bluuebunny/crossref_metadata_2025_split huggingface dataset:
Air pollution nanoparticle exposure reduces neurotrophin signaling and causes hippocampal neural stem cell quiescence in mouse brain
Authors: Zhang Hongqiao , Zhang Nathan , Li Andrew , Diaz Arnold , Shkirkova Kristina , Ge Brandon , Florentino Abigail , Sioutas Constantinos , Mack William J , Bonaguidi Michael Anthony , Finch Caleb E 
Published: December 2022

AbstractBackgroundExposure to urban air pollution particles is strongly associated with higher risks of accelerated cognitive decline, cerebral atrophy, and dementia in multiple population studies. Among possible mechanisms is the decrease of neurotrophins, shown for BDNF in human exposures, which have critical roles in regulating adult neurogenesis and synaptic plasticity.MethodC57BL/6 mice were exposed to nano‐sized particulate matter (nPM, batch nPM2016a) from urban traffic air pollution for 8 weeks and the mRNAs of neurotrophins and receptors in mouse brain were measured by qPCR assay and neural stem cells measured by immunohistochemistry.ResultnPM exposure altered mRNA levels of neurotrophin genes (Ngf, Bdnf, Ntf‐3 and Ntf‐4/5) with brain region‐specificity. In cerebral cortex (CX), Ngf and Ntf‐3 were decreased (17% and 29% respectively), Ntf‐4/5 increased (78%), and Bdnf unchanged. In hippocampus (HP), Bdnf and Ntf‐4/5 were decreased (40% and 38% respectively) while Ngf and NTF‐3 unchanged. In olfactory bulb (OB), only Bdnf was decreased (10%). The mRNAs of neurotrophin receptors (Trka, Trkb, Trkc and p75Ntr) in CX, HP and OB were less responsive to nPM exposure, and only shown by OB with 22% decrease of p75Ntr and 14% decrease of Vgr (VGF nerve growth factor inducible). Exposure to nPM increased the quiescence of neural stem cells in hippocampal SGZ by IHC assay (Control 69.3% VS nPM 76.6%, P = 0.02), but did not alter the total number of neural stem cells. .ConclusionChronic air pollution exposure altered neurotrophin signaling with factor‐ and brain region‐specificity, and increased neural stem cell quiescence.
Transitioning to Elecsys automated immunoassay for fresh CSF biomarkers to support the diagnosis of Alzheimer’s disease in Australia
Authors: Li Qiao‐Xin 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) biomarker proteins, amyloid β1‐42 (Aβ42) and Tau (Phospho‐tau 181 [pTau] or Total‐tau [tTau]), in the cerebrospinal fluid (CSF) are used to support the clinical diagnosis of AD, and for enrolment of patients into therapeutic trials. Currently Roche Elecsys Generation I (GI) for frozen CSF is used, which will be replaced by Generation II (GII) for routine diagnostics use. This study examined the correlation of the biomarkers obtained from the automated Elecsys GI vs the manual INNOTEST immunoassays and the concordance of diagnostics outcome between the two methods. In addition, we also examined performance of GII on fresh CSF.MethodCerebrospinal fluid (CSF) samples were collected from local hospitals/clinics and from the study cohort of the Australian Imaging Biomarkers and Lifestyle study of Aging (AIBL). Aβ42, pTau and tTau were measured with both Elecsys and INNOTEST. Most recent collected CSF with a paired frozen and fresh CSF were assayed in parallel of both GI and GII.ResultIn the cohort of 34 collected frozen CSF from the AIBL cohort, the Spearman r correlations between INNOTEST and Elecsys methods were 0.91, 0.98, and 0.97 for Aβ42, pTau181, tTau, respectively. From 166 clinical diagnostic CSF samples (from local hospitals and clinics), the correlation was 0.89, 0.93, 0.88, respectively. Using the Aβ42 and pTau as primary parameters, the diagnostic outcome is highly concordant between the two methods in these two groups. Initial data from the paired frozen and fresh CSF showed GI and GII correlated well (r = 0.9643). Assessments on the GII cohort are ongoing.ConclusionThe automated Elecsys is highly correlated with the INNOTEST and offers high throughput and excellent precision with lower interassay/interlaboratory variation. This supports the use of Elecsys for CSF AD diagnostics in routine practice. The availability of fresh CSF analysis on GII will make the test more easily accepted into routine pathology setting.
