bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thermodynamics of amyloid formation
Authors: Nagel‐Steger Luitgard , Fazelnia Nazanin , Willbold Dieter 
Published: December 2023

AbstractBackgroundIs amyloid formation an exothermic process with the potential to damage brain tissue by local hyperthermia? In our study we aim to find answers to the above question. Several proteins, i.e. lysozyme and amyloid‐β peptide, known to form amyloid structures are investigated primarily by differential scanning calorimetry (DSC) in order to determine their thermodynamic properties.MethodExperiments in DSC are complemented by a set of other biophysical methods in order to clarify molecular parameters for the evaluation of the heat capacity measurements.ResultFor this purpose a seeded amyloid formation assay has been designed. In this assay the structural conversion of a given amount of monomeric protein is accelerated and synchronized by the addition of preformed amyloid fibril fragments to result in reproducible heat bursts caused by amyloid formation.ConclusionFirst results are reported and the measured enthalpies are related to known enthalpies from protein structural conversion processes.
Acute response of astrocytes under rose bengal photoinduction‐mediated vascular injury
Authors: Norris Christopher M. , Gant John C , Rogers Colin B , Nelson Peter T , Sompol Pradoldej 
Published: December 2023

AbstractBackgroundCerebrovascular pathology, often found in autopsy confirmed Alzheimer’s disease (AD), is widely believed to exacerbate AD pathophysiology and complicate anti‐AD treatment strategies. Perivascular cells such as astrocytes maintain the microenvironment for proper brain cell function and vascular integrity. Early occurrence of cerebral small vessel disease and astrocyte reactivity could lower the threshold of neuronal disorders and AD. Studies of astrocyte and microvascular pathology and function in the brain have been limited and reaction of astrocytes to vascular damage has yet to be fully understood.MethodAAV‐Gfa‐EGFP or AAV‐Gfa‐GCaMP6 was injected into the barrel cortex of wild type mice followed by glass window installation. After 3 weeks recovery, rhodamine dextran was IV‐injected and intravital brain imaging through two‐photon microscopy was performed at pre‐ and post‐photoinduction. Photoactivation of IV‐injected Rose Bengal dye (RB) technique was used to create vascular pathology. ImageJ was used for data analysis and GraphPad prism was used for statistical analysis.ResultAfter photoinduction, green fluorescence intensity was increased in blood stream of both EGFP and GCaMP expressing brains. This result indicates a leakage of brain parenchyma component to blood stream. Astrocytic EGFP fluorescence intensity and astrocyte processes complexity were reduced after photoinduction in a time‐dependent manner. Interestingly, astrocyte calcium signaling was strikingly increased after photoinduction and returned back to the baseline at ∼1,000s post‐induction. The highest peak of astrocyte calcium signaling was located near a site of vascular damage, indicated by an increased in rhodamine fluorescence intensity in the brain parenchyma area. Astrocytic GCaMP intensity at the astrocyte endfeet surrounding small vasculature was increased, on the other hand, GCaMP intensity at the astrocyte processes are decreased in a time‐dependent manner. Consistently, we observed a reduction of vascular diameter after photoinduction in both EGFP and GCaMP expressing brains.ConclusionAcute vascular injury induced by rose bengal photoinduction altered astrocyte integrity and cellular signaling. This injury model resembles vascular constriction and hemorrhages found in human brain that could accelerate neurodegeneration and AD progression.
Lithium carbonate treatment decrease neuroinflammation and ameliorates long‐term memory in a Down syndrome animal model
Authors: de Souza Larissa Estessi , Spelta Lidia Emmanuela Wiazowski , Buchpiguel Carlos A , Real Caroline Cristiano , Faria Daniele de Paula 
Published: December 2023

