bluuebunny/crossref_metadata_2025 huggingface dataset:
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

Background

Astrocytes 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.

Method

Participants 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.

Result

Higher 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.

Conclusion

Our 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

Background

Accelerated 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.

Methods

Participants 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.

Results

Despite 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).

Conclusion

Acceleration 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

Background

The 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.

Method

A 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.

Result

Infusion‐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%.

Conclusion

With 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

Background

Traditionally 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.

Method

Recent 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.

Result

The 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.

Conclusion

While 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

Background

Arterial 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.

Method

Fifty‐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.

Result

te‐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.

Conclusion

This 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

Background

Individuals 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.

Method

AC 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.

Result

63 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.

Conclusion

AC 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

Background

Responses 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).

Method

Individuals 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.

Result

Physiological 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]).

Conclusion

The 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

Background

Genetic 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.

Method

Our 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.

Result

Forty‐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.

Conclusion

Our 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.
Identifying patients with cognitive impairment in a large health system: an innovative initiative to facilitate detection in primary care
Authors: Gaster Barak , Suchsland Monica Zigman , Fitzpatrick Annette L. , Liao Joshua M. , Belza Basia , Hsu Amy P , McKiddy Sarah , Olivari Benjamin S. , Raetz Jaqueline G.
Published: January 2025

The prevalence of Alzheimer’s disease and related disorders (ADRD) is rising, and primary care providers (PCPs) will increasingly play a role in its detection. We developed an evidence‐based intervention to facilitate cognitive evaluation in primary care. We then implemented it as a set of web‐based trainings which were combined with specific tools embedded in the electronic health record (EHR) for PCPs to use in their practices. The model was adapted from the Gerontological Society of America’s KAER (Kickstart, Assess, Evaluate, Refer) Toolkit, and rolled out across 14 community‐based primary care clinics in a large health system. Outcome measures included: 1) the number of cognitive assessments entered into the EHR; 2) the number of patients diagnosed with mild cognitive impairment (MCI); and 3) change in PCP confidence and attitudes in identifying and managing dementia assessed by a validated survey tool, the General Practitioner’s Attitudes and Confidence Scale for Dementia (GPACS‐D). The number of cognitive assessments entered into the EHR in the six months before the intervention compared to the six months after increased from a mean of 5.2 to 21.2 per month (p<0.01); the number of patients newly diagnosed with MCI increased from a mean of 23.5 to 32.2 per month (p = 0.03); and fifty PCPs who completed the GPACS‐D survey reported significant improvement in confidence and attitudes (mean total attitude and confidence score increase from 3.33 to 4.09, p<0.01). This data suggests an initiative like this can improve cognitive evaluation and increase identification of MCI across a large primary care network. The initiative’s methods are designed to be easy to replicate, without requiring hiring new staff or building new services, making it highly scalable. The educational videos and EHR tools developed are available at no charge to anyone who wants to adapt this approach. Easy to deploy, with clear, reproducible outcomes, it has the potential to improve ADRD care. As new therapeutics for ADRD become available, initiatives such as this will increasingly be needed to improve referrals to specialists, foster an engaged primary care workforce for collaboration, and improve the lives of patients living with ADRD.
RWD insights into disease progression
Authors: Eriksdotter Maria
Published: January 2025

Background

The new anti‐Aβ antibody drugs aducanumab and lecanemab (approved in the US, not yet in Europe) must be followed up closely and regularly long‐term. Previous knowledge on progression of AD in routine clinical settings longterm is crucial when introducing new dementia medications. The Swedish national quality database on dementia/cognitive disorders, SveDem, where data on different dementia disorders at the time of the dementia diagnosis since 2007 and on mild cognitive impairment (MCI) since 2021 with annual follow‐ups of MMSE scores can provide this unique information.

Methods

SveDem, www.svedem.se is to date the largest database in the world on different dementia disorders and from 2021 also on MCI. The registry includes individuals at the time of the MCI or dementia diagnosis with annual follow‐ups, at present with >122, 000 persons, who are followed through the chain of care. By linking SveDem to other registers, data on diagnostics including biomarkers, comorbidities, treatment, care, mortality and prognosis can be obtained.