Chronic conditions, multimorbidity, and its trajectory in relation to incident dementia: a prospective study
Authors: Chen Hui , Zhou Yaguan , Zuo Guangmin , Xu Xiaolin , Yuan Changzheng 
Published: December 2022

AbstractBackgroundMany single chronic conditions and multimorbidity have been related to dementia in previous studies. However, the long‐term relation of multimorbidity and its developmental trajectory with dementia remains unclear.MethodThe study included 5,998 dementia‐free participants (58.9% female, mean [standard deviation] age = 73.5 [6.8] years) from the Health and Retirement Study. Data on the health status, including self‐reported diagnosis of eight chronic conditions (high blood pressure, diabetes, cancer, lung diseases, heart diseases, stroke, psychological disorders, and arthritis) were collected from 1994 to 2008. Trajectories of multimorbidity development (including “no new condition, 31.2%”, “slow growth, 25.1%”, “steady growth, 32.2%”, and “rapid growth, 11.4%”) were identified using group‐based trajectory modeling methods. Incident dementia were detected during 2008 to 2018. Cox proportional hazard models were used to assess the relations of number of chronic diseases and its developmental trajectory to dementia.ResultDuring the study follow‐up (median [IQR] = 8 [6‐10]), a total of 741 (12.3%) participants developed dementia. Number of chronic conditions was associated with risk of subsequent dementia (hazard ratio [HR] for per condition increment = 1.14; 95% confidence interval [CI] = 1.08 to 1.20). The associations were consistently observed across major study subgroups. Psychological disorders (HR = 1.72, 1.42 to 2.08) and stroke (HR = 1.64, 1.32 to 2.02) demonstrated the strongest relations, followed by diabetes (HR = 1.23, 1.03 to 1.48) and heart diseases (HR = 1.21, 1.03 to 1.43). Moreover, participants with “rapid growth” trajectory of multimorbidity development were observed to have the highest dementia risk (HR = 1.38, 1.09 to 1.76), compared to the “no new condition” group.ConclusionOur study provided evidence that the number of coexisting conditions and the faster development of multimorbidity were both associated with higher risk of subsequent dementia. Further investigations are warranted to understand the underlying mechanisms.
Crop Filling: artefact removal for real‐world clinical neuroimaging data
Authors: LaPoint Molly R. , Whitfield Tim , Walker Zuzana , Oxtoby Neil P 
Published: December 2022

AbstractBackgroundThe use of standard clinical neuroimaging data for quantitative research is often precluded by imaging artefacts caused by real‐world limitations. For example, partial coverage (cropping) of T1‐weighted MRI scans can occur when a memory clinic prioritises visual ratings on T2‐weighted MRI, and so the T1 scan field‐of‐view is reduced to minimise the overall acquisition time. This study investigated cropping‐induced biases in T1‐MRI volumetric measurements and proposed and validated a solution.MethodThis study involved 1.5T T1‐weighted and T2‐weighted MRI data from 577 participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI): 173 cognitively normal (CN); 262 mild cognitive impairment (MCI); 114 probable Alzheimer’s disease dementia (AD). The ADNI data was preprocessed to resemble clinical data seen in the CODEC dataset from the Essex Memory Clinic in the UK. The T1w scans were artificially cropped to a field of view of 120mm laterally. The T2w scans were down‐sampled to have axial slice thickness of 5mm. FreeSurfer’s synthSR tool was used to synthesize a super‐resolved T1wSR from the down‐sampled T2w. The T1wSR image was registered to the cropped T1w using mri_robust_registration, with the data from the T1wSR used to fill the missing voxels in the cropped image. FreeSurfer’s recon‐all tool was used