AbstractBackgroundIndividuals with Down Syndrome (DS) have an increased genetic risk for developing Alzheimer’s Disease (AD), due to a higher expression of genes related to the pathophysiological development of the disease and to the inflammatory process. Brain damage is already substantial when the first clinical signs of AD appear, it is essential to study therapeutic alternatives that delay its development. As lithium carbonate has been identified as a neuroprotective and neuroplastic agent in neurodegeneration, the aim of this study is to evaluate the treatment effect of lithium carbonate in the neuroinflammation and long‐term memory of Ts65Dn animal model of DS.MethodTs65Dn mice (trisomy confirmed by genotyping) were treated with a lithium carbonate microdose (0.25 mg/kg dissolved in water) for 18 months and compared to non‐treated animals. To evaluate the treatment, [11C]PK11195 PET images were acquired at the ages of 5, 14, 20 and 24 months. Whole brain images were quantified in SUV (Standardized Uptake Value) and long‐term memory was assessed by the novel object recognition test (1).Result[11C]PK11195 uptake was increased at 14 months in the non‐treated animals when compared to the respective age of 5 months (+29%), although not statistically significant. However, when mice were treated with lithium, this increase was not detected. Compared to 14 months, at the ages of 20 and 24 months, there was a decreased uptake in the non‐treated animals (Ts65Dn: ‐52%, p = 0.01 at 20 months; Ts65Dn: ‐59%, p = 0.006; at 24 months) and whereas in Ts65Dn‐lithium, the uptake did not change significantly among the ages. There was a decrease in the long‐term memory index in the non‐treated animals, at the ages of 20 (p = 0.03) and 24 months (p = 0.009), compared to 14 months‐old whereas in the treated animals the memory was preserved.ConclusionThe treatment with lithium carbonate prevented glial cells alterations during life‐span and preserved long‐term memory of a Down syndrome animal model indicating that this treatment can contribute to a healthy brain aging in this syndrome.
Defining and characterizing neocortical tau resistance in preclinical Alzheimer’s Disease
Authors: Properzi Michael J , Townsend Diana , Klinger Hannah M , Boyle Rory , Coughlan Gillian T , Hanseeuw Bernard J , Amariglio Rebecca E. , Rentz Dorene M. , Jacobs Heidi I.L. , Price Julie C , Chhatwal Jasmeer P. , Schultz Aaron P. , Hohman Timothy J. , Donohue Michael C. , Johnson Keith A. , Sperling Reisa A. , Buckley Rachel F. 
Published: December 2023

AbstractBackgroundTopographical staging of tauopathy in preclinical Alzheimer’s disease (AD) posits early deposition in the entorhinal region (medial temporal lobe; MTL) followed by spread to adjacent neocortical (NEO) regions. Predictive models support a cascade of tau deposition as baseline MTL tau robustly predicts NEO tau accumulation. In clinically normal (CN) Ab+, elevated tau in MTL and NEO is associated with accelerated progression to dementia relative to those with only elevated MTL tau. The frequency and profile of neocortical tau resistance (defined as MTL+/NEO‐) remain unclear.MethodWe defined tau resistance using two longitudinal datasets. To compare directly across MTL (entorhinal/amygdala/parahippocampal) and NEO (inferior‐temporal/fusiform/middle‐temporal/inferior‐parietal) composites, we averaged regional SUVrs within each composite then normed them to independent samples of younger CNAb‐ adults. We selected CN participants from ADNI and HABS with ≥2 time‐points of Flortaucipir‐PET (nHABS = 200; nADNI = 149; cerebellar‐greyreference). We extracted slopes from a linear mixed model covarying for age, APOEe4 and Abstatus. We compared baseline MTLnormed values with slopes in a NEOnormed. We defined tau resistance as those with elevated baseline MTLnormed tau‐PET but no change in NEOnormed tau‐PET over time. We used non‐parametric group comparisons to determine differences in a range of variables (Table1).ResultWe found a poor to moderate correlation between baseline MTLnormed values and adjusted NEOnormed slopes (rHABS = 0.12; rADNI = 0.36; Fig.1), with a non‐linear association at higher levels of MTLnormed. In HABS, tau resistance was identified in 13% (n = 10) of those with elevated MTLnormed. There was a trend for Black/African American individuals to be less tau resistant (Table.1). In ADNI, 26% were identified (n = 11), there was a trend toward less APOEe4 carriers in the resistant group. Although the ranges of change were different across the two cohorts, adjusted MTLnormed and NEOnormed slopes were similarly strongly correlated (rHABS = 0.69; rADNI = 0.74; Fig.2).ConclusionOur preliminary findings suggest that resistance to neocortical tau in CN exists in up to a quarter of those with elevated MTL. Given the complexities with determining cross‐sectional and longitudinal tau‐PET thresholds, our approach to identifying MTL+ or NEO+ may be too conservative. Future work will validate tau resistance via cognitive decline and clinical progression.
The late onset Alzheimer’s disease‐associated TREM2 R47H regulates susceptibility to ferroptosis
Authors: Li Gang 
Published: December 2023