Results

From SveDem have shown that mortality in dementia disorders over a 10‐year time period is decreasing, partly associated with changes in drug prescribing practices. Among the different dementia disorders, SveDem data show that AD has the best survival while the highest mortality is found in persons with DLB/PDD. Follow‐up data on use of the current dementia drugs choline esterase inhibitors (ChEIs) in an AD population of > 17 000 persons showed ChEIs to be associated with small but persistent cognitive benefits long term (5 years). Moreover, based on SveDemdata, ChEI treatment was found to be associated in an AD population with reduced risk for myocardial function, stroke, heart failure, kidney dysfunction and overall mortality. Additional data on disease progression will be presented.

Conclusion

Clinical routine long‐term data on large populations of persons with AD (and other dementia disorders) treated with or without current dementia drugs, on prognosis, progression and mortality already exist to be used for long‐term comparisons with new approved AD medications. Moreover, the quality data base SveDem collects data regularly and will start gathering data on the new anti‐amyloid dementia drugs on effects/progression if approved in Europe.
Development of a serum miRNA panel for detection of Alzheimer's Disease
Authors: Zhang Xinyu , Su Chang , Cao Yuan , Yang Songtao , Qin Qi , Tang Yi
Published: January 2025

Background

An urgent need exists for minimally invasive testing for accurate detection of Alzheimer’s disease (AD). Circulating microRNAs (miRNAs) have been investigated as a promising candidate biomarker for AD diagnosis and prediction because of their involvement in multiple brain signaling pathways in both health and disease. This study developed and validated a serum miRNA panel in discriminating clinically diagnosed AD from age‐matched cognitively healthy controls.

Method

383 serum samples (194 AD, 189 cognitively healthy controls) were divided into three cohorts: discovery (n=59), training (n=126), and validation (n=198). In the discovery cohort, 49 miRNAs curated from literature databases were verified using individual serum sample via reserve transcriptase‐quantitative Polymerase chain amplification (RT‐qPCR). A logistic regression model was built with 11 differentially expressed miRNAs using the training cohort, and the final panel comprising 7 miRNAs with superior diagnostic performance was established. The diagnostic efficacy of the 7‐miRNA panel was further evaluated in the validation cohort by the receiver operating characteristic (ROC) analysis.

Result

Of the initial 49 screened serum miRNAs, 11 differentially expressed miRNAs were selected for logistic regression model construction based on their potential for detecting AD patients (AUC ≥ 0.7). After model optimization and validation via RT‐qPCR, a 7‐miRNA panel (miR‐146a‐5p, let‐7i‐5p, miR‐21‐5p, miR‐29c‐3p, miR‐92a‐3p, let‐7f‐5p, and miR‐1285‐5p) was identified with area under the curve (AUC) of 0.970 and 0.932 in the training and validation cohorts, respectively. The sensitivity of 7‐miR test was 88%, and the specificity was 85% in the validation cohort.

Conclusion

These findings suggest that the 7‐miRNA signature in serum serves as a novel noninvasive tool for the adjunctive diagnosis of AD. The panel shows promise for clinical application, setting the stage for future studies across diverse populations.
Plasma Proteomic Determinants of Small Vessel Disease of the Brain: the Multi‐Ethnic Study of Atherosclerosis
Authors: Kalani Rizwan , Fohner Alison E , Austin Thomas R. , Emrani Sheina , Jensen Paul N. , Frazier‐Wood Alexis , Bertoni Alain G. , Shah Sanjiv J. , Habes Mohamad , Rashid Tanweer , Charisis Sokratis , Walker Keenan A. , Longstreth William T , Tirschwell David L , Psaty Bruce M. , Floyd James , Tahir Usman A , Gerszten Robert Edgardo , Rotter Jerome I , Rich Stephen S , Heckbert Susan R. , Hughes Timothy M.
Published: January 2025

Background

The identification of novel blood‐based biomarkers of small vessel disease of the brain (SVD) may improve pathophysiologic understanding and inform the development of new therapeutic strategies for prevention. We evaluated plasma proteomic associations of white matter fractional anisotropy (WMFA), white matter hyperintensity (WMH) volume, enlarged perivascular space (ePVS) volume, and the presence of microbleeds (MB) on brain magnetic resonance imaging (MRI) in the population‐based Multi‐Ethnic Study of Atherosclerosis (MESA).

