bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glial changes are associated with cerebrovascular integrity in hyperhomocysteinemia‐induced VCID in mouse and human brain
Authors: Weekman Erica M , Winder Zachary , Rogers Colin B , Abner Erin L , Sudduth Tiffany L , Price Brittani R. , Woolums Abigail , Hawthorne Danielle , IV Charles E Seaks , Patel Ela , Dugan Adam , Fister Shuling X , Wasek Brandi , Bottiglieri Teodoro , Fardo David W. , Wilcock Donna M. 
Published: December 2023

AbstractBackgroundWith the aged population estimated to double by 2050 and the rate of dementia expected to triple, it is critical to identify treatments for dementia. One of the leading causes of dementia is vascular contributions to cognitive impairment and dementia (VCID), and is frequently found co‐morbidly with Alzheimer’s disease, the other leading cause of dementia. A modifiable risk factor for VCID is hyperhomocysteinemia (HHcy), which is defined as elevated levels of plasma homocysteine (a non‐protein‐forming amino acid), and most late‐life HHcy is caused by impaired B vitamin absorption. Although HHcy is a risk factor for VCID, the mechanism through which it induces cognitive impairment remains unclear.MethodWe used human and mouse brain tissue to determine glial and vascular changes associated with HHcy. Wild‐type (C57Bl6J) mice were placed on a HHcy or control diet for 6, 10, 14, or 18 weeks. Using qPCR, we investigated pro‐ and anti‐inflammatory cytokines. We also determined changes in microglia (IBA‐1) and identified the number of microhemorrhages and cognitive changes. In humans, we identified 31 autopsied research volunteers with antemortem homocysteine levels; 13 cases had normal plasma homocysteine levels (<14µmol/L) and 18 had high plasma homocysteine levels (>14µmol/L). We determined whether the level of plasma homocysteine was associated with microglia (IBA‐1) and astrocytes (GFAP) as well as microhemorrhages and atherosclerosis severity in the frontal and occipital cortices. Both gene expression and protein inflammatory markers were measured to determine associations with plasma homocysteine.ResultIn our mouse model of HHcy, we identified a time course of glial changes that first begins with an increase in pro‐inflammatory cytokines and increases in microglial staining at 6 weeks on diet. This is followed by cognitive changes at 10 weeks on diet. Finally, at 14 weeks on diet, we see significant cognitive deficits due to HHcy. In human tissue, HHcy was associated with more microglia but fewer astrocytes, a significant decrease in inflammation and increased microhemorrhages in the frontal cortex.ConclusionTaken together, this data shows that in both mouse and human tissue, HHcy induces significant glial and vascular pathology that could be driven by inflammatory effects.
Longitudinal changes in driving behaviours among older adults with different A/T/N biomarker profiles
Authors: Long Kelly , Bayat Sayeh , Babulal Ganesh M. 
Published: December 2023

AbstractBackgroundThe pathophysiological process of Alzheimer’s disease (AD) spans approximately 10‐15 years. To define AD by its pathologic processes, the A/T/N classification framework was proposed constituting β‐amyloid (A), tau (T), and neurodegeneration (N) biomarkers derived from cerebrospinal fluid (CSF) or imaging. With these biomarkers, individuals can be divided into four categories: normal (A‐T‐N‐), AD pathologic change (A+T‐N‐), AD (A+T+N‐, A+T‐N+, A+T+N+), and suspected non‐AD pathology (SNAP) (A‐T+N‐, A‐T‐N+, A‐T+N+). Recent evidence indicates that daily driving behaviours can identify preclinical AD, solely based on CSF β‐amyloid (A), with high accuracy. This study aims to determine the extent to which longitudinal changes in driving behaviour vary between individuals with different A/T/N profile categories.MethodParticipants were enrolled in a longitudinal study on driving and preclinical AD biomarkers from Washington University School of Medicine. Temporospatial driving behaviours were collected with a data logger installed in participant vehicles over a period between January 2015 and March 2020. CSF collected within three years of each driving event was used to assign A/T/N categories. The cohort included 132 cognitively normal (Clinical Dementia Rating of 0) older adults (>65). Changes in driving behaviours over time were modelled for each group using linear mixed‐effects models. A Z‐test was used to determine if the slopes significantly differed between individuals with normal biomarkers and the remaining groups.ResultParticipants were classified as 59 individuals with normal biomarkers, 9 with AD pathologic change biomarkers, 45 with AD biomarkers, and 19 with SNAP biomarkers. Compared to normal aging, the AD pathology group had a statistically significantly higher increase in average occurrences of under‐speeding (p = 0.001), a significant decrease in average trip duration (p = 0.021), and a significant decrease in the average standard deviation of vehicle speed (p = 0.029). The AD group had no significant differences from the normally aging group. The SNAP group showed a significantly higher increase in the average occurrences of over‐speeding (p<0.001) than normal aging.ConclusionDriving behaviours and their rate of change over time vary between individuals with different A/T/N profile categories. These differences provide an opportunity to strengthen our understanding of the disease trajectory.
Gestational Hypertension and Midlife Cognition: The CARDIA Study
Authors: Jiang Xiaqing , Schreiner Pamela J. , Gunderson Erica P. , Yaffe Kristine 
Published: December 2023

