bluuebunny/crossref_metadata_2025_split huggingface dataset:
Revised diagnostic criteria for Vascular Cognitive Disorders: the VASCOG‐2 criteria
Authors: Sachdev Perminder S. , Bentvelzen Adam C. ,   VasCog‐2 Criteria Consortium
Published: January 2025

AbstractBackgroundSeveral sets of diagnostic criteria have been published for vascular cognitive disorders (VCD) since the 1960s. The International Society for Vascular Behavioral and Cognitive Disorders (VASCOG) working group published a comprehensive and operationalized criteria set in 2014. Considering the significant developments in the field in the last decade, an international expert group was commissioned to revise these criteria using the Delphi process.MethodsA modified Delphi consensus method was used, involving an iterative, multi‐staged series of structured surveys with feedback of anonymized responses from experts in the fields of cerebrovascular disease and dementia. Three rounds were planned, with the possibility of a fourth round, if required to reach consensus. Literature reviews on topics related to the criteria were conducted by a team of researchers, which informed the first structured questionnaire. Each salient point in the criteria was put to consensus, and relevant recent reviews and publications provided for background information. Consensus was defined as agreement or disagreement on any statement of ≥ 75%, near consensus as 66 – 75%, and <66% as non‐consensus. Statements that reached consensus were removed from subsequent rounds, as were most that had non‐consensus, with some being reworded. One in‐person meeting in Gothenburg, Sweden and one virtual meeting were held for experts to discuss contentious issues and advise on the process.ResultsSeventy experts from a broad range of international regions and disciplines consented to participate, and 54 completed the Round 1 survey. The final round is being completed, after which the revised criteria will be finalized for formal approval by all participants. In addition to the criteria for clinical use, which include neuroimaging criteria, a set for research use will be agreed upon.ConclusionsThe updated VASCOG‐2 criteria could serve as the international standard for VCD diagnosis, thereby facilitating diagnostic consistency between clinicians and researchers.
Prebiotic‐based snack from banana improves cognitive decline via decreased brain inflammation and brain oxidative stress in obese rats
Authors: Sa‐nguanmoo Piangkwan , Apaijai Nattayaporn , Pintana Hiranya , Chunchai Titikorn , Arunsak Busarin , Kerdphoo Sasiwan , Pratchayasakul Wasana , Devahastin Sakamon , Chattipakorn Nipon , Chattipakorn Siriporn C 
Published: January 2025

AbstractBackgroundConsuming prebiotics demonstrated therapeutic potential against obesity, as illustrated by our previous study on xylooligosaccharide (XOS), revealing that XOS reduced adiposity, diminished systemic inflammation, and restored cognitive function in obese insulin‐resistant rats through the gut‐brain axis. Fresh bananas at various ripening stages are being transformed into snacks, indicating potential as prebiotic‐based treats enriched with fructooligosaccharide and inulin. Despite those findings, there remains a notable gap in the literature concerning the impact of these prebiotic‐based snacks on brain inflammation, reactive oxygen species (ROS) production, and cognitive function in high‐fat diet (HFD)‐induced obese rats.MethodSeventy‐two male rats were divided into two groups, receiving either a normal diet (ND) or an HFD for total 16 weeks. At 13th week, ND‐fed rats were randomly assigned to 6 subgroups (n = 6/group) to receive either vehicle (NDV, 21 ml/kg/day), prebiotic‐based snacks prepared from bananas at ripening stages 2‐5 (NDS2‐5) (7.47 g dissolved in reversed osmosis water, 21 ml/kg/day in each subgroup), and inulin (NDI, 2 g/kg/day). Similarly, HFD‐fed rats were divided into 6 subgroups (n = 6/group): HFD‐fed rats receiving vehicle (HFV), prebiotic‐based snacks prepared from bananas at ripening stages 2‐5 (HFS2‐5) and inulin, with the same dose as ND‐fed rats, for 4 weeks. Cognitive function was assessed by novel object recognition (NOR). Serum malondialdehyde (MDA) levels, gut microbiota, brain inflammation, and brain ROS production were determined at the end of treatment.ResultThe HFV group exhibited elevated serum MDA levels, increased brain mitochondrial ROS production, heightened TNF‐α levels, indicating brain inflammation, and an augmented Firmicutes to Bacteroidetes (F/B) ratio, indicating gut dysbiosis, when compared to the NDV group (p<0.05, Figure 1). Additionally, the HFV group showed cognitive decline, evidenced by a reduced percentage preference index in the NOR test (p<0.05, Figure 1). Remarkably, HFV rats receiving a prebiotic‐based snack showed reduced serum MDA levels, brain mitochondrial ROS production, brain inflammation, and improved gut dysbiosis, resulting in enhanced cognitive function. (p<0.05, Figure 1).ConclusionA prebiotic‐based snack at all ripening stages holds promise as a neuroprotection against HFD‐induced obesity, offering multifaceted benefits by mitigating oxidative stress, gut dysbiosis, brain inflammation, and attenuated cognitive dysfunction in HFD‐fed rats.
Interrogating the cognitive‐behavioural impairment in a motor‐dominant neurodegeneration (ALS), based on brain state dynamics of resting‐state EEG
Authors: Metzger Marjorie 
Published: January 2025

