMH‐SynthSeg to measure WMH burden. HF‐MRI (1.5‐3T) scans obtained within 8±12 months of LF‐MRI acquisition were used for comparison. Whole brain, hippocampal, and lateral ventricle volumes and WMH were quantified from HF and LF scans in patients and controls, normalized to intracranial volume (mean±SD).

Results

Brain volumes quantified on LF‐ and HF‐MRI were correlated, including hippocampal (r = 0.82, 95% CI 0.72‐0.93), whole brain (r = 0.97, 95% CI 0.96‐1.0) and lateral ventricle (r = 0.98, 95% CI 0.96‐1.0) volumes (all p<0.0001). WMH burden was also correlated (r = 0.80, 95% CI 0.66‐0.91) between LF‐ and HF‐MRI scans. Compared to controls, hippocampal volumes were smaller among those with MCI or AD (2.3±0.2−3 versus 2.6±0.3−3, p = 0.0001). A similar reduction in whole brain volume was observed in MCI/AD patients (591.2±19.8−3 versus 621.3±20.5−3, p = 0.0001), which was accompanied by ventricular enlargement (18.6±7.4−3
cf. 13.1 ±7.3−3, p = 0.0007).

Conclusion

Point‐of‐care LF‐MRI of patients with MCI or dementia due to AD is feasible and generates accurate brain volumes and WMH burden when combined with machine learning algorithms. Collectively, our findings demonstrate LF‐MRI’s potential in cost‐effective image evaluation for cognitive impairment that may reduce disparities in access. Our findings also highlight the future potential for routine longitudinal assessment, disease staging, and monitoring during anti‐amyloid treatment.
Oral Microbial Dysbiosis Associated with Alzheimer’s Dementia in Puerto Ricans: A Preliminary Report
Authors: Morales Hiram , Herrero‐Rivera Carlos Alberto , Soler‐Llompart Cecilia Michelle , Sala‐Morales Ana Cecilia , Olivieri‐Henry Gerianne , Godoy‐Vitorino Filipa , Sepulveda Vanessa
Published: January 2025

Background

New studies have linked epidemiological and pathophysiological relationships between oral microbiota and Alzheimer’s disease (AD), a neurodegenerative disease more prevalent in the Puerto Rican population. Dysbiosis of the oral microbiome induces periodontal disease, which increases systemic chronic inflammation, an important component in the multifactorial pathogenesis of AD. This project aims to characterize the oral microbiota’s composition and diversity in AD patients compared to healthy controls, and explore the potential role of oral dysbiosis in dementia.

Method

A total of 52 participants were recruited (28 with Alzheimer’s Disease and 24 healthy controls), IRB #2290033626. Evaluations included a complete medical history and physical exam, and psychologic assessments with the Montreal Cognitive Assessment (MOCA) and Clinical Dementia Rating (CDR). Blood samples were collected for genotyping of the APOE gene. Oral samples were collected for genomic DNA extractions and microbiome characterization using 16S rRNA genes (V4 region) via Illumina MiSeq.

Result

A statistically significant difference in bacterial composition was found in beta‐diversity between AD group and Controls (p‐value = 0.027). Among cognitive stages by CDR (p‐value = 0.04), a significant difference in beta‐diversity is also seen between participants with “no dementia”, “mild dementia”, and severe dementia”, which also correlates with distinctive richness at the genus‐level. LEFSe and Correlation analysis showed an increased abundance of oral genus Haemophilus in controls as compared to AD, and in increase in Corynebacterium in AD patients. Additionally, there is an increase in the proinflammatory bacteria Prevotella and a decrease in anti‐inflammatory bacteria Proteobateria also occurs in AD participants with abundance correlating with grades of cognitive impairment.

Conclusion

This research underscores the intricate interplay between oral microbiota dysbiosis, periodontal disease, chronic inflammation, and Alzheimer’s Disease (AD). Our preliminary findings suggest a potential association between alterations in oral microbiota composition and the presence and severity of AD. Further investigation, including periodontal assessments and analysis of chronic inflammatory markers, is warranted to elucidate the mechanistic links and potential therapeutic avenues in managing AD within the Puerto Rican population.
Fibrinogen as a Key Binding Partner in Human Plasma for Lecanemab Biosimilar IgG
Authors: Bellier Jean‐Pierre , Viera Andrea M. Román , Christiano Caitlyn , Anzai Juliana A. U. , Moreno Stephanie , Campbell Emily C. , Godwin Lucas , Li Amy , Chen Alan Y. , Alam Sarah , Saba Adrianna , Yoo Han bin , Yang Hyun‐Sik , Chhatwal Jasmeer P. , Selkoe Dennis J. , Liu Lei
Published: January 2025

Background

Therapeutic monoclonal antibodies targeting amyloid beta‐protein (Ab), such as lecanemab, represent a promising approach for disease‐modification in Alzheimer’s disease (AD). Due to its relatively short half‐life, lecanemab is given as a bi‐monthly infusion (typically 10mg/kg). Binding to high abundance plasma proteins (PPB) can influence the pharmacokinetics of drugs in the blood, including their half‐life.

Method

In this study, we investigated the potential of PPB for lecanemab using a biosimilar synthetized from publicly available lecanemab sequence (Lec‐bs). Lec‐bs biosimilar immunoreactivity was assessed in human plasma fractions obtained by size exclusion chromatography using both ELISA and Western blotting. The binding of lec‐bs to candidate PPB was validated through Western blotting, ELISA, and surface plasmon resonance analysis.

Result

Using a combination of equilibrium dialysis, ELISA, and Western blotting of human plasma, we first describe the presence of likely PPB for Lec‐bs, and then identify fibrinogen as a probable major plasma protein binding partner for Lec‐bs. Utilizing surface plasmon resonance, we confirmed that Lec‐bs binds to fibrinogen, albeit with lower affinity (318 µM) than to monomeric Ab (324 nM).

Conclusion

In the context of lecanemab therapy, these results suggest that fibrinogen levels may influence free antibody levels in blood and that fibrinogen may act as a reservoir for lecanemab. More broadly, these results indicate that PPB may be an important consideration for the clinical use of therapeutic antibodies in neurodegenerative disease.