Methods

Eligible MESA participants had 2941 plasma proteins measured from stored blood samples (collected in 2016‐2018) using the antibody‐based Olink proteomics platform, and completed brain MRI scans in 2018‐2019. Participants with quality control exclusion of protein measurements, missing covariate data, and poor quality or missing MRI outcome variables were excluded. The cross‐sectional association between the abundance of each plasma protein (normalized protein expression – a relative protein quantification unit measured on a log2 scale) was modeled separately with WMFA, WMH volume, total ePVS volume, and the presence of MBs using multivariable linear or modified Poisson regression, adjusting for demographic variables, estimated glomerular filtration rate (eGFR), and SVD risk factors. The Benjamini‐Hochberg procedure was used to control the false discovery rate (FDR) <0.05 to account for multiple hypothesis testing. For proteins independently associated with the SVD markers on MRI, penalized regression with least absolute shrinkage and selection operator (LASSO) was used to create a parsimonious proteomic model.

Results

Eligible participants (total N=709) had a mean age of 73 years, 53% were women, 25% were Black, 17% were Chinese, 19% were Hispanic or Latino, and 39% were White (Table 1). After adjustment for demographics, eGFR, and SVD risk factors, 769 plasma proteins were associated with WMFA (FDR <0.05) (Figure). LASSO regression identified a 37‐protein model predictive of WMFA (Table 2). We did not find plasma proteins to be independently associated with WMH volume, ePVS volume, or the presence of MBs.

Conclusion

Multiple circulating proteins – implicated in central nervous system myelination, lipid metabolism, angiogenesis, coagulation, cellular adhesion and migration, appetite regulation, energy homeostasis, systemic inflammation, and immune regulation – were independently associated with WMFA in a multi‐ethnic cohort of older adults.
Attention Network Dysfunctions in Lewy Body Dementia and Alzheimer’s Disease
Authors: Su Li
Published: January 2025

Background

Attention deficits are notable in Lewy body dementia (LBD) and in Alzheimer’s disease (AD), however, its underlying neurobiology and neuropathology are unclear. Functional magnetic resonance imaging (fMRI) and electroencephalograph (EEG) provides information about attention deployment and regional neural oscillatory deficits in LBD and AD. In this study, we combined fMRI and EEG to detect neural correlates of attention dysfunctions in LBD and AD.

Method

We recruited 33 patients with LBD, 15 patients with AD and 19 elderly healthy controls. All participants underwent a 3T fMRI scanning and a subsequently EEG recording. During fMRI and EEG, participants performed the same modified Attention Network Task (ANT) to investigate the alert, orient, executive and conflict attention dysfunctions. Here, we have focused on the EEG part of the study while using the fMRI data to localise the EEG signal on the cortex.

Result

Behaviourally, although both LBD and AD maintained a relative normal executive/conflict attention, we found that LBD had alert attention deficits and AD showed apparent orient attention dysfunctions. Based on source‐level EEG analyses, LBD had frontal‐central deficits for alert attention while AD showed inferior frontal and precentral impairments for orient attention. In addition, the insular and inferior frontal areas was hyper‐activated in LBD and AD for executive/conflict attention. Apart from these areas, LBD showed complementary temporal‐central‐occipital network for the modified ANT task. Furthermore, the oscillational sources for the ANT effects indicated that alpha and theta bands were partly impaired in dementia patients.

Conclusion

In summary, using source localised EEG, we found that attention dysfunctions in LBD and AD have engaged different neural networks. This has important implications in understanding the symptomology in LBD such as recurrent visual hallucinations and cognitive fluctuation.
Discovery of Genes Underlying Cognitive Resilience in Individuals Predisposed to Alzheimer's Disease Risk
Authors: Tsai Wei , McNiff Caitlin E. , Reddy Joseph S. , Wang Xue , Quicksall Zachary , Nho Kwangsik , Dunn Amy R , Allen Mariet , Heckman Michael G. , Ren Yingxue , Zhao Na , Kantarci Kejal , Mielke Michelle M. , Petersen Ronald C. , Kaczorowski Catherine C. , Carrasquillo Minerva M. , Saykin Andrew J. , Ertekin‐Taner Nilüfer
Published: January 2025

Background

Two main risk factors of Alzheimer’s disease (AD) are aging and APOE‐ε4. However, some individuals remain cognitively normal despite having these risk factors. They are considered “cognitively resilient”. This study aimed to identify molecular factors that confer cognitive resilience in APOE‐ε4 carriers ≥ 80 years of age and may serve as biomarkers.

