bluuebunny/crossref_metadata_2025_split huggingface dataset:
A transcriptional mechanism for retromer misregulation
Authors: Roque Cláudio Gouveia , Baleriola Jimena , Hengst Ulrich 
Published: December 2020

AbstractBackgroundTranscription factors (TFs) regulate gene expression and define cellular homeostasis. This occurs via poorly resolved combinations of TFs that synergistically coordinate transcriptional decisions (Lambert et al., 2018). TFs are also drivers of pathology (Lee and Young, 2013), as aberrant transcriptional changes commonly develop in disease states. Recent transcriptomic profiles of the Alzheimer’s disease (AD) brain indicate that specific groups of genes become deregulated during the course of disease progression (Mathys et al., 2019; Small et al., 2005; Zhang et al., 2013), highlighting the need to understand how TF‐mediated mechanisms of gene expression fail during AD pathogenesis.MethodCellular models of disease counterpointed with analyses of AD postmortem tissue that employed a combination of DNA‐, RNA‐, and protein‐based approaches.ResultWe report the characterization of a transcription factor heterodimer linked to Alzheimer’s disease (AD). This complex is enriched in the dorsolateral prefrontal cortex of late‐onset AD patients and functions as a sensor of β‐amyloid stimuli in neurons. We additionally identify the retromer, a master orchestrator of endosome sorting and amyloid precursor protein metabolism (Small and Petsko, 2015), as an AD‐relevant transcriptional target of this heterodimer, and connect its accumulation in AD to disrupted retromer gene expression.ConclusionOur findings support a mechanism of retromer dysfunction promoted by an AD‐associated transcriptional pathway. Conceptually, they also argue for the importance of probing TF interactions as a way to understand gene expression, both in normalcy and during disease pathogenesis.
The relationship between waist‐to‐hip ratio, BMI index and cognitive impairment in those aged 40 years or above: A cross‐sectional study in a rural area of Xi’an, China
Authors: Shang Suhang , Zhang Binyan , Wang Jin , Jiang Yu , Chen Chen , Dang Liangjun , Qu Qiumin 
Published: December 2020

AbstractBackgroundThe relationship between obesity, body weight and cognitive impairment is still controversial. To analyze the correlation between BMI index, waist‐to‐hip ratio and cognitive impairment.MethodThis study is a cross‐sectional survey conduct during October 2014 to March 2015. Subjects who aged 40 and above and lived in a village in the suburbs of Xi'an, China were selected as the research sample. Cognitive function was assessed using the Mini Mental State Scale (MMSE). Cognitive impairment was defined as a Mini‐Mental State Examination (MMSE) score lower than the cutoff value. Specifically, the cutoff value was ≤17 for the illiterate, ≤20 for the primary school educated, and ≤24 for those educated at the junior high school level or above. Height and weight were measured to calculate the BMI index; waist circumference and hip circumference were measured to calculate the waist‐hip ratio. Multivariate logistic regression was used to correct for confounding factors.ResultA total of 1792 subjects were enrolled in the study, including 726 males (40.5%), and were aged 40‐85 (average 55.53 ± 9.92) years. 230 subjects (12.8%) were diagnosed as having cognitive impairment. BMI index was 25.29 ± 3.14 kg/m2, and 433)24.2%( had BMI index <23 kg/m2. WHR was 0.88 ± 0.06, and 462 subjects had WHR> 0.92. Univariate analysis showed that those with a BMI index <23 kg/m2 (<23 vs 23‐25 vs 25‐27 vs ≥27 kg/m2, 16.2% vs 12.0% vs 12.1% vs 11.3%, P = 0.120), and those with WHR >0.92 (<0.84 vs 0.84‐0.88 vs 0.88‐0.92 vs ≥0.92, 12.1% vs 11.9% vs 11.0% vs 16.2%, P=0.082) tended to have higher risk for cognitive impairment. Multivariate logistic regression analysis showed that WHR ≥ 0.92 (OR = 1.619, 95% CI 1.161‐2.258, P = 0.005) and BMI <23 kg/m2 (OR = 1.366, 95% CI 0.969‐1.927, P = 0.075) was ( or tend to) positive correlated with cognitive impairment.ConclusionIn the population aged 40 or above in rural areas of Xi'an, China, abdominal obesity and low body weight were positive correlated with cognitive impairment.
Estrogen‐modulating breast cancer therapies and the incidence of Alzheimer’s disease
Authors: Branigan Gregory L , Soto Maira , Neumayer Leigh , Rodgers Kathleen E , Brinton Roberta Diaz 
Published: December 2020