AbstractBackgroundGenome‐wide association studies (GWAS) have identified TREM2 R47H as one of the genetic risk factors associated with late‐onset Alzheimer’s disease (LOAD). However, the mechanism underlying the contribution of this variant to the pathogenesis of, and/or the susceptibility to LOAD is still elusive.MethodDisease‐associated functional SNPs were identified and characterized by coupling Reel‐seq (Regulatory element‐sequencing), a high‐throughput mapping technique, with SDCP‐MS (SNP‐specific DNA competition pulldown‐mass spectrometry), a proteomics analysis. Ferroptosis was validated by combining MTT assay, MDA assay as well as C11‐BODIPY staining in human microglial cells.Resultrs75932628, an exonic SNP encoding for TREM2 R47H, is part of a cis‐regulatory element modulating TREM2 expression by recruiting a protein complex that contains two iron chaperons. Iron suppresses TREM2 expression by disrupting the binding of these proteins to rs75932628 and this disruption is further enhanced more by the risk allele A than the non‐risk allele G. Moreover, down‐regulation of TREM2 inhibits GPX4 expression via a TREM2‐mediated signaling pathway, resulting in ferroptosis due to accumulation of lipid peroxides.ConclusionIron, as the most abundant heavy metal in nature, induces ferroptosis by down‐regulating GPX4 via the LOAD‐associated TREM2 R47H.
The Digital Clock Drawing Test and Delayed Recall Predict Informant‐Rated Functional Impairment in Individuals with Cognitive Impairment
Authors: Jannati Ali , Gomes‐Osman Joyce Rios , Banks Russel R , Toro‐Serey Claudio R , Ciesla Marissa R , Tobyne Sean , Showalter John , Pascual‐Leone Alvaro 
Published: December 2023

AbstractBackgroundNearly 6.7 million people aged 65 and older in the US are living with Alzheimer’s disease (AD). Early detection of dementia presents a difficult challenge, as the earliest signs of cognitive decline often go undetected. Thus, more sensitive and clinically meaningful cognitive screening tools are needed. Evaluating the patient’s dependence in activities of daily living is critical to detect progression toward dementia. The Linus Health DCTclock™ employs AI‐enabled analyses of the clock drawing process to evaluate cognitive and motor function. We evaluated the utility of four DCTclock composite scales including Spatial Reasoning, Drawing Efficiency, Information Processing, and Motor Skills, 22 DCTclock subscales, and the 3‐word Delayed Recall score from the Digital Clock and Recall (DCR™) to predict the informant‐rated functional activities questionnaire (FAQ) score in older adults ranging from cognitively unimpaired to individuals with mild cognitive impairment (MCI) and AD‐related dementia (ADRD).Method939 participants in a multisite study (age mean±SD = 72.1±6.7; 57.1% female; years of education mean±SD = 15.4±2.7; primary language English), classified as cognitively unimpaired (n = 406), MCI (n = 293), or ADRD (n = 238) were included. We conducted cross‐validated regularized logistic regressions with FAQ score ≥6 or ≥9 (mild or moderate functional impairment, respectively) as dependent variable and DCTclock composite scales, subscales, and Delayed Recall score as predictors, in addition to age, sex, and education.ResultCombination of DCTclock subscales and Delayed Recall predicted FAQ≥6 and ≥9 with AUCs = 0.79 and 0.81, respectively. DCTclock composite scales predicted FAQ≥ 6 and ≥9 with AUCs = 0.75 and 0.77, respectively. Combination of DCTclock composite scales and Delayed Recall predicted FAQ≥6 and ≥9 with AUCs = 0.77 and 0.79, respectively. DCTclock subscales by themselves predicted FAQ≥6 and ≥9 with AUCs = 0.77 and 0.79, respectively.ConclusionThe DCR, a brief digital cognitive assessment with automatic scoring that can be completed in primary‐care settings, can infer the effect of cognitive impairment on a patient’s functional activity with great accuracy and within a few minutes. This makes the DCR an empowering tool for primary‐care providers in practical evaluation of patients with cognitive impairment.
Diet Association with Intracranial Atherosclerosis in High Risk Individuals
Authors: Cherian Laurel J , Agarwal Puja , Agrawal Sonal , James Bryan D , Leurgans Sue E. , Bennett David A. A , Aggarwal Neelum T. , Schneider Julie A 
Published: December 2023