to estimate regional brain volumes in cropped , crop‐filled and original T1w images, with results compared using Bland‐Altman analysis, R2 correlation metric, and T‐test between original and cropped/crop‐filled values.ResultFigure 1 shows an example T1w from ADNI (coronal/axial view, AD patient): original (top); artificially cropped (centre); crop‐filled (bottom). Table 1 shows groupwise demographics of the ADNI participants and overall experimental results. Figure 2‐5 shows Bland‐Altman plots and R2 correlation metric for the volumes of three AD‐relevant brain regions: hippocampus, middle temporal gyrus, and ventricles. Results suggest that the proposed crop‐filling solution works well: low percentage bias (<1% crop‐filled; ∼2% cropped), high correlation (R2∼0.9 crop‐filled; ∼0.85 cropped).ConclusionThe new crop‐filling methodology was effective at removing this specific artefact seen in clinical neuroimaging data. This is an important step towards making real‐world neuroimaging data amenable to quantitative analyses.
Sex differences on a digitally‐administered cognitive assessment battery in adults at‐risk for development of Alzheimer’s disease.
Authors: Bryk Kelsey Nicole , Myers Jennifer Rae , Madero Erica N. , Campitelli Anthony , Gills Joshua L. , Jones Megan , Paulson Sally , Gray Michelle , Glenn Jordan M. 
Published: December 2022

AbstractBackgroundSex differences in cognition have been well‐established among both healthy individuals and various clinical populations, including patients diagnosed with Alzheimer’s disease (AD). Specifically, females with AD experience greater cognitive impairment than men. However, cognitive sex differences among a population at‐risk for AD have not been elucidated. Therefore, the purpose of this study was to examine sex differences among at‐risk individuals using a digital cognitive assessment battery.MethodData collected are part of the ongoing Digital Cognitive Multi‐domain Alzheimer’s Risk Velocity Study investigating the effects of a 2‐year digital lifestyle intervention on individuals at‐risk for developing AD. Risk factors were determined via the Australian National University‐Alzheimer’s Disease Risk Index (ANU‐ADRI); two positive risk factors for AD (e.g.: history of diabetes, smoking, and/or traumatic brain injury) and no more than one protective factor (e.g.: high level of physical activity) were required for participation. Participants (age 45–75) completed six digital assessments measuring executive function, inhibition, processing speed, attention, associative learning, and associative memory. Independent sample t‐tests were used to analyze group differences (female vs male) in cognitive performance.ResultA significant difference between sexes exists for associative memory. Specifically, females had greater accuracy in recognizing previously presented images as compared to their male counterparts (Females = 0.3691 + 0.1072; Males = 0.3186 + 0.1115; p = .007; Cohen’s d = .465). While males and females did not differ in their time spent gazing at the novel image, females demonstrated a significantly better accuracy at identifying which image pairs they had seen previously compared to their male counterparts (Females = 0.3691 + 0.1072; Males = 0.3186 + 0.1115; p = .007; Cohen’s d = .465). No other differences in cognitive performance were observed.ConclusionThis study demonstrates that at‐risk women demonstrate a more accurate behavioral response during an associative memory task than their male counterparts. These results are counter to evidence suggesting females with AD experience greater cognitive impairment, indicating that other factors should be considered to understand the process of dementia‐related cognitive decline and cognitive impairment differences between sexes among patients with AD.