AbstractBackgroundAmyotrophic lateral sclerosis (ALS) shares pathological and genetic underpinnings with frontotemporal dementia (FTD). ALS manifests with diverse symptoms, including progressive neuro‐motor degeneration, muscle weakness, but also cognitive‐behavioural changes in up to half of the cases. Resting‐state EEG measures, particularly spectral power and functional connectivity, have been instrumental for discerning abnormal motor and cognitive network function in ALS [1]–[3]. Based on our recent findings using EEG microstates [4], we hypothesized that dynamic analysis of time‐varying spectral EEG measures at source‐level can further interrogate the altered functional network that underpin the cognition and behaviour in ALS as a motor‐dominant neurodegeneration.MethodFor this purpose, we aimed to identify transient brain states associated with specific functional networks and to characterise the spatio‐temporal and spectral alterations in these brain states using high‐density resting‐state EEG, recorded from 99 individuals with ALS and 78 healthy controls (HC). Using a time‐delay embedded Hidden‐Markov‐Model on source‐reconstructed EEG data [5], we identified transient and recurrent brain states characterised by spectral power and coherence. The model was trained to convert source‐reconstructed time courses into sequences of functional networks (brain states).ResultTwelve brain states were identified with distinct patterns of spectral power and coherence for individuals with ALS and HC. The Brain States 1, 3, 7 and 9 showed significant association between brain states fractional occupancy and behavioural decline (Beaumont Behavioural Inventory [7]; >0.25, q<0.03, >0.65), while state 5 showed association with fluency decline (Edinburgh Cognitive and Behavioural ALS scale [8]; = ‐0.3, q = 0.004, = 0.83). States 1, 7 and 10 were characterised by frontal lobe activation (spectral power higher than the average within the state), while state 3 exhibited activation in the sensorimotor network. Highest spectral power during state 5 was in the supplementary motor area, a region primarily associated with motor planning but also possibly associated with language [9].ConclusionThis study demonstrated the utility of resting‐state EEG and its temporal decomposition based on spatio‐spectral dynamics for investigating and interrogating the less‐dominant cognitive‐behavioural decline in ALS. It shows clear potentials for applications in cognate conditions such as FTD and Alzheimer’s disease with a dominant cognitive‐behavioural decline.
Complement receptor 1 length polymorphism impacts glial functions relevant to Alzheimer’s disease
Authors: Daskoulidou Nikoleta , Morgan Paul 
Published: January 2025

AbstractBackgroundGenome‐wide association studies (GWAS) in Alzheimer’s disease (AD) implicate complement in pathogenesis. Complement receptor 1 (CR1; CD35) is a top AD‐associated GWAS hit; the long variant, CR1*2, associates with risk. The roles of CR1 in brain and how variants influence AD risk are poorly understood. We investigated the impact of the AD‐associated CR1 length polymorphism on phagocytosis in induced pluripotent stem cell (iPSC)‐derived microglia and astrocytes.MethodsDonors were screened for erythrocyte expression of CR1 variants to identify homozygote donors (CR1*1/CR1*1, CR1*2/CR1*2); peripheral blood mononuclear cells (PBMCs) were isolated and reprogrammed to iPSCs. Clones were differentiated into microglia and astrocytes, confirmed by specific marker expression, then tested for phagocytosis of diverse targets (pHrodo‐E.coli bioparticles, pHrodo‐human synaptoneurosomes, Alexa‐488‐amyloid β fibrils), either unopsonised or opsonised with human serum or Factor I (FI)‐depleted human serum. Uptake of fluorescent targets was measured in real‐time.ResultsCR1*1 and CR1*2 homozygote iPSC lines were established, differentiated into microglia and astrocytes, confirmed by cell‐specific marker expression. CR1 was expressed in all iPSC‐microglia and astrocytes for both variants. iPSC‐microglia and astrocytes were phagocytic and phagocytosis was enhanced by target opsonisation with human serum; FI depletion of serum reduced the enhancing effect. Comparison of CR1*1 and CR1*2 expressing microglia and astrocytes showed that expression of CR1*2, the AD risk variant, enhanced phagocytosis of opsonised targets.ConclusionsCR1 is an important component of microglial and astrocytic phagocytic activity; CR1*2‐expressing cells showed increased phagocytosis of opsonised targets, providing clues to mechanism of association with AD risk.
Abrupt‐Onset Dementia: Differential Diagnosis and Clinical Characteristics of a Rare Condition
Authors: Piura Yoav D , Brigham Tara , Dabrh Moain Abu , Day Gregory S 
Published: January 2025