AbstractBackgroundGlobally, neurological disorders rank as the leading cause of disability‐adjusted life‐years, and the second‐leading cause of deaths. The high global prevalence and economic impact of Alzheimer’s disease presents a significant public health challenge while the identification of therapies to prevent Alzheimer’s disease (AD) remains a challenge. Worldwide, breast cancer is the most common non‐skin cancer in women. Approximately 1 in 8 women will be diagnosed with breast cancer during their lifetime. Currently, Alzheimer’s disease affects 1 in 9 persons in the US over the age of 65, two thirds of whom are women.MethodThe objective of this study was to determine whether exposure to hormone modulating therapies targeting estrogen for the treatment of breast cancer impact the risk of AD using medical informatics and the Symphony claims data set. The Symphony data set contains claims from private‐payer and Medicare insurance data sets from across the United States. Survival analysis was used to determine the association between estrogen modulating therapy exposure and diagnosis of AD in the post index date follow‐up period. A propensity score approach was used to minimize measured and unmeasured selection bias.ResultIn this cohort study of propensity score matched perimenopausal to postmenopausal aged women with breast cancer, estrogen modulating therapy exposure was associated with decrease in diagnosis of neurodegenerative disease, most specifically Alzheimer’s disease. Kaplan‐Meier curves for AD‐free survival were analyzed to measure the overall rate and proportion of patients in each treatment group who went on to develop neurodegenerative disease.ConclusionAmong female patients with breast cancer, exposure to estrogen modulating therapies, specifically tamoxifen and steroidal aromatase inhibitors, was associated with a decrease in diagnosis of AD and Dementia. As a result, translational studies investigating the mechanisms by which these therapeutics impact AD risk are currently underway.
Beta‐amyloid‐associated episodic memory variation correlates with subicular volume in non‐demented old aged individuals
Authors: Kagerer Sonja M , Schroeder Clemens , Van Bergen Jiri M. G. , Schreiner Simon J. , Meyer Rafael , Steininger Stephanie C. , Laetitia Vionnet , Gietl Anton F. , Treyer Valerie , Buck Alfred , Pruessmann Klaas P. , Hock Christoph , Unschuld Paul G. 
Published: December 2020

AbstractBackgroundThe aggregation of cortical Amyloid β (Aβ) is a hallmark of Alzheimer's Disease (AD). Aβ accumulates during the preclinical stage and characterizes old aged adults at increased risk for AD. Also, low episodic memory (EM) performance within the normal range is linked to an increased risk for AD. This study is aimed at identifying hippocampal subfield atrophy associated with increased risk for AD, as reflected by cortical Aβ burden, and low EM.Method69 non‐demented old aged adults were administered 11C‐PiB‐PET and 18F‐Flutemetamol‐PET for measuring Aβ. Ultra high‐field 7 Tesla MRI (TR/TE = 4.8 ms/2.1 ms, 0.6mm3) was used for assessment of hippocampal subfields volumes. Subjects were dichotomized in high versus low levels of cortical Aβ and high versus low EM, as measured by the Verbal Learning and Memory Test (VLMT).ResultMultiple analysis of Variance (MANOVA) showed significant differences in hippocampal subfield volumes. Most distinguished effects on variation of volumes resulted for coexistent criteria "high‐ Aβ" and "low EM" (λ=0.34, p=0.039). Strongest effects resulted for subiculum and molecular layer (F(1,59)= 16.8, p = 0.002). The interaction between cortical Aβ and episodic memory performance was significant for subiculum only (F(1, 57) = 5.90, p = 0.018).ConclusionOur data indicate an association between low subicular volume and increased risk for AD in nondemented old aged persons. While our data is consistent with earlier data on subicular atrophy in preclinical AD, it also highlights promise of multivariate analysis for identifying biological risk phenotypes associated with sporadic AD.
Hyperphosphorylation, cytoskeleton and cell‐surface binding aptamers: Developing markers and understanding molecular changes in early stage Alzheimer’s disease
Authors: Parekh Parag A. , Mu Qingshan , Badchappe Andrew , Bhavane Rohan , Srivastava Mayank , Stupin Igor , Bhandari Prajwal , Devkota Laxman , Ghaghada Ketan , Annapragada Ananth 
Published: December 2020