AbstractBackgroundHealthy diet reduces cognitive decline and dementia. Vascular risk factors are associated with increased atherosclerosis, but associations between dietary pattern and atherosclerosis in older brains are unclear. This study investigates associations between diet pattern and risk of atherosclerosis in individuals with preexisting hypertension (HTN) or myocardial infarction (MI).MethodStudy includes 677 autopsied participants (mean age at death = 91.1±6.1, 71% women) of the Rush Memory and Aging Project, a longitudinal clinical neuropathological cohort study, with complete dietary and neuropathology data. The mean MIND and Mediterranean diet (MedDiet) scores (assessed annually using a 144‐item Food Frequency Questionnaire) were computed (mean interval to death = 5.85±3.92 years). HTN and MI history was self‐reported. Large vessel atherosclerosis was evaluated at the circle of Willis, and severity of intracranial atherosclerosis was assessed based on the number of atherosclerotic plaques, extent of involvement in each vessel, and the degree of vessel occlusion to create a 4 level grading system (0‐3). All regression models were adjusted for age, sex, education, caloric intake, and APOE4.ResultOf the 677 subjects, 362 (53%) had mild, 142 (21%) had moderate, and 29 (5%) had severe atherosclerosis. There was no direct relationship between diet and atherosclerosis. Both MI (β = 3.031 (p = 0.003)) and HTN (β = 2.063(p = 0.015)) were associated with intracranial atherosclerosis. The interaction models indicated significant interaction of hypertension with MedDiet (β = ‐0.077, p = 0.029) and a qualitatively similar interaction with MIND diet (β = ‐0.212, p = 0.055) for intracranial atherosclerosis. Interaction of MI with MIND (p = 0.007) and MedDiet(p = 0.006) was also significant for intracranial atherosclerosis. In stratified analysis, among individuals with preexisting MI (N = 130), those with better diet have lesser odds of intracranial atherosclerosis (MedDiet: OR(95% CI) = 0.88 (0.81, 0.97)); (MIND: OR(95% CI) = 0.77 (0.59, 1.01)).ConclusionIn older adults with a history of hypertension or myocardial infarction, a healthy dietary pattern is associated with less severe intracranial large vessel atherosclerosis. These data suggest that healthy diets may be more effective in maintaining brain vascular health in persons with a history of vascular risk or disease. In‐vivo studies of dietary habits and brain health, specifically in those at high vascular risk are needed.
Associations between blood‐based biomarkers and other outcomes related to Alzheimer’s disease
Authors: Göschel Laura , Dell'Orco Andrea , Hoede Patty , Koertvelyessy Peter , Fillmer Ariane , Aydin Semiha , Cano Stefan , Melin Jeanette , Pendrill Leslie , Lehmann Sylvain , Ittermann Bernd , Teunissen Charlotte E. , Flöel Agnes 
Published: December 2023

AbstractBackgroundBlood‐based biomarkers (BBM) have shown promising potential in diagnosis and prognosis of patients affected by Alzheimer’s disease (AD) pathology. This observational study analyzed the cross‐sectional relation between BBMs and disease relevant outcomes (e.g., cognition, imaging modalities).MethodThe study sample comprised individuals with subjective cognitive decline (N = 35), mild cognitive impairment (N = 30), dementia due to suspected AD (N = 27) and healthy controls (N = 35). Data for the following measures were assessed: 1) AD‐related BBMs measured in plasma on Simoa: amyloid beta ratio 42/40 (Ab42/40), tau phosphorylated at threonine‐181 (p‐Tau 181), glial fibrilic acid protein (GFAP), and neurofilament light chain (NfL), 2) several cognitive parameters, 3) structural volumes, functional connectivity and brain metabolite concentrations measured by 7T magnetic resonance imaging (MRI) and spectroscopy (MRS), and 4) concentrations of general blood count. Linear mixed models were used to assess associations between the AD‐related BBMs (1) and the other measures (2 to 4).ResultWhile none of the associations between Ab42/40 and the AD‐related outcome measures reached significance (p > 0.05), higher concentrations of p‐Tau 181, GFAP and NfL were associated with lower values for MMSE, memory and executive function and parietal cortical thickness, as well as higher concentrations of MRS Myo‐inositol and blood creatinine (figure 1). Additionally, GFAP and NfL were associated with lower MRS N‐Acetylaspartic acid (NAA), and GFAP was associated with smaller hippocampus volume. Beta‐coefficients and p‐values for all associations are provided in table 1.ConclusionUnlike Ab42/40, abnormal concentrations of p‐Tau 181, GFAP and NfL showed strong and robust associations to other AD‐related outcome measures making them a better target for screening, diagnosis and possibly prognosis for individuals with AD.
An exploratory analysis of the relationship between cerebral flood flow, mood, and fluid cognition in older adults
Authors: Farris Kristen M , Ashford Nathanial K , Miglani Jasroop K , Parsey Carolyn M , Levendovszky Swati Rane , Hanson Angela J 
Published: December 2023