Method

We applied weighted gene co‐expression network analysis (WGCNA) to generate consensus co‐expression networks from blood of participants in two antemortem cohorts, the Mayo Clinic Study of Aging (MCSA, n=105), and the Alzheimer’s Disease Neuroimaging Initiative (ADNI, n=91), using RNA‐sequencing and microarray data, respectively. We associated these networks with resilience (resilient vs non‐resilient), cognitive endophenotypes and hippocampal volume. Preservation between consensus networks from blood and those derived from postmortem brain tissues of AD and control donors from AMP‐AD (n=1174) was evaluated. We validated the human findings in four AD mouse models. Finally, machine learning models were utilized to discriminate cases (AD+mild cognitive impairment (MCI)) from controls in MCSA, ADNI and ANMerge antemortem cohorts.

Result

Four consensus networks were significantly correlated with a memory phenotype (logical memory delayed recall=LMDR) and hippocampal volume in both MCSA and ADNI. Among these, blood expression module M3 was most preserved with the brain transcriptome. M3 was enriched with NDUF hub genes that are involved in the mitochondrial respiratory chain. Expression levels of M3 and many blood NDUFs had significant associations with better LMDR and hippocampal volume. In brain, NDUFs were upregulated in controls compared to AD, and their expression levels were associated with better global cognition and decreased AD neuropathology. Many NDUFs were significantly downregulated in the hippocampus or cortex of AD mice compared to wild‐types. Lastly, models that included blood NDUFs improved diagnostic accuracy of AD+MCI compared to models that only included demographic and risk variables (age, sex, APOE‐ε4) in MCSA, ADNI and ANMerge. In MCSA and ADNI, adding NDUFs’ expression to models that included established blood biomarkers (Aβ42/40, ptau181, NFL) further improved diagnostic accuracy.

Conclusion

Our results suggest that mitochondrial NDUFs are centrally‐linked peripheral molecular signatures that may be resilience factors against AD and serve as both therapeutic targets and novel diagnostic biomarkers.
Default mode network and posterior resting‐state electroencephalographic alpha rhythms in Alzheimer’s disease patients
Authors: Babiloni Claudio
Published: January 2025

Background

Alzheimer’s disease dementia (ADD) is the most common neurodegenerative dementing disorder, explaining about 60‐70% of 50 million patients worldwide (www.who.int). Some previous studies in ADD patients showed significant neurodegenerative processes as revealed by reduced gray matter volume in the cerebral cortex, including the default mode network (DMN) cortical networks from structural magnetic resonance imaging (sMRI). Other studies in these patients reported a magnitude reduction in the resting‐state eyes‐closed electroencephalographic (rsEEG) alpha rhythms reflecting vigilance dysfunctions. Here, we tested the hypothesis of a significant relationship between these neurodegenerative and neurophysiological readouts, thus suggesting the sensitivity of rsEEG alpha rhythms to intrinsic AD processes.

Methods

Clinical, sMRI, rs functional MRI, and rsEEG rhythms in demographic‐ and age‐matched ADD (N = 45), subjective memory complaint (SMC, N = 160), and healthy cognitively unimpaired (Nold, N = 40) persons were available from an international archive (www.pdwaves.eu). Individual alpha frequency peak was used to determine the alpha frequency band on a personal basis. The eLORETA freeware estimated rsEEG sources. Freeware platforms served to analyze MRI data.

Results

The core results showed (1) lower DMN volumes and posterior rsEEG alpha rhythms in the ADD than Nold participants and (2) a positive association of the functional connectivity of basal forebrain‐DMN and the posterior rsEEG alpha rhythms in the SMC participants negative but not positive to amyloid PET biomarkers (Figure 1).

Conclusions

A prominent relationship was observed between DMN and the posterior rsEEG alpha rhythms across physiological and AD‐related aging, suggesting the enrichment of the A‐T‐N Framework with "Pathophysiology" (P) EEG biomarkers.
Differences between white matter hyperintensities lesion load across allostatic load risk in cognitive complaint subjects
Authors: Contreras Patricio Riquelme , Henriquez Fernando , Campo Cecilia Gonzalez , Buller‐Peralta Ingrid , Thumala Daniela , Lillo Patricia , Okuma Cecilia , Demanet Michele , Damm María Francisca , Godoy Claudio Román , Alvez Pamela Guevara , Wael El‐Deredy , Muniz‐Terrera Graciela , Chonchol Andrea Slachevsky
Published: January 2025

Background

Chronic exposure to stress, quantified by allostatic load (AL), has been postulated as a cause of structural brain changes in the context of dementia. White matter hyperintensities (WMH), detected in MRI FLAIR, are a common brain abnormality representing small vessel disease or degenerative changes in the brain. Here, we studied differences in tract‐specific WMH volume across three risk levels of AL in Chilean subjects with cognitive complaint, to explore links between chronic stress exposure and prodromal steps of dementia.