AbstractBackgroundHyperphosphorylated tau (pTau) is a characteristic of AD, leading to intracellular “tau tangles” followed by dementia. However, intracellular tau is difficult to measure in vivo, requiring a probe to enter the cell. Proteomic changes on the diseased cell‐surface however, provide a diagnostic target that eliminates the need for a probe to enter the cell. We therefore sought cell surface markers of pathological neurons in the process of hyperphosphorylating tau.MethodSH‐SY5Y cells differentiated to a neuronal phenotype were rendered hyperphosphorylative by okadaic acid, and aptamers specifically binding these cells were captured using a modified cell‐SELEX methodology. Mass spectrometric proteomics identified the binding targets. Target presence was validated on SH‐SY5Y cells, P301S mouse brain tissue and human AD brain tissue by immunofluorescence. Gene‐expression data were analysed to identify the utility of the target as a diagnostic marker. A Gd‐bearing nanoparticle targeted using the lead aptamers was injected i.v. in 2‐month P301S mice and T1‐weighted MRI imaging was used to assess binding as a predictor of future tau pathology.ResultAptamers identified by sequencing of the enriched aptamer pools were demonstrated to specifically bind hyperphosphorylative SH‐SY5Y cells . Proteomic analysis suggested Vimentin and keratin6A/6B as potential binding targets. Analysis of hyperphosphorylative SH‐SY5Ycells, human AD tissue and P301S mouse brain tissue confirmed increased levels of cell‐surface Vimentin. Meta‐analysis revealed that Vimentin is expressed at higher levels in the diseased state. Further pathway analysis identified alternative targets related to desmosomes. Two month old P301S mice had no tau pathology, but the targeted MRI particles were still ∼80% accurate in identifying the transgenic mice and predicting future tau pathology.ConclusionOur results suggest that Vimentin and other related desmosomal molecules could be prognostic markers of future tauopathy, and also suggest a need to investigate cell‐surface changes under conditions that cause tauopathies. Targeted MRI particles are promising as an indicator of future tau pathology.
Polygenic risk scores can predict AD‐related pathologies
Authors: Cara Jared , Collens Julie , Beach Thomas G. , Cruchaga Carlos , Schneider Lon , Shah Kaanan P. 
Published: December 2020

AbstractBackgroundAlzheimer’s disease is defined by the presence of amyloid plaques and tau tangles in the brain leading to cognitive decline. Risk for AD is multifactorial with genetic factors playing a large role in disease risk. Specifically, presence of the APOE e4 allele is a strong risk factor for late onset AD. Beyond APOE, many variants have been identified as risk factors for AD, however with smaller effects.MethodPolygenic risk scores are a well‐established method for combining information across genetic factors with individually small effects on disease risk to predict an individual’s disease risk. We use this approach to develop genetic predictors of AD‐related pathologies such as amyloid. Specifically, we developed a PRS, that in combination with age and sex, is predictive of the presence of amyloid in an individual’s brain. We use pathological measures of protein aggregates in postmortem brain tissue as our training data set for model development however our tests can be applied antemortem via a blood test. We evaluate performance of our PRS and previously published scores in all individuals and subset by APOE e4 status.ResultWe show the performance of our PRSs to predict AD related pathologies in independent validation datasets. We also show performance metrics compared to PET and CSF measurements within the ADNI dataset as a comparison to established methods used in AD patients. Finally, in comparison to published AD PRSs, we found our pathology PRSs performed as well or better than in predicting specific pathology phenotypes. When used as a screening tool for clinical trial enrollment, our PRS assays can reduce the overall cost of patient enrollment by reducing the number of screen failures after a negative amyloid PET scan.ConclusionOur PRSs are predictive of AD related pathologies and can be useful as a screening tool within the context of a clinical trial. The cost savings for clinical trial enrollment varies based on the size of the trial. Thus, incorporating genetics early within a clinical trial will be valuable for enrollment. This information can also be used to identify important biomarkers of response as the trial progresses.
The impact of concomitant LATE‐NC on hyperphosphorylated tau pathology and cognitive decline in Alzheimer’s disease
Authors: Walker Lauren , McAleese Kirsty E. , Erskine Daniel , Attems Johannes 
Published: December 2020

AbstractBackgroundLimbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC) is present in approximately 57% of Alzheimer’s disease (AD) cases and is associated with accelerated cognitive decline and accelerated disease progression. Hyperphosphorylated tau (HP‐τ) burden in AD is associated with cognitive deficits; it is unknown if LATE‐NC is associated with HP‐τ burden. In post‐mortem AD cases, we investigated the association between LATE‐NC and early and late HP‐τ and the impact of LATE‐NC on clinical measures of cognition.Method46 AD cases underwent neuropathological assessment for LATE‐NC [1] and quantitative assessment for early conformational HP‐τ (MC‐1) and intermediate/late stage HP‐τ (AT8) in the frontal, entorhinal, temporal, parietal and occipital cortices. Cognitive decline (n=20) was calculated from longitudinal mini‐Mental State Examination (MMSE; n =37).Result29 cases (63%) exhibited LATE‐NC (AD+). No significant differences in AT8 were revealed, however, observationally, AT8 was higher in all regions of AD+ cases. MC‐1 burden was significantly lower in the entorhinal cortex (P<0.05), and observational lower in all regions in the AD+ cases. No association between MC‐1 or AT8 with LATE‐NC score were revealed. MMSE score and cognitive decline was not significantly different between AD+ and AD‐ groups (both P>0.9) and linear regression revealed no influence of LATE‐NC on cognitive scores.ConclusionAD+ cases exhibit lower burden of MC‐1 and higher burden of AT8 pathology indicating possible advanced progression of the disease compared to AD‐ cases. The presence of LATE‐NC is not associated with differences in cognitive scores in AD. (1) Nelson et al (2019) doi:10.1093/brain/awz099.
Lobar distribution of white matter abnormalities in Alzheimer’s, vascular and mixed dementias
Authors: Lee Hyunwoo , Wiggermann Vanessa , Rauscher Alexander , Beg Mirza Faisal , Popuri Karteek , Tam Roger , Lam Kevin , Jacova Claudia , Sossi Vesna , Pettersen Jacqueline , Benavente Oscar R. , Hsiung Ging‐Yuek Robin 
Published: December 2020

AbstractBackgroundVascular dementia (VaD) is often difficult to distinguish from Alzheimer’s disease (AD).[O’Brien_2015] Areas of cognitive/clinical decline due to cerebrovascular diseases depend on the frequency and location of the lesions, and may overlap with those found in AD.[Suri_2014] Moreover, AD and cerebrovascular diseases frequently occur simultaneously, leading to heterogeneous ‘mixed dementia (MixD)’.[Wang_2012][Langa_2004] It is unclear whether the presence of both neurodegenerative and cerebrovascular pathologies further aggravates dementia‐related imaging abnormalities. We investigated whether the lobar distribution of white matter hyperintensities (WMHs) on MRI differed among AD, VaD and MixD.MethodN=17 participants (cross‐sectional; subtypes:7 MixD/5 Subcortical VaD/5 AD; Sex: 11M/6F; Age: 75±8yrs) were scanned on a 3T Philips Achieva. T1‐weighted MP‐RAGE images were processed with Freesurfer 6.0. Areas of WMHs were segmented on Fluid Attenuated Inversion Recovery (3D‐FLAIR) images using a combination of intensity thresholding and manual correction. Left and right frontal, temporal, occipital and parietal lobes plus basal ganglia volumes were constructed using the Freesurfer segmentation outputs. Individual WMH masks were transformed to their respective T1‐weighted spaces, and the ratios of WMH volumes to different lobar volumes were calculated.ResultAverage WMH volumes were (mean±SD) AD: 5191±4693mm3, MixD: 34680±17059mm3 (sig. greater than AD), SVaD: 20896±14920mm3 (n.s. from MixD or AD). We used a linear model to predict the ratios of WMH to lobar volumes from the diagnosis subtypes, adjusting for age and sex. A significant diagnosis‐subtype effect was found in both the left and right frontal lobes. (p=0.012 and 0.045, respectively). In the left frontal lobe, the proportion of WMHs was significantly greater in the MixD subgroup compared to the AD (p=0.0045) or the VaD (p=0.026) subtypes. In the right frontal lobe, the proportion was greater in the MixD subtype compared to the AD (p=0.018) but not compared to VaD (p=0.074) subtype. AD vs. VaD were not significantly different in either sides (p=0.5).ConclusionThe MixD subtype of our pilot study cohort was characterized by a significantly greater presence of WMHs in the frontal lobar areas. Future studies are warranted to investigate the characteristics of underlying tissue abnormalities that could be specific to the diagnosis subtypes.
Differences due to sex in cortical thickness and CSF biomarkers in