AbstractBackgroundGestational hypertension (GH) increases the risk of cardiovascular diseases, which may contribute to worse cognitive outcomes, and yet little is known about the long‐term impact of GH on cognition. We investigated the association of GH with midlife cognitive performance and decline in the Coronary Artery Risk Development in Young Adults (CARDIA) Study.MethodsWe studied 1,273 parous Black and White women (106 with GH and 1167 without GH) aged 18‐30 years at baseline (1985‐86) who were followed up to Year 30 (mean age 55.2±3.6 years) when five cognitive tests measuring global cognition, memory, processing speed, executive function, and verbal fluency were administered. Accelerated decline over five years was defined as a decline ≥1.5 standard deviations from the mean change on each of the three tests available at year 25, measuring processing speed, memory, and executive function. GH, defined as having new onset hypertension in pregnancy without proteinuria, was self‐reported for each pregnancy since the previous visit up to 30 years. We conducted linear and logistic regression to assess the association of GH with cognitive performance and decline.ResultsCompared with women who did not develop GH during pregnancy, those with GH were more likely to be Black (62% vs 50%) and have obesity (22% vs 11%), and lower diet quality (CARDIA A Priori Diet Quality Scores) at baseline. After adjusting for age, race, education, number of pregnancies, and baseline cardiovascular and behavior risk factors (diabetes, obesity, smoking, alcohol use, physical activity, and diet quality), having GH was significantly associated with lower cognitive performance (z‐standardized) at year 30 in global cognition (‐0.27, 95% CI ‐0.44 to ‐0.11), processing speed (‐0.25, 95% CI ‐0.44 to ‐0.07), and verbal fluency (‐0.20, 95% CI ‐0.38 to ‐0.02). Additional adjustment for hypertension, diabetes, and obesity up to Year 30 did not change the results. GH was also associated with higher odds of experiencing an accelerated decline in processing speed over 5 years (9.2% vs. 4.5%, odds ratio 2.48, 95% CI 1.07 to 5.74), after adjustment for all covariates.ConclusionGH is independently associated with worse cognitive performance and accelerated decline in midlife.
Biofluid activity and levels of the angiotensin‐converting enzyme may translate into distinct neuropsychiatric symptoms associated with cerebrospinal fluid amyloid‐beta effects and tauopathy in dementia with Lewy bodies and Alzheimer’s dementia
Authors: de Oliveira Fabricio Ferreira , Miraldo Marjorie Câmara , Castro‐Neto Eduardo Ferreira , de Almeida Sandro Soares , Matas Sandro Luiz de Andrade , Bertolucci Paulo Henrique Ferreira , da Graça Naffah‐Mazzacoratti Maria 
Published: December 2023

