bluuebunny/crossref_metadata_2025_split huggingface dataset:
AHEADx: Revolutionizing Early Alzheimer’s Disease Diagnosis Through Blood with Integrated Acoustofluidics and Photonic PCR Technologies
Authors: Belcea Eric V , Johnson Kim G , Liu Andy , Luo Sheng , Sanders Laurie H , Lee Luke P , Huang Tony J 
Published: January 2025

AbstractBackgroundThis study introduces the Automated High‐purity Exosome isolation‐based AD diagnostics system (AHEADx). By analyzing and understanding the molecular cargo (proteins and miRNAs) carried by circulating exosomes, researchers found brain‐derived exosome (BDE) levels of P‐S396‐tau, P‐T181‐tau, and Aβ1‐42 are elevated up to 10 years prior to clinical symptoms. Currently, there is no available technology capable of simultaneously isolating and screening exosomal biomarkers for efficient and personalized precision medicine giving early AD diagnosis.MethodThis NIH funded study will develop and validate AHEADx via integrated acoustofluidics (i.e., the fusion of acoustics and microfluidics) and photonic PCR on‐chip technologies that are capable of fully automated, rapid, precise exosome isolation and accurate analysis for AD diagnostics. AHEADx consists of two units: a rapid (<1 min) acoustofluidic separation unit for exosome isolation from biofluids with high yield and purity (both >90%), and a rapid (<6 min) photonic PCR unit achieving detection limits of ∼1 copy/µL for nucleic acids and ∼5 copies/µL for proteins.Compared with state‐of‐the‐art exosome isolation and analysis technologies, AHEADx system has the following advantages:• Automated and fast operation in a point‐of‐care, handheld system• High‐purity (>90%), high‐quality exosome isolation for accurate biomarker detection• High‐sensitivity (∼1 copy/µL for nucleic acids and ∼5 copies/µL for proteins) detection of a comprehensive (∼20) panel of AD biomarkersResultTo validate the potential for clinical use, we will test plasma samples from 100 AD patients and 100 healthy individuals all with known amyloid, phospho tau and total tau biomarker status measured in their CSF. The Duke University Neurology Biobank and the Duke University and University of North Carolina Alzheimer’s Disease Research Center (Duke/UNC ADRC) will provide samples.ConclusionWe predict the AHEADx platform will be capable of the simultaneous isolation and analysis of exosome‐derived biomarkers for early AD neuropathological diagnosis. The AHEADx platform’s ability to accurately detect AD biomarkers in the preclinical stages as a point of care handheld instrument could revolutionize diagnosis of AD pathology in the office setting, enhance understanding of AD progression, and significantly impact research into effective treatments.
Astrocyte Reactivity and White Matter Integrity in the Context of Alzheimer’s Disease Pathologies
Authors: Li Oceanna Yueran , Turnbull Adam , Lin Feng Vankee 
Published: January 2025

AbstractBackgroundAstrocytes that become reactive in response to damage (e.g., due to typical brain aging or Alzheimer’s Disease/AD pathologies) can have both adaptive (e.g., maintaining myelination and clearing debris) and maladaptive (e.g., facilitating the spread of AD pathologies) functions. Here, we investigate how two protein markers of astrocyte reactivity (glial fibrillary acidic protein/GFAP and chitinase‐3‐like protein 1/YKL‐40) relate to medial temporal lobe (MTL) WM integrity and episodic memory in older adults with and without AD pathologies. We hypothesize that astrocyte reactivity would maintain WM stability and support memory when AD pathologies are absent.MethodParticipants with at least two repeated DTI sessions, 2 years apart, and cerebrospinal fluid (CSF) proteomics data were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) GO/2 sample (n=56). We selected two CSF proteomics biomarkers of astrocyte reactivity based on previous meta‐analyses – GFAP and YKL‐40. WM stability in MTL networks was quantified via correlation coefficients of mean diffusivity between baseline and 2‐year follow‐up. CSF‐based beta‐amyloid and p‐tau at baseline were also included. A mean episodic memory composite was calculated across both timepoints.ResultHigher GFAP and lower YKL‐40 levels at baseline were related to higher stability of MTL networks. The relationship between GFAP, but not YKL‐40, was moderated by beta‐amyloid pathology. When beta‐amyloid was absent, higher GFAP was related to greater WM stability and memory; higher WM stability mediated links between higher GFAP and better mean memory. When beta‐amyloid was present, higher GFAP was related to worse p‐tau but not to WM stability.ConclusionOur study examined the relationships between two protein markers of astrocyte reactivity, AD pathology, and MTL network WM stability. We replicated the interaction GFAP and beta‐amyloid in predicting p‐tau that implicates reactive astrocytes in the beta‐amyloid dependent propagation of p‐tau. The correlation between GFAP levels and both WM stability and memory in the absence of beta‐amyloid suggests astrocytic reactivity in healthy aging may contribute to the maintenance of WM connectivity. Alternatively, higher YKL‐40 was related to worse WM stability regardless of AD pathology suggests that YKL‐40 may reflect a reactive astrocyte state that is detrimental in healthy aging.
Accelerated midlife epigenetic age associates with poor later life brain health in the 1946 British Birth Cohort
Authors: Groves James , Maddock Jane , Keshavan Ashvini , Coath William , Nicholas Jennifer M , Wagen Aaron Z , Cash David M , Barkhof Frederik , Richards Marcus , Cole James H. , Schott Jonathan M 
Published: January 2025