Cerebral perfusion and glucose metabolism profiling reveal special phenotypes in the hAPOE3, hAPOE4, Trem2 risk, and doubled risks mice
Authors: Lin Peter Bor‐Chian , Persohn Scott C , Bedwell Amanda A , Jiang Lei , Eldridge Kierra , Speedy Rachael , Kotredes Kevin P , Pandey Ravi S , Williams Harriet M , Oblak Adrian L , Sasner Michael , Howell Gareth R , Carter Gregory W , Lamb Bruce T , Territo Paul R 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is the most common cause of dementia in the United States. Approximately 95% of patients have sporadic Late‐Onset AD (LOAD) which lacks an inheritance pattern. Therefore, identifying phenotypic patterns is critical for understanding disease progression.Among all the genetic markers which being identified as AD risks, and APOE4 confers the strongest one. The GWAS analysis also revealed a LOAD‐associated locus on the gene of TREM2. As the microglial receptor of APOE, the R47H variant on TREM2 increases the AD risk. In this study, how these risk alleles affect the brain phenotypes were assessed by MODEL‐AD.MethodWe established an analytical scheme which elucidates the cerebral perfusion and metabolism profiles across 27 brain regions by using 64Cu‐PTSM and 18F‐FDG PET imaging platform in the mice with wild‐type, humanized APOE3 (hAPOε3/ ε3), humanized APOE4 (hAPOε4/ ε4), TREM2 risk (Trem2R47H/R47H), and doubled risks (hAPOε4/ ε4:Trem2R47H/R47H) alleles.Also, RNA‐seq results from the hemisphere samples were used to conduct the correlation between PET measurements and the gene expression changes from each animal cohort.ResultLongitudinal analysis (4mo animals as reference) revealed aging effects in each cohort. The male hAPOE4 mice and both sexes of Trem2 risk animals had hypo‐perfusion and metabolism, while female hAPOE4 mice showed an uncoupled hyper‐perfusion and hypo‐metabolism phenotype. In the doubled risks mice, perfusion and metabolism showed a mixed regional‐dependent phenotype.Cross‐sectional analysis (wildtype mice as reference) showed the effects of humanized genes. A reduction in glucose metabolism was discovered. Intriguingly, male risks mice also showed reduced in perfusion, while the female mice showed a metabolic uncoupling profile.Cross‐sectional analysis (hAPOE3 mice as reference) showed the effects of risk alleles. An overall reduction in both perfusion and metabolism was discovered in all animal cohorts.To confirm these findings, RNAseq showed the genes involved in cerebral perfusion, glucose transportation, and metabolism regulation were altered, which are consistent with the findings.ConclusionThese data suggest that the new perfusion‐metabolism strategy may help to identify AD‐related patterns. Moreover, they replicate clinical manifestations of subjects with the same variants. Finally, additional studies are needed to elucidate the mechanisms and etiology of this uncoupling phenomenon.
Tau heterogeneity in Aβ positive patients
Authors: Landau Susan M. , Lee Jia Qie , Murphy Alice , Ward Tyler J. , Harrison Theresa M. , Baker Suzanne L. , Jagust William J. 