AbstractBackgroundThe term rapidly progressive dementia (RPD) may be applied to patients with precipitous declines in cognitive function resulting in dementia within one year or complete incapacitation within two‐years of symptom onset. Although most patients present with subacute, progressive declines, selected patients develop complete incapacitation within seven days of symptom onset. The differential diagnosis and clinical characteristics of patients with abrupt‐onset dementia are not known.Method187 patients with RPD were prospectively enrolled from February 2016 to September 2023 in a study of RPD at Mayo Clinic (Jacksonville, Florida) and Washington University (Saint Louis, Missouri). Patients with ≤7 days from first symptom to onset of RPD were labelled as abrupt onset. Patient characteristics, results of investigations, and causes of abrupt‐onset dementia were further characterized. We further explored the causes of abrupt‐onset dementia in the extant literature to refine the differential diagnosis and approach to evaluation and management of these patients.ResultTwo patients in our study of RPD had abrupt‐onset RPD (2/187, 1.1%), attributed to autoimmune and vascular. An additional 63 cases were identified through comprehensive meta‐narrative review of the literature (40 publications). Causes of abrupt‐onset dementia include vascular, infectious, inflammatory, and toxic. Compromise of structures within the Papez circuit was a common unifying feature common across patients with varying etiologies, informing the localization of abrupt‐onset dementia. 20% cases had potentially treatment‐responsive causes of abrupt‐onset dementia.ConclusionCases of abrupt‐onset dementia are rare overall and associated with a limited differential diagnosis. Evaluation of patients with abrupt‐onset dementia should prioritize testing for vascular, autoimmune, infectious, and toxic causes. Early‐recognition of patients with potentially treatment‐responsive causes of dementia may promote earlier intervention leading to better outcomes in selected patients.
Original Adverse Outcome Pathway linking neuronal exposure to nanoparticles to the onset of Alzheimer’s disease
Authors: Schneider Benoit 
Published: January 2025

AbstractAlzheimer’s disease (AD) is the most common dementia in humans that today concerns 50 million individuals worldwide and will affect more than 100 million people in 2050. Except for familial AD cases (<5% of AD patients) for which AD pathology connects to mutations in critical genes involved in the processing of the amyloid precursor protein into neurotoxic Aß peptides, it remains unknown what provokes the overproduction and deposition of Aß peptides in the brain of sporadic AD cases (>95% of AD patients). Some nanosized materials, e.g., nanoparticles (NPs), are suspected of playing a role in the growing incidence of AD, due to their reactivity with biological systems, easiness of crossing physiological barriers, capacity to reach the central nervous system and accumulate in the brain. Incriminated NPs are the ultrafine air‐borne particulate matter and manufactured NPs, such as titanium dioxide (TiO2) NPs widely used in food and cosmetic industries or carbon black (CB) NPs used in rubber and as black pigment. Both TiO2‐ and CB‐NPs display neurotoxicity, but the mechanisms by which those NPs affect neuronal homeostasis and place neurons on the path to degeneration are unknown.Combining in vitro and in vivo approaches, we provide prime evidence that TiO2‐ and CB‐NPs bind a plasma membrane neuronal receptor, the cellular prion protein PrPC, well‐known for its implication in prion diseases, and corrupt PrPC signaling activity. Dysregulation of PrP signaling by TiO2 ‐ or CB‐NPs pomotes the NADPH oxidase‐mediated overproduction of reactive oxygen species that alter neuronal redox equilibrium and the activation of 3‐phosphoinositide‐dependent kinase 1, at the root of an increased vulnerability of NP‐exposed neurons to inflammation and the overproduction of neurotoxic Aß peptides. By showing that neuronal exposure to some TiO2‐ and CB‐NPs induce molecular signs of AD, these mechanistic data provide new insight into how human exposure to some engineered and environmental NPs may predispose to neurodegenerative diseases.Identifying the mechanisms by which nanoparticles and other pollutants alter neuronal homeostasis would enable the generation of a database of pollutant‐associated Adverse Outcome Pathways and provide clues for counteracting the adverse effects of those pollutants on the central nervous system.
The association of cardiovascular risk factors and depressive symptoms on cognitive function in the U.S. POINTER study
Authors: Thro Amber A , Garcia Katelyn R , Krueger Kristin R , Howard Marjorie , Snyder Heather M , Baker Laura D , Papp Kathryn V 
Published: January 2025