Method

The study included 135 subjects with cognitive complaint from a chilean cohort. Based in MoCA test, subjects were classified in mild cognitive impairment (MCI) (47) and subjective cognitive complaint (SCC) (88). To measure AL, we employed 15 metabolic, cardiovascular and immunity biomarkers, and the scores were classified in low, medium, and high risk levels of AL. WMH were calculated with Lesion Segmentation Toolbox, in SPM 12, and segmented according to John Hopkins University (JHU) and Human Connectome (HCP) atlases. To explore differences in tract‐specific WMH volume per risk level AL, we used a Kruskal Wallis test in each cognitive group (SCC and MCI). In significant tracts, a U Mann ‐ Whitney test was performed to establish the paired AL risk groups with significance.

Result

In the MCI group, we found a higher tract‐specific WMH load as a function of AL risk level in 10 tracts of the JHU atlas, and in 31 tracts of the HCP atlas. Differences were observed between low and medium‐risk of AL, with medium‐risk group showing a higher WMH load than low‐risk group.

Conclusion

We observed significative differences in tract‐specific WMH lesion between low and medium risk of AL, only in MCI. It is according with literature that show the WMH burden could be associated with cognitive deficit, but not it’s risk. In this study, we further establish a link between chronic stress exposure and WM structural changes in early stages of neurocognitive disorders. We suggest that AL is a global measurement that could mediate the relation between vascular or neurodegenerative factors to WMH origin. Use of neurodegenerative and cardiovascular biomarkers can be useful to explore this mediation.
Choroid plexus volume as a novel candidate neuroimaging marker of the Alzheimer's continuum: a prospective cohort study
Authors: Jiang Jiwei , Li Wenyi , Jiang Shirui , Xu Jun
Published: January 2025

Background

The clinical role and potential mechanisms of the choroid plexus (ChP) in Alzheimer's disease (AD) remains unclear.

Method

This prospective cohort study enrolled 607 participants [110 healthy controls (HCs), 269 mild cognitive impairment (MCI), and 228 AD dementia] from the Chinese Imaging, Biomarkers, and Lifestyle study between January 1, 2021, and December 31, 2022. Relationship between ChP volume and the cerebrospinal fluid (CSF) pathological hallmarks (Aβ42, Aβ40, Aβ42/40, tTau, and pTau), neuropsychological tests [Mini‐Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Neuropsychiatric Inventory (NPI), and Activities of Daily Living (ADL) scores], and multimodal neuroimaging measures were analyzed using partial Spearman’s correlation. The mediating effects of ChP volume were examined on the relationship between CSF hallmarks and neuropsychological tests. The ChP volume performance to differentiate the presence/absence of cerebral Aβ42 deposition was determined using receiver operating characteristic analysis. Generalized linear mixed‐effects models discerned the association between baseline ChP volume and longitudinal changes in neuropsychological tests in patients on AD continuum.

Result

The participants' mean age was 65.99±8.79 years. Patients with AD dementia exhibited a larger baseline ChP volume than the other participants (P<0.001; Figure 1). ChP volume enlargement correlated with decreased Aβ42 and Aβ40 levels; lower MMSE and MoCA and higher NPI and ADL scores; lower volume, cortical thickness, and corrected cerebral blood flow in other cognition‐related regions (all P < 0.05). ChP volume alone mediated and ChP–hippocampal volume combined chain mediated the association of CSF Aβ42 and Aβ40 levels with the MMSE scores (16.91%, 37.15%, 14.25%, and 27.82%, respectively; Figure 2). ChP volume better identified the presence/absence of cerebral Aβ42 deposition than hippocampal volume (AUC: 0.762 vs. 0.724; Figure 3). Baseline ChP volume was associated with subsequent decline and faster worsening in the MMSE, MoCA, and ADL scores with 10.03±4.45 months' follow‐up (all P<0.001).

Conclusion

ChP volume is a novel, candidate, non‐invasive neuroimaging marker associated with neurodegenerative changes in Alzheimer’s continuum. It can detect early cerebral Aβ42 deposition and predict prognosis in clinical practice.
Plasma insulin is an early biomarker of amyloid‐β pathology in Alzheimer’s disease
Authors: Chen Yuhan , Wang Zhibo , Mao Zhiqi
Published: January 2025

Background

Evidence suggests that type 2 diabetes (T2D) is an independent risk factor for Alzheimer's disease (AD), sharing similar pathophysiological traits like impaired insulin signaling. However, how plasma insulin changes with AD key pathologies and its diagnostics value remain unclear.