Published: December 2022

AbstractBackgroundA substantial proportion of individuals on the AD continuum have tau PET burden that is not elevated, suggesting that they may be in an earlier stage on the AD continuum and/or have other copathologies that account for their impairment. To examine these possibilities, we compared Aβ+, cognitively impaired individuals with lower tau burden to theirAβ+ high tau counterparts across a variety of biomarker and clinical measurements.MethodWe identified Aβ+, impaired (MCI or AD) patients from ADNI with high and low tau burden using contemporaneous amyloid PET (florbetapir or florbetaben) and tau PET (flortaucipir) scans. The high/low tau threshold was the 90th percentile SUVr of Aβ‐ cognitively normal individuals for a composite flortaucipir region of interest spanning most of the medial/lateral temporal lobes and extratemporal neocortex relative to inferior cerebellar grey matter (Figure 1). We compared Aβ+ high vs low tau groups on AD/cerebrovascular biomarkers, and demographic, cognitive, risk factor, and clinical measurements.ResultOf 218 Aβ+ impaired ADNI patients, 91 (42%) had cortical tau in the normal range. Compared to their high tau counterparts, low tau individuals were more likely to be male, older, have more years of education, and lower Aβ (within the elevated/abnormal range), but did not differ on proportion of ApoE4 carriers. Low tau individuals were also more likely to have cardiovascular risk factors and cerebrovascular pathology, but had less severe hippocampal atrophy and temporoparietal hypometabolism and better cognitive performance than high tau individuals. Examination of baseline tau (Figure 2A) and longitudinal tau (Figure 2B) rankings across 70 FreeSurfer‐defined regions revealed a highly overlapping set of medial/lateral temporal regions common to both high/low groups.ConclusionFor impaired individuals on the AD pathway, low tau PET burden is associated with heterogeneous group characteristics that support a role for copathologies in accounting for cognitive symptoms, but also point to the less advanced stage of cognitive and biomarker progression in this group. Despite these striking group differences, the set of regions in which tau was highest in the brain was strikingly consistent between groups, suggesting a common spatial accumulation pattern regardless of the degree of tau burden.
The contribution of hyperhomocysteinemia and hypoperfusion to amyloid‐beta induced cerebral endothelial cell dysfunction
Authors: Carey Ashley M , Parodi‐Rullan Rebecca M , Fossati Silvia 
Published: December 2022

AbstractBackgroundCerebrovascular dysfunction has been implicated as a major contributor to Alzheimer’s Disease (AD) pathology, with particularly endothelial cell (EC) stress promoting the focal ischemia, cerebral blood flow impairments, and blood brain barrier (BBB) permeability that are pathologically characteristic in AD. Recent evidence has emerged suggesting a link between cardiovascular (CV) diseases and AD pathology, particularly showing that CV/cerebrovascular risk factors, including hyperhomocysteinemia (Hhcy) and hypoperfusion (oxygen and glucose deprivation (OGD)), contribute to AD pathology and risk. Despite this, the underlying molecular mechanisms for this interaction remain unclear. Previously our lab has demonstrated that amyloid beta (Aβ), particularly Aβ40‐Q22 (the vasculotropic Dutch mutant), promotes TRAIL death receptor (DR)‐mediated apoptosis, barrier permeability, and angiogenic impairment within human cerebral ECs. We tested the hypothesis that Hhcy and hypoperfusion exacerbate Aβ‐induced cerebral EC TRAIL DR‐mediated apoptosis, barrier dysfunction, and angiogenesis defects.MethodHuman cerebral microvascular ECs were challenged with AβQ22 and/or homocysteine (Hcy) in the presence/absence of hypoperfusion. Apoptotic mediator expression, caspase activation, and DNA fragmentation were measured to assess apoptosis. BBB protein expression and trans‐endothelial‐electrical‐resistance (TEER) were measured to assess EC barrier integrity. Angiogenesis inhibition and activation assays were utilized to measure EC angiogenic capability.ResultAβQ22 and Hcy challenge independently upregulated EC expression of TRAIL DR‐related apoptotic mediators and caspase activity, and, at certain time‐points, resulted in an additive upregulation of apoptotic mediators and caspase activity. AβQ22, Hcy, and hypoperfusion individually increased DNA fragmentation within cerebral ECs. Combination treatments of AβQ22 and Hcy created an additive effect on DNA fragmentation. Hypoperfusion and AβQ22 independently decreased BBB protein expression and TEER, while an additive decrease was observed with the combined challenges. AβQ22 and Hcy independently decreased angiogenesis progression, with some timepoints revealing an additive decrease with the combination treatment.ConclusionThe presence of CV risk factors seems to exacerbate Aβ induced‐EC apoptosis, barrier dysfunction, and angiogenic impairment, revealing several of the specific molecular mechanism through which amyloidosis and CV risk factors may additively act to produce EC dysfunction and death in AD pathology.