AbstractBackgroundASL, a common MRI measure of cerebral blood flow (CBF), is thought to be a potential tool in the detection of preclinical Alzheimer’s disease. This exploratory analysis examined the relationship between CBF, mood, and fluid cognitive performance on the NIH Toolbox Cognition Battery (NIHTB‐CB) as part of an ongoing triglyceride intervention study.Method20 female older adults (age 65.6 ± 7.6) underwent ASL MRI when fasting and two hours after a triglyceride intervention. 3D pCASL MRI with background suppression was used to measure CBF in ml/100g/min using label duration = 1.8 s, post‐labeling delay = 2 s, labeling offset = 25‐30 mm, slices = 30, resolution = 2×2×4 mm3, SENSE‐factor = 2, TR/TE = 5000/18 ms. We also performed a reference scan (M0, 1 minute) identical to the one above but with no labeling or background suppression and TR = 10,000 ms. CBF was measured globally and in four regions of interest: angular gyrus (AG), posterior cingulate (PC), temporal lobe, and the hippocampus. Subjects completed the Generalized Anxiety Disorder Scale (GAD‐7) and MoCA at screening. The NIHTB‐CB was completed following the second MRI, and age‐adjusted scores were used in all analyses.ResultBaseline global CBF, AG CBF, and hippocampal CBF negatively correlated with GAD‐7 scores (r = ‐.797, p<.0001; r = ‐.635, p = .0026; r = ‐.620, p = .0036, respectively). In contrast, global CBF and hippocampal CBF positively correlated with performance on the MoCA (r = .501, p = .0243; r = .546, p = .0126, respectively). Post‐intervention CBF in 3 of the 4 areas of interest positively correlated with fluid measures on the NIHTB‐CB, including the Flanker (AG: r = .528, p = .0166), Picture Sequence Memory Test (AG: r = .501, p = .0245; temporal lobe: r = .578, p = .0077), List Sorting Test (PC: r = .508, p = .0241), and fluid composite scores (AG: r = .610, p = .0043).ConclusionGreater anxiety correlated with lower baseline CBF overall and in the AG and hippocampus. Post‐lipid CBF correlated with better performance in working memory, executive function, and episodic memory. These results align with our predictions based on each of these regions’ functions. Further research exploring the relationship between mood and CBF is warranted, as well as investigating the effects of APOE4 status on these associations.
The influence of auditory change on cognitive processes associated with aging in virtual reality
Authors: Kamal Farooq , Segado Melanie , Perron Maxime , Lau Brian , Shaigetz Vincent Gagnon , Alain Claude , Choudhury Nusrat 
Published: December 2023

AbstractBackgroundWith increased age, older adults experience subtle changes in their cognitive functioning. For example, it is well established that our ability to complete dual‐tasking activities decreases with increased age and cognitive decline. One issue with current dual‐task paradigms is the lack of ecological value in lab‐based environments. The present study employed working memory (WM) tasks designed within an immersive and interactive virtual reality (VR) environment by the National Research Council Canada, to examine the processing of unattended input using event‐related potentials (ERPs) which measure the changes in the electrical activity of the brain.MethodTwenty young adults (ages 17‐30) and twenty healthy older adults (ages 65+) were recruited from the Rotman Research Institute. Participants were engaged in a VR‐WM task while to‐be‐ignored auditory stimuli were presented. The difficulty of the VR tasks was designed to be either very easy or very difficult. Auditory stimulus with an average intensity of 60‐90 dB SPL were presented in a fast (low saliency) and a slow (high saliency) presentation rate.ResultDuring the VR task, young adults’ accuracy was significantly higher in the easy condition than in the difficult condition (p < .001). When auditory stimuli were presented rapidly, a robust ERP was elicited at the frontal (p = 0.005) and central (p = 0.003) brain regions. The slowly presented auditory stimulus elicited a robust ERP at the central brain region (p = 0.003). Preliminary data indicates that accuracy was lower in older adults than young adults for both conditions. Older adults also had lower accuracy in the hard condition than in the easy condition.ConclusionThe ERPs examined here show that participants were able to successfully switch processing priorities away from the VR‐WM task to salient auditory stimulus, but that older adults were less efficient than younger adults. These tools (VR, auditory stimuli, and ERPs) may be useful at detecting subtle electrophysiological and cognitive changes that occur with age and cognitive decline. They may offer promise to identify the pathology underlying cognitive impairment in aging and could reveal the electrophysiological changes associated with conversion to dementia at an individual level in clinical and non‐clinical settings.