AbstractBackgroundCardiovascular risk factors and depressive symptoms have both been independently shown to be negatively associated with cognitive function. However, the nature of the influence of comorbid depressive symptoms and cardiovascular risk on cognitive function is unclear, and there have been inconsistent findings as to which cognitive domains may be most associated with this relationship.MethodU.S. POINTER is a randomized controlled trial of two multidomain lifestyle interventions. We examined the baseline relationship between cardiovascular risk, depressive symptoms, and cognitive function in 2103 U.S. POINTER participants (mean age = 68.19±5.16y). The Framingham Risk Score (FRS) using lipids was used to calculate the 10‐year risk of developing cardiovascular disease, and depressive symptoms were assessed using the 15‐item Geriatric Depression Scale (GDS). Cognitive function was measured using composite scores (global, episodic memory, executive function, and processing speed) derived from the U.S. POINTER modified Neuropsychological Test Battery. After computing correlations, generalized linear regression models were used to determine the presence of an interaction between GDS (using a median split of 0‐1 and 2+) and FRS for each cognitive composite while controlling for demographic variables.ResultHigher GDS was significantly associated with lower global cognition (r = ‐0.04, p = 0.04) and slower processing speed (r = ‐0.06, p = 0.01) but not episodic memory (r = ‐0.03, p = 0.17) or executive function (r = ‐0.02, p = 0.37). FRS was negatively associated with global cognition (r = ‐0.25, p<0.01), episodic memory (r = ‐0.27, p<0.01), executive function (r = ‐0.13, p<0.01), and processing speed (r = ‐0.20, p<0.01). Regression models identified the presence of an interaction between FRS and GDS with global cognition (p<0.01). Specifically, participants with lower GDS scores (0‐1) had higher global cognition at lower levels of FRS than those with higher GDS scores (2+), but as FRS approached 16%, participants with lower GDS scores had lower global cognition than those with higher GDS scores. The presence of an interaction between FRS and GDS was also found with the executive function (p<0.01) and processing speed (p = 0.04) composites, but not with the episodic memory (p = 0.12) composite.ConclusionIn U.S. POINTER participants at baseline, the effect of cardiovascular risk on global cognition, executive function, and processing speed may vary depending on the presence and severity of depressive symptoms.
Calcium‐ and Tyrosine Kinase‐Dependent Suppression of Macroscopic Homomeric Kv1.2 and Heteromeric Kv1.1/1.2 current by Amyloid Beta (1‐42) Peptide: Implications for Alzheimer’s Disease
Authors: Jamshidi Dina , Yaklin Logen , Burch Sebastian , DeBoeuf Kristi , Farley Joseph 
Published: January 2025

AbstractBackgroundThe roles of Aβ in the pathogenesis of Alzheimer ’s disease (AD) include disruption of synaptic communication/function and synaptic plasticity mechanisms thought to underlie learning and memory. Exactly how these abnormal processes arise is incompletely understood, but evidence suggests that dysregulation of intracellular Ca2+ levels is involved in alterations of neuronal excitability, synaptic remodeling, and neurodegeneration in AD. Our lab has focused on the potential involvement of voltage‐gated potassium channels (VGKCs) in these processes, particularly Kv1.x family members. VGKCs contribute to resting membrane potential, regulate Ca2+ influx, and their inhibition may lead to and synapto‐ and neuro‐toxicity through hyperexcitability and excess glutamate release. Kv1.x family members are expressed as homotetramers, or as select heterotetramers (e.x Kv1.1/1.2) contributing to the diversity of electrical signaling. Previously, we have observed rapid and robust suppression (50% in 30 minutes) of macroscopic current by Aβ(1‐42) in homomeric Kv1.1 expressing Xenopus laevis oocytes. We sought to understand 1) if suppression by Aβ(1‐42) is exclusive to Kv1.1, or is able to affect other Kv1.x members such as homomeric Kv1.2 and heteromeric Kv1.1/1.2 channels 2) The extent to which the suppression is Ca2+ dependent, and 3) whether the suppression is additionally dependent on endogenous tyrosine kinase activity.MethodStage V/VI Xenopus laevis oocytes were injected with Kv1.2 cRNA or both Kv1.1 and 1.2 cRNA for homomeric and heteromeric expression respectively. The effects of bath application of 1 μM of Aβ(1‐42) were evaluated using two‐electrode voltage clamp electrophysiology (TEVC), and Ca2+ dependency was evaluated using BAPTA‐AM (a Ca2+ chelator) and Cyclosporin A (CsA; a PP2B inhibitor). Oocytes were additionally incubated in genistein, a non‐specific tyrosine kinase inhibitor.ResultFor both homo‐and heteromeric channel expressing oocytes, incubation in BAPTA‐AM significantly reduced suppression by ∼45%, while incubation with CsA blocked any suppressive effects of Aβ(1‐42). Oocytes incubated in genistein significantly blocked Aβ‐suppression at a level greater than CsA and BAPTA‐AM (>98%).ConclusionReducing intracellular Ca2+ and inhibiting Ca2+ activated signaling molecules such as PP2B and tyrosine kinases reduces suppression of macroscopic Kv1.x current by Aβ(1‐42).
Plasma biomarkers of vascular injury and cerebrovascular reactivity in APOE4 carriers
Authors: Kapoor Arunima , Dutt Shubir , Nguyen Amy , Gaubert Aimée , Alitin John Paul M , Sible Isabel , Marshall Anisa J , Shenasa Fatemah , Engstrom Allison C , Shao Xingfeng , Bradford David , Rodgers Kathleen E. , Wang Danny JJ , Nation Daniel A. 
Published: January 2025