AbstractBackgroundAccelerated epigenetic ageing has been associated with various age‐related health outcomes, but its relevance for dementia risk prediction is unclear. We investigated whether accelerated midlife epigenetic age associates with poor later‐life brain health.MethodsParticipants were 230 individuals from Insight 46, drawn from the 1946 British Birth Cohort, a population‐based study of individuals born in the first week of March 1946. DNA methylation was measured at 53 years using Infinium MethylationEPIC BeadChip and GrimAge and PhenoAge were calculated. ‘Age acceleration’ was derived for each clock (AgeAccelGrim and AgeAccelPheno), as previously. At 69‐71 years, we measured MRI whole brain and white matter hyperintensity volume, amyloid‐PET burden, plasma neurofilament light, and MRI Brain Age (with chronological age subtracted to produce the Brain‐Predicted Age Difference/Brain‐PAD). For n=176 with follow‐up MRI aged 72‐75 (n=176), whole brain atrophy was calculated using the boundary shift integral. CSF p‐tau181 was measured in n=64.ResultsDespite participants’ highly similar chronological age (mean=53.4 years, SD=0.2), there was considerable variation in AgeAccelGrim (SD=4.8yr) and AgeAccelPheno (SD=5.6yr). Linear regression revealed that accelerated GrimAge was associated with smaller later‐life whole brain volume, (b=‐1.9ml, p=0.010), whilst accelerated PhenoAge was associated with greater whole brain atrophy (b=0.403, p=0.001). Neither GrimAge nor PhenoAge acceleration was associated with amyloid‐PET burden. Accelerated PhenoAge was associated with higher white matter hyperintensity burden (b=0.03, p=0.04). Acceleration in both GrimAge (b=0.4pg/ml, p=0.001) and PhenoAge (b=0.4pg/ml, p=0.001) was linked to higher plasma neurofilament light, and both AgeAccelGrim (r=0.32, p=0.010) and AgeAccelPheno (r=0.35, p=0.005) were positively correlated with CSF p‐Tau181. MRI brain age (Brain‐PAD) was significantly correlated with AgeAccelGrim (r=0.15, p=0.02) but not AgeAccelPheno (r=0.08, p=0.2).ConclusionAcceleration of midlife epigenetic age was associated with a wide range of features of poor brain health ∼20 years later, in a population‐based sample. Epigenetic clocks may hold promise as tools for future brain health prediction.
Evaluating the safety of anti‐amyloid monoclonal antibody infusions in alternative sites of care
Authors: Miller Christine , Filibeck Don , Pica Lauren , Prosser Barbara 
Published: January 2025