AbstractBackgroundAmyloid‐β‐degrading enzymes such as the angiotensin‐converting enzyme (ACE‐1) might be surrogates of the amyloid‐β load in the brain potentially triggering tauopathy and behavioral features in dementia.MethodsConsecutive outpatients with probable dementia with Lewy bodies (fourth consensus report of the DLB Consortium) were paired with outpatients with late‐onset Alzheimer’s dementia (AD, National Institute on Aging – Alzheimer’s Association) by sex, Clinical Dementia Rating and Mini‐Mental State Examination scores, and with cognitively healthy controls by sex and age (±1 year). Behavioral symptoms were assessed by way of the Neuropsychiatric Inventory. APOE genotyping (rs7412&rs429358) was undertaken with TaqMan® Real‐Time PCR technology, while conventional PCR was used for the ACE insertion/deletion polymorphism. Cerebrospinal fluid (CSF) amyloid‐β42, amyloid‐β38, ACE‐1, tau and phospho‐tau Thr181 were quantified with enzyme‐linked immunosorbent assays, whereas CSF and plasma ACE‐1 activities were measured using a fluorescence method. Adjusted general linear models were used to examine relationships between log‐transformed behavioral symptoms and biomarkers of interest at p<0.05.ResultsParticipants with DLB (n = 27;78.48±9.0years‐old;eleven APOE‐ε4 carriers) were paired with participants with AD (n = 27;81.00±5.8years‐old;twelve APOE‐ε4 carriers) and controls (n = 27;78.48±8.7years‐old;four APOE‐ε4 carriers); two thirds were women. CSF ACE‐1 activity was associated with CSF ACE‐1 levels (p<0.0001) and with plasma ACE‐1 activity (p<0.0001), no differences among the participants. Only in DLB, the ACE deletion allele was cumulatively associated with higher plasma ACE‐1 activity (p = 0.049). Use of ACE inhibitors did not affect CSF ACE‐1 levels. For APOE‐ε4 carriers with DLB, agitation was inversely associated with amyloid‐β38, CSF and plasma ACE‐1 activities. For APOE‐ε4 non‐carriers with DLB, appetite and eating abnormalities were associated with CSF ACE‐1 levels and activity, tau and tau/phospho‐tau, and inversely associated with amyloid‐β42/amyloid‐β38. CSF ACE‐1, tau, tau/phospho‐tau, and tau/amyloid‐β42 were associated with disinhibition for APOE‐ε4 carriers with AD, and with aberrant motor behavior for APOE‐ε4 non‐carriers with AD. For APOE‐ε4 carriers with AD, irritability was associated with CSF ACE‐1 and inversely associated with amyloid‐β42. All other behavioral associations with ACE‐1 were independent of measures of amyloidosis or tauopathy.ConclusionsBiofluid activity and CSF levels of ACE‐1 may be surrogates for CSF amyloid‐β levels and tauopathy unevenly associated with behavioral symptoms across dementia syndromes.
Blood and CSF proteome alterations, and regional brain volumetry patterns associated with neuropsychiatric symptoms in a memory clinic cohort
Authors: Rabl Miriam , Clark Christopher , Richiardi Jonas , Maréchal Bénédicte , Bowman Gene L. , Dayon Loic , Popp Julius 
Published: December 2023

AbstractBackgroundNeuropsychiatric symptoms (NPS) are common in older people, may precede cognitive decline, and are associated with worse long‐term prognosis. However, the underlying pathophysiology remains unclear. Therefore, our main objective was to examine systemic and central nervous system (CNS) protein signatures and regional brain volumetry patterns related to NPS as indicators of pathophysiological mechanisms that may have diagnostic or therapeutic implications.MethodWe included older subjects with normal cognition or cognitive impairment (mild cognitive impairment and mild dementia) participating in a longitudinal memory clinic study. NPS were assessed through the Neuropsychiatric Inventory Questionnaire (NPI‐Q). CSF biomarkers of Alzheimer’s disease (AD) were quantified in all participants. We performed untargeted proteomics in plasma and CSF, as well as MRI volumetry using the MorphoBox research application to ascertain regional brain volumes, both at baseline, and assessed their associations with NPS. Pathway enrichment analysis was used to identify systemic and CNS pathway alterations associated with regional brain volumes and NPS.ResultThe strongest correlations between regional brain volumes and NPS severity were found for white matter (WM) right temporal lobe (r = ‐0.41), third ventricle (r = 0.40), WM frontal lobe (r = ‐0.38) and right hippocampus (r = ‐0.38) (all p<0.001). Most regional brain volumes correlated with NPS severity after considering the presence of AD pathology, defined according to CSF AD biomarkers. Twenty‐four out of 282 plasma proteins and 67 out of 605 CSF proteins were altered in relation to NPS. Pathway enrichment analysis revealed brain region‐specific proteomic alterations associated with NPS (Fig.1). The most common pathway alterations were immune reaction, hemostasis, and protein metabolism.ConclusionOlder adults with NPS have region‐specific differences in brain volumes, particularly in white matter that are accompanied by systemic and CNS signatures related to immune activation, hemostasis, and protein metabolism. These findings show the potential of combining untargeted proteomics and MRI volumetry to detect pathophysiological changes related to NPS.
Two Approaches to Advance Care Planning for People with Dementia: Acceptability among US and Dutch Healthcare Providers
Authors: Jingyuan Xu , Smaling Hanneke J.A. , Mehr David R. , Craig Kevin , Achterberg Wilco P. , van der Steen Jenny T. 
Published: December 2023