AbstractBackgroundAPOE4 carriers exhibit cerebrovascular dysfunction which may contribute to the development of cognitive decline and dementia; however, the mechanisms underlying this pathophysiology remain unknown. Impaired cerebrovascular reactivity (CVR) may be associated with vascular injury, inflammation, and endothelial dysfunction. To examine whether these processes may be involved in CVR deficits in APOE4 carriers, we explored whether plasma levels of vascular injury markers indicative of inflammation and endothelial dysfunction are associated with impaired CVR to hypercapnia and hypocapnia in older APOE4 carriers.MethodSixty‐five independently living older adults (mean age = 69.3 years; SD = 8.6; age range 55‐89 years; 30.8% male) free of dementia or clinical stroke were recruited from the community and underwent venipuncture and brain MRI. Plasma was assayed for vascular injury markers (Serum amyloid A (SAA), C‐reactive protein (CRP), intercellular adhesion molecule 1 (ICAM‐1), vascular cell adhesion molecule 1 (VCAM‐1)) and values were log‐transformed. APOE genotyping was conducted on blood samples. Pseudo‐continuous arterial spin labeling MRI quantified whole brain cerebral perfusion during CVR to hypocapnia (0.1Hz paced breathing; vasoconstriction).ResultAdjusting for age and sex, multiple linear regression analysis revealed a significant association between whole brain CVR to hypocapnia and circulating levels of SAA, VCAM‐1 and ICAM‐1. Analyses stratified by APOE4 status revealed a significant association between whole brain CVR to hypocapnia and levels of SAA [B = ‐5.39, 95% CI (‐9.78, ‐1.01), p = .018], VCAM‐1 [B = ‐10.70, 95% CI (‐17.59, ‐3.82), p = .004] and ICAM‐1 [B = ‐10.95, 95% CI (‐17.44, ‐4.46), p = .002] in APOE4 carriers but not non‐carriers.ConclusionFindings suggest that elevated levels of vascular injury markers are associated with deficits in cerebral vasoconstriction, particularly in APOE4 carriers at genetic risk for Alzheimer’s disease. SAA, VCAM‐1 and ICAM‐1 are known to be involved in inflammation and endothelial dysfunction, and elevated levels are associated with cerebrovascular resistance and cognitive impairment. Our findings suggest that APOE4 carriers may be particularly vulnerable to these pathophysiological processes. Further longitudinal studies may elucidate whether inflammation and endothelial dysfunction precede or precipitate CVR deficits and contribute to cognitive decline in APOE4 carriers.
Application of restricted mean survival time method in Clinical Trials for Alzheimer disease
Authors: Shan Guogen 
Published: January 2025

AbstractBackgroundThe restricted mean disease progression (RMDP) is a measure of disease progression from baseline to a pre‐specified follow‐up visit. The RMST is a new statistical tool for survival analysis that is increasingly used in clinical trials. The RMST can be easily interpreted as the average survival time of patients from baseline to the pre‐specified follow‐up time.MethodWe developed a new restricted mean disease progression (RMDP) scale to estimate time savings based on the RMST approach.ResultWe found that the mean squared error (MSE) of the two new methods based on the RMDP is 30% less than that of the existing methods.ConclusionThe saved time of the two new approaches is more accurate than that of the exiting methods in many applications.