MR spectroscopic neurometabolite profile in aged rodents: a study in Sprague‐Dawley and Wistar rats, and C57bl/6J mice
Authors: Lehtimäki Kimmo , Dudek Mateusz , Oksman Juho , Puoliväli Jukka , Thompson Paul , Pearce Andy , Almond Sarah , Miszczuk Diana 
Published: December 2022

AbstractBackgroundCognitive decline and Alzheimer’s disease (AD) are closely related to aging in human population and the need for translational biomarkers is of crucial importance. Several approaches have been proposed to study Alzheimer’s disease in rodent models, including transgenic mice and rats to model either amyloid‐ or tau‐pathologies. We have shown age‐related 1H‐MRS phenotype in female Fisher rats (22‐24 months, Bolognin et al. 2014 Neurobiol Aging:2134‐46) with reduced N‐acetyl aspartate (NAA), GABA and glutamate, and increased myo‐inositol together with other AD‐like biomarkers (increased CSF levels of AbPP and Tau, defect in Morris Water Maze, Khatoon et al 2015 J Alzheimer’s Disease: 557‐564). The aim of this study was to explore if similar 1H‐MRS phenotype is present in other strains of aged rats and mice to allow easier access to cohorts of aged rodents and enable utilization of different strains to model pathology.MethodEighteen male Sprague‐Dawley rats (n=10/8, 4/24 months), 24 male Wistar rats (n=12/12, 3.25 /21.75 months) and 23 male C57Bl/6J mice (n=12/11, 4.75/23 months) were used. Hippocampal MRS was performed at 11.7T magnet using PRESS sequence and metabolites analyzed using LCModel.ResultAlthough the evaluation was done at slightly different ages, all three models shared a similar phenotype in hippocampal metabolites, i.e. decreased GABA and glutamate, and increased glutamine and myo‐inositol. NAA was significantly reduced in aged Wistar rats and C57Bl/6J mice whereas the SD rats showed only non‐significant trend of decrease.ConclusionBased on the current data, the MRS phenotype is remarkably repeatable in aged rats (SD, Wistar) and in aged C57Bl/6J mice. Furthermore, the pattern of increased myo‐inositol with decreased levels of glutamate and NAA is descriptive of human AD. Aged rodents can therefore model biochemical changes potentially related to natural aging/AD.
Cross‐country Effects of the Tailored Activity Program to Reduce Neuropsychiatric Symptoms and Other Dementia‐related Symptoms: Results from Randomized Trials
Authors: Gitlin Laura N. , Aravena Jose , Koeuth Sokha , Gajardo Jean 
Published: December 2022

AbstractBackgroundThe Tailored Activity Program (TAP) is a nonpharmacological approach shown to reduce neuropsychiatric symptoms and other dementia‐related clinical symptoms in people living with dementia and family caregivers.MethodTAP has been tested in 8 different randomized trials (stage 3 efficacy) in four different countries and is currently used in over 9 countries with varying results.ResultAcross 8 trials, TAP was found to have a wide range of benefits including reducing functional dependence and neuropsychiatric symptoms, improving quality of life of both people living with dementia and their caregivers, and enhancing caregiver well‐being. Findings from trials also demonstrate differences in outcomes among samples. For example in a USA trial involving 250 families, TAP compared to attention control resulted in differential effects for Black and White families. Statistically and clinically significant reductions in agitation and aggression (frequency and severity scores) were found for Black families in TAP compared to White families in TAP and those in the control group. In contrast, White caregivers receiving TAP reported less depressive symptoms than other groups.ConclusionComparing outcomes across trials highlights the role of contextual factors and how country specific needs for dementia care may impact outcomes from nonpharmacological interventions. The comparison also reveals multiple challenges concerning dissemination and implementation of TAP (stage 4 and 5) such as lack of workforce preparation, payment mechanisms, and knowledge and acceptability of nonpharmacological approaches.