AbstractBackgroundAdvance care planning (ACP) may include concrete treatment orders or important goals or both. Providers may differ on these approaches to ACP, which may also differ across countries. We investigated the acceptability and preferences for these two ACP approaches for people with dementia among healthcare providers from the Netherlands (NL) and the US.MethodFifty providers from each country, whose specialty includes providing end‐of‐life care for people with dementia, viewed short animation videos about the two approaches of ACP and completed a semi‐structured interview. Qualitative content analysis summarized the comments of the providers on each ACP approach (reasons and conditions for acceptability, (dis)advantages, barriers and facilitators), and the reasons for their preferences.ResultExcept for three nurse practitioners from the US, all participants were physicians (e.g., NL: elderly care physicians, family physicians; US: geriatricians, internists, family medicine physicians). The acceptability and preferences were similar in the two countries. Both approaches were considered acceptable for people with dementia by the vast majority of providers (concrete orders approach: 86% (both countries); important goals approach: 96% (NL) and 98% (US)). Slightly more providers preferred the important goals approach compared to the concrete one (NL: 42% vs. 34%; US: 46% vs. 36%), others had no preference. While the concrete approach may facilitate immediate decisions in emergent situations and may be easier for providers to conduct with available forms, the important goals approach takes the life view of the person with dementia into consideration, can be implemented in more situations and may be easier for the person with dementia. Differences between the two countries included the role of the family caregivers and the power of providers to make decisions.ConclusionProviders found both approaches acceptable, but there was diversity in the preferred approach in both countries. Future research should investigate how the preference of individual providers interacts with the preferences of people with dementia and family caregivers, and whether this influences the experience of ACP and subsequent care provision. Examining administrative, legal, and educational issues that may shape preferences may inform more patient‐centered ACP.
MiR‐431 attenuates synaptic plasticity and memory deficits in APPswe/PS1dE9 mice
Authors: Zhu Xiaolei , Xu Yun 
Published: December 2023

AbstractBackgroundSynaptic plasticity impairment plays a critical role in the pathogenesis of Alzheimer’s disease (AD), and emerging evidence has shown that microRNAs (miRNAs) are alternative biomarkers and therapeutic targets for synaptic dysfunctions in AD. Our previous miRNA assay data have shown that miR‐431 is downregulated in the hippocampus of APPswe/PS1dE9 (APP/PS1) mice. However, the potential role of miR‐431 in AD has not been fully defined.MethodLv‐miR‐431 (1×109 TU/ml, 2 µl), Lv‐Smad4 (1×109 TU/ml, 2 µl) or AAV‐sh‐Smad4 (5×1012 GC/ml, 200 nl) was slowly injected into the bilateral hippocampus of APP/PS1 mice. The behavioral or electrophysiological tests were performed 1 month following the injection, and the mice were then sacrificed for other experiments. QRT‐PCR was used to detect the expression of miR‐431 in plasma and hippocampus. Golgi staining and electron microscopy were performed to evaluate the synaptic structure. Western blot was employed to test the levels of synaptic associated proteins. Immunofluorescence staining and ELISA were utilized to assess hippocampal Aβ levels. Cut&Tag assay and ChIP were used to explore and confirm the potential targets of Smad4.ResultThe level of miR‐431 was downregulated in the plasma of amnestic mild cognitive impairment (aMCI) and AD patients, and it was also decreased in the hippocampus and plasma of APP/PS1 mice. MiR‐431 overexpression in the hippocampus ameliorated synaptic plasticity and memory deficits of APP/PS1 mice, while it didn’t affect the Aβ levels. Smad4 was identified as a target of miR‐431, and Smad4 overexpression reversed the protective effects of miR‐431 in APP/PS1 mice. Furthermore, Smad4 knockdown modulated the expression of synaptic proteins including SAP102, and protected against synaptic plasticity and memory dysfunctions in APP/PS1 mice.ConclusionMiR‐431 attenuates synaptic impairment at least partially by Smad4 inhibition and miR‐431/Smad4 may be a potential therapeutic target for AD treatment.
Digitally supported lifestyle program to promote brain health among older adults (LETHE pilot trial) – Study design and progress
Authors: Rosenberg Anna , Untersteiner Helena , Guazzarini Anna Giulia , Lehtisalo Jenni , Thunborg Charlotta , Bruinsma Jeroen , Colombo Matteo , Crutzen Rik , Diaz Ana , Fotiadis Dimitrios , Hilberger Hannes , Huber Simone , Kivipelto Miia , Loukas Vassilis , Lötjönen Jyrki , Pirani Mattia , Schnalzer Bianca , Hanke Sten , Mangialasche Francesca , Mecocci Patrizia , Stögmann Elisabeth , Ngandu Tiia , Consortium LETHE 
Published: December 2023