AbstractBackgroundThe approval of anti‐amyloid monoclonal antibodies (mAbs) provides a novel approach to the treatment of Alzheimer’s disease. Infusions in alternative sites of care can benefit the patient financially and logistically, but coverage is largely payor dependent. The purpose of this study is to describe observations from this national complex specialty pharmacy around the safety of anti‐amyloid mAb infusions in alternative sites of care, including the home.MethodA multidisciplinary team conducted a retrospective review of medical records for patients receiving anti‐amyloid mAbs from 01/01/2023‐12/31/2023, including infusion‐related reactions and adverse events reported by the patient or caregiver. Thirty patients received a total of 194 infusions administered by registered nurses employed by this organization. Fifty‐seven infusions were provided in the home environment, and 137 infusions were conducted in the pharmacy’s ambulatory infusion centers.ResultInfusion‐related reactions occurred in 14.5% of infusions: hypotension 11%, hypertension 1.5%, headache 1.5%, and paresthesia 0.5%. The infusion rate was slowed during 1% of infusions. No infusions were discontinued due to infusion‐related reactions. No signs or symptoms of hypersensitivity or other infusion‐related reactions were observed by the nurse or reported by the patient during drug administration or the post‐infusion observation period. Patients completed mini‐mental state exams with the registered nurse during 94% of clinical assessments performed with the infusions. Symptoms associated with amyloid‐related imaging abnormalities (ARIA) were reported during 18% of assessments at the following rates: confusion 11%, headache 7%, altered mental status 6%, disorientation 3%, dizziness/vertigo 3%, irregular verbal communication 2%, gait difficulty 1%, visual disturbance 1%. One patient discontinued therapy after confirmatory MRI. Other adverse events reported during ≥2% of infusions include falls 7%, enlarged vocal cords 4%, nausea 2%, and flu‐like symptoms 2%.ConclusionWith the prevalence of Alzheimer’s disease expecting to reach 13 million by 2050, a wider scope of services needs to be considered for this patient population. Anti‐amyloid mAb infusions can be safely and successfully administered in alternative sites of care, including the home.
Exploring Therapeutic Potentials and Pathways of Psychedelics in Alzheimer’s Disease‐Related Dementia
Authors: Sinha Jitendra Kumar , Ghosh Shampa , Singh Krishna Kumar , Singh M P , Raghunath Manchala 
Published: January 2025

AbstractBackgroundTraditionally associated with recreational and spiritual uses, psychedelics have gained attention in psychotherapy for their therapeutic potential. Functioning as potent 5‐hydroxytryptamine (5HT) agonists, these compounds have demonstrated the ability to enhance neural plasticity by activating serotoninergic and glutamatergic systems. Despite these recognized effects, their role in treating neurodegenerative disorders, particularly dementia, remains relatively unexplored.MethodRecent studies have unveiled modulatory and beneficial impacts of psychedelics, including N, N‐dimethyltryptamine (DMT), Lysergic acid diethylamide (LSD), and Psilocybin, in Alzheimer’s disease (AD)‐related dementia. These compounds target neurotransmitter imbalances and molecularly modulate AD‐related signaling pathways, such as the Brain‐derived neurotrophic factor (BDNF) pathway, mTOR activation, and other autophagy regulators.ResultThe controlled administration of psychedelics, contingent on dosage, presents a novel therapeutic intervention for AD‐related dementia, warranting exploration for drug development. This review critically examines existing literature on the therapeutic potential and pathways of psychedelics for AD‐related dementia.ConclusionWhile promising, further studies are imperative to establish long‐term safety, efficacy, and optimal treatment protocols. Integrating psychedelics into the treatment paradigm may offer a transformative approach to address the unmet needs of individuals with AD‐related dementia and their caregivers.
Unmasking early cerebral blood flow alterations with time‐encoded ASL in Alzheimer's continuum
Authors: Falcon Carles , Montesinos Paula , Vaclavu Lena , Kassinopoulos Michalis , Minguillon Carolina , Fauria Karine , Cascales‐Lahoz Diego , Contador José , Fernández‐Lebrero Aida , Navalpotro Irene , Puig‐Pijoan Albert , Grau‐Rivera Oriol , Kollmorgen Gwendlyn , Quijano‐Rubio Clara , Molinuevo Jose Luis , Zetterberg Henrik , Blennow Kaj , Suarez‐Calvet Marc , Osch Matthias J.P. Van , Sanchez‐Gonzalez Javier , Gispert Juan Domingo 
Published: January 2025