Method

A total of 304 participants were included in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), assessing plasma insulin and cerebrospinal fluid (CSF) AD pathology. We explored the cross‐sectional and longitudinal associations between plasma insulin and AD pathology and compared their associations across different AD clinical and pathological stages. We also explored the potential diagnostic value of plasma insulin on AD pathology using the receiver operating characteristic (ROC) curves.

Result

In the non‐demented group, A+ participants (e.g., as reflected by CSF Aβ42) exhibited significantly reduced plasma insulin levels compared to non‐demented A‐ participants (P < 0.001). Furthermore, A+T‐ participants (e.g., as reflected by CSF Aβ42 and CSF p‐tau181) had lower plasma insulin levels than A‐T‐ participants in the non‐dementia group (P = 0.002). No significant differences were observed in the dementia group (Figure 1). In addition, a notable positive correlation was found between plasma insulin levels and CSF Aβ42 (P < 0.001) in all participants. When stratified by clinical status and pathological status, this association only existed in the A‐ group (P = 0.002) and the non‐demented group (P < 0.001) (Figure 2). Moreover, plasma insulin at baseline was significantly associated with longitudinal changes in CSF Aβ42 (P = 0.02), while baseline CSF Aβ42 was not associated with longitudinal changes in plasma insulin (Figure 3). Regarding the diagnostical value, plasma insulin alone demonstrated acceptable accuracy in distinguishing A+ from A‐ individuals in the whole participants (area under the curve [AUC]=0.61) and more prominent in the non‐dementia group (AUC = 0.65) than in the dementia group (AUC = 0.52). When added age, sex, and APOE ε4 status were as predictors, the AUC of plasma insulin reached 0.8 in the whole participants.

Conclusion

These findings pinpoint the association between plasma insulin and early Aβ pathology in the early stages of AD, suggesting that plasma insulin can serve as an early biomarker of Aβ pathology.
Patients with Controlled and Uncontrolled Type 2 Diabetes: Systemic Oxidative Stress and Systemic Inflammation as Predictors of Peripheral and Central Neuropathy
Authors: Oo Thura Tun , Skarr Max , Mon Yee Yee , Htwe Kyi Kyi
Published: January 2025

Background

Diabetes mellitus increases the risk of cognitive decline and neuronal degeneration. In diabetes, persistently elevated blood sugar levels cause not only the generation of reactive oxygen species (ROS), but also systemic inflammation (1). This raises an intriguing question: do patients with controlled or uncontrolled diabetes exhibit similar levels of oxidative stress and systemic inflammation as reliable predictors of peripheral neuropathy and cognitive decline?

Method

In 2019, 150 participants with diabetes mellitus who had been diagnosed for more than 5 years were voluntarily enrolled. Blood was obtained to measure systemic oxidative stress and inflammation. Vibrometer and Mini‐Mental State Examination (MMSE) were used to assess peripheral and central neuropathy, respectively. The association with peripheral and central neuropathy was evaluated using multivariate logistic regression analyses.

Result

Using HbA1C (6.5%) targets for categorization, 60% of participants were controlled diabetes patients and 40% were uncontrolled patients. The plasma malondialdehyde level was significantly higher in patients with uncontrolled diabetes than patients with controlled diabetes (63% Vs. 23%, P < 0.05). The C‐reactive protein (CRP) level significantly higher in patients with uncontrolled diabetes than patients with controlled diabetes (70% Vs. 35%, P < 0.05). In patients with uncontrolled diabetes, there was a correlation between the level of plasma malondialdehyde and sensory neuropathy as well as cognitive decline (r = 0.774, P < 0.05 and r = 0.734, P < 0.05, respectively), whereas we found the correlation between the level of CRP and sensory neuropathy as well as cognitive decline (r = 0.873, P < 0.05 and r = 0.688, P < 0.05, respectively). Both sensory neuropathy and cognitive decline were uncorrelated with the level of plasma malondialdehyde in patients with controlled diabetes, and neither was there a correlation with the level of CRP.

Conclusion

This study demonstrated that systemic oxidative stress and systemic inflammation are reliable clinical predictors of peripheral and central neuropathy in uncontrolled diabetes, but not in controlled diabetes.