AbstractBackgroundDementia prevention is a global public health priority. The FINGER multimodal lifestyle intervention is the only intervention model so far that has demonstrated significant cognitive and other health benefits in at‐risk older adults. LETHE proposes a new multimodal precision prevention approach where FINGER intervention is complemented with digital tools to optimize intervention delivery, personalize recommendations based on individual risk profile, and support risk factor self‐management. The multinational 2‐year randomized controlled LETHE pilot trial aims to test the feasibility of a digitally supported, adapted FINGER intervention among older adults at risk of cognitive decline and dementia.MethodA total of 160 individuals aged 60‐77 years and with risk factors for dementia but no substantial cognitive impairment are recruited at four sites (Austria, Finland, Italy, Sweden; N = 40 per country). Digital readiness and experience with smart devices are required. Participants are randomized 1:1 to 1) structured multimodal lifestyle intervention (dietary guidance, exercise, cognitive training, vascular/metabolic risk management, social stimulation, sleep/stress management) where in‐person individual and group‐based activities are supported with the LETHE smartphone app developed in the project; or 2) self‐guided lifestyle intervention (regular health advice and access to a simplified app with no personalized/interactive content). Both groups wear a smartwatch to gather passive data (e.g., activity, sleep). Primary outcomes are retention rate, adherence to intervention and engagement with the app, and change in dementia risk based on validated risk scores (CAIDE, LIBRA). Secondary outcomes are lifestyle changes and changes in cognition, stress‐related symptoms, sleep, health‐related quality of life, and health literacy. Participant experiences will also be explored. The LETHE Advisory Board (members of the public) provided feedback on the trial protocol.ResultTrial is registered at ClinicalTrials.gov (NCT05565170), and ethical approval has been obtained in each country. Recruitment started in September 2022 and will be completed in Spring 2023. Updates and results on study progress will be presented.ConclusionLETHE pilot trial will inform about the feasibility of technological solutions and a digitally assisted lifestyle program to support brain health among older adults. If proved to induce sustained behavioural changes, digital tools could offer potential for large‐scale, cost‐effective dementia prevention programs.
AT(N) Classification and Clinical Characterization by CSF Biomarkers in Patients with Corticobasal Syndrome
Authors: Ishiguro Takanobu , Kasuga Kensaku , Tokutake Takayoshi , Tsukie Tamao , Konno Takuya , Onodera Osamu , Ikeuchi Takeshi 
Published: December 2023

AbstractBackgroundCorticobasal syndrome (CBS) is clinically characterized by asymmetric cortical and extrapyramidal deficits. CBS is caused by various pathological conditions including primary tauopathy and Alzheimer’s disease (AD). To clarify whether there are differences in clinical features of CBS between AD pathology and non‐AD pathology, we classified CBS patients based on AT(N) system by cerebrospinal fluid (CSF) biomarkers and assessed the clinical characteristics of the classified groups.MethodWe assessed retrospectively 19 CBS patients (7 males and 12 females) diagnosed by neurologists at our hospital between 2014 to 2021. They all fulfilled the clinical symptoms of probable or possible CBS according to the Armstrong criteria of corticobasal degeneration. CSF AT(N) biomarkers, A marker: Aβ42 and Aβ42/Aβ40 ratio, T marker: phosphorylated tau (Thr181) [p‐tau], N marker: total tau [t‐tau] and neurofilament light chain [NfL], were evaluated. The positive/negative of each biomarker was judged according to the cutoff value calculated in a cohort independent of this study. We used Aβ42/Aβ40 ratio as the A marker and NfL as the N marker in this study. Each patient was classified AT(N) group. Clinical characteristics were compared between biological AD (i.e., A+T+) group and non‐AD group.ResultThe concordance of A markers (Aβ42 and Aβ42/Aβ40 ratio) was 68.4%, and that of N markers (t‐tau and NfL) was 15.8% in patients with CBS. NfL had more positive rates than t‐tau in CBS patients. Based on CSF biomarker profile, CBS patients were classified as AD group (n = 4, 21%), Alzhehimer’s and concomitant suspected non‐Alzheimer’s pathologic change group (n = 2, 11%) and non‐AD pathologic change group (n = 13, 68%). AD group showed lower scores of MMSE (p = 0.037), more frequent presence of Gerstmann syndrome (p = 0.007), predominance of right limb symptoms (p = 0.015), and more common in non‐motor symptoms onset (p = 0.029) than non‐AD group.ConclusionBy applying the AT(N) classification to CBS patients, we found that 21% of patients exhibited AD pattern by CSF biomarkers. The clinical differences between AD group and non‐AD group may reflect the different pathological backgrounds. NfL could be more sensitive than t‐tau as the N marker in detecting neurodegeneration of CBS.