AbstractBackgroundArterial spin labelling (ASL) is a non‐invasive MRI technique for quantifying cerebral blood flow (CBF), used for monitoring changes over the course of a disease or treatment. A crucial parameter in ASL is the post‐labelling delay (PLD), determined by the time it takes for blood to travel from the labeling location to the tissue under investigation. Time‐encoded ASL (te‐ASL) utilizes multiple PLDs for more accurate quantification. This study aims to enhance our understanding of CBF changes across the AD continuum, emphasizing the utility of te‐ASL over single‐PLD ASL in detecting early CBF changes.MethodFifty‐nine adults (≥ 60 years) along the AD continuum (24 cognitively unimpaired [CU] Aβ‐, 18 CU Aβ+, and 17 cognitively impaired [CI] Aβ+; Table 1) underwent CBF measurements using te‐ASL. Single‐PLD CBF measurements were derived based on the longest PLD (2000 ms) of the te‐ASL acquisition. CBF measurements were averaged across brain areas previously reported to be hypoperfused in AD. Associations between mean CBF and CSF biomarkers of Aβ, phosphorylated tau (pTau) proteins, synaptic dysfunction (GAP43, neurogranin, SNAP25, synaptotagmin‐1), and neurodegeneration (neurofilament light [NfL]), as well as cognitive scores, were investigated in CU participants. CSF Aβ42 and Aβ40 were assessed with Roche NeuroToolKit immunoassays, while pTau181 was measured with the Elecsys® Phospho‐Tau (181P) CSF immunoassay (Roche Diagnostics International Ltd). Sex and age were confounding variables.Resultte‐ASL exhibited superior sensitivity in detecting CBF hypoperfusion in CI Aβ+ subjects compared to single‐PLD ASL (Figure 1). Te‐ASL also revealed CBF hypoperfusion in CU Aβ+ subjects. In CU individuals, lower CBF correlated with decreased levels of CSF Aβ42/40 and increased levels of CSF pTau181, GAP43, neurogranin, SNAP25, and NfL (p < 0.05; Figure 2). No association was found between mean CBF and cognitive scores.ConclusionThis study provides compelling evidence that CBF reduction occurs earlier in the AD continuum than previously thought. te‐ASL emerges as a more sensitive tool than single‐PLD ASL for detecting subtle CBF changes across AD stages. Importantly, lower CBF in CU individuals correlates with multiple AD biomarkers, highlighting its potential as an early biomarker for AD progression.
Manifestation of Adult children of patients having Alzheimer’s dementia
Authors: Li Kuan‐Ying , Yang Yuan‐Han 
Published: January 2025

AbstractBackgroundIndividuals with his parents having Alzheimer’s dementia (AD) have a 4 to 10 times higher risk of developing AD compared to those without family history. The increasing risks of developing AD may result from several underlying mechanisms to be clarified for further strategies of management. We are going to report the demographic and biological characteristics of adult children (AC) of AD parents cohort with its clinical significances in Taiwan.MethodAC of AD patients age from 50‐79 years old were recruited from the neurological outpatient department of Kaohsiung Municipal Ta‐Tung Hospital, Taiwan. The paired individuals, adult children with his/her parents were received annual following up in clinical, neuropsychological, and neuroimaging including PET/CT with 18F‐Florbetaben (FBB) imaging session, using DiscoveryTM MI DR PET/CT system (General Electric Medical Systems, Waukesha, Wisconsin, USA) examinations and assays of blood for genetic and protein analyses. This study was approved by Kaohsiung Medical University Hospital Institutional Review Board. Written informed consent was obtained from all participants before including in this study.Result63 AC with age 59.3 ± 5.8 years, female predominant (76.2%), baseline MMSE 28.3 ± 1.8, CASI 94.7 ± 3.4, and having at least one of APOE e4 allele 34.9%, have recruited. 19 voluntary participants (25.4%) completed 18F‐FBB PET. 9 of 19 (47.4%) were classified as amyloid‐positive based on visual assessment, rated by a senior board‐certificated nuclear medicine physician with experience in interpretation of 18F‐FBB PET who evaluated all images according to the guideline of 18F‐FBB PET interpretation, blind to all clinical information.ConclusionAC of AD patients have higher proportion of having APOE4 allele and higher proportion of having amyloid PET (+). It may imply AC does increase the risk of developing AD, and AC with amyloid PET (+) could be preclinical AD.
Music To My Eyes? Exploring the pupil old/new effect to familiar and unfamiliar music in people with logopenic variant Primary Progressive Aphasia
Authors: Brotherhood Emilie V , Core Lucy , Levett Benjamin Aaron , O'Neill Eleanor , Firth Nicholas C. , Yong Keir X X , Warren Jason D , Crutch Sebastian J 
Published: January 2025

AbstractBackgroundResponses to individualized music in people living with dementia can be indicated by both verbal and non‐verbal cues. Evidence suggests that elevated pupil dilation responses to familiar vs. unfamiliar music are preserved in people living with typical Alzheimer’s disease (tAD), and to an extent in people with its atypical ‘visual’ variant (Posterior Cortical Atrophy; PCA) (Brotherhood et al., 2023). In the present work, we investigate whether this finding is also observable in individuals with the atypical ‘language‐led’ variant of Alzheimer’s disease, logopenic variant Primary Progressive Aphasia (lvPPA).MethodIndividuals with lvPPA or tAD (and cognitively normal adults) are currently being recruited via the Specialist Cognitive Disorders clinic at the National Hospital for Neurology and Neurosurgery, London, UK. We are simultaneously recording in‐the‐moment multiple physiological responses (e.g. pupillometry, electrodermal activity) while each participant listens to 30 different musical clips (classical (5 pieces), 1960s (10 pieces), 1970s (10 pieces), and five reversed pieces). Each clip has an a priori familiarity rating (known/unknown), participant‐rated pleasantness and familiarity, and participant‐rated ability to evoke a memory (yes/no). We will collect complementary basic clinical, audiometry and music experience data. Alongside pupillometry, multistrand physiological data via Empatica E4 devices will enable exploration of potential differential cardiovascular (heart rate/heart rate variability) and/or electrodermal activity (EDA) responses to familiar and unfamiliar music using within‐group linear regression models with robust standard errors.ResultPhysiological responses from a priori‐predicted and subjective ratings of music familiarity will be reported for each participant group, controlling for demographic factors including participant age and disease severity. Prospective results will provide further insight into what is currently known about pupillometry responses to familiar/unfamiliar music in atypical AD (PCA) and tAD (e.g. Estimated mean % increase in known vs unknown songs [95%CI]: Controls 1.8% [1.2, 2.5]; tAD 2.6% [0.6, 4.6]; PCA 2.0% [1.0, 4.0]).ConclusionThe results of this work will provide insight into the extent to which differential responses to music at the physiological level is retained within lvPPA. This may both support the notion of individualized music provision, and potentially provide a mechanism for these individuals to communicate their subjective experience of music using a non‐verbal mechanism.
Genetic counseling and testing in individuals at high risk for familial Alzheimer’s Disease from Latin America
Authors: Llibre‐Guerra Jorge J. , Bagnati Pablo Miguel , Castaño Marisol Londoño , Fernandez Maria L , Mora‐Henao Beatriz E , Mendez Patricio Chrem , Londoño Luz E Varela , Aguillon David Fernando , Surace Ezequiel , Manco Juan D Barbaran , Restrepo‐Fernández Carlos M , Ziegemeier Ellen , Vigo Gabriela , Varga‐Cuadros Gabriel A , McDade Eric , Bateman Randall J. , Allegri Ricardo , Lopera Francisco 
Published: January 2025

AbstractBackgroundGenetic testing for individuals with dominantly inherited Alzheimer’s disease (DIAD) is now of greater relevance due to the existence of therapeutic trials available to this population. However, the impact and main drivers influencing the decision to seek genetic testing are relatively unknown in Latin America (LatAm). Here we present results from a regional genetic counseling and testing protocol implemented in LatAm.MethodOur aim was to investigate the psychosocial impact of genetic testing in asymptomatic individuals from families with DIAD. A non‐randomized, controlled, prospective observational trial was conducted. Asymptomatic, first‐degree relatives of patients with DIAD from families with a presenilin 1, pathogenic variant (p.I416T or p.M146L) were interviewed before and after genetic testing. Group allocation was done according to participants’ choice (non‐randomized). Participants who received their genetic status (GS) were allocated to the test group, while those who opted out were allocated to the observational group. The primary outcome included change from baseline in depression, general anxiety, and health‐related anxiety in the test group relative to the observational group, using linear mixed effects models and chi‐squared tests.ResultForty‐five participants from Colombia and Argentina were invited and enrolled in the study. Thirty‐six individuals completed the genetic counseling sessions, and 25/36 (69.4%) learned their GS. Compared to families in Colombia, participants from Argentina were more likely to seek counseling and learn their GS (8/23, 34.9% vs, 17/20, 85.0%, respectively). Following genetic counseling, we found no significant differences between the group that learned their GS and those who did not learn their GS in anxiety (mean = 13.5, SD = 3.2 vs. 15.1, SD = 2.5, p = 0.2) or depression (mean = 5.4, SD = 2.3 vs. mean = 8.0, SD = 6.5, p = 0.6) scores. For both groups, anxiety and depression scores remained below cutoffs for clinical concern and without significant changes relative to baseline value levels.ConclusionOur pilot study shows that a structured genetic counseling and testing protocol for individuals at‐risk of DIAD is safe. We found relevant cross‐country differences in willingness to learn genetic status, which may reflect differences in religion, educational level, and urban vs rural areas, among others. Future studies should include larger cohorts and expand to other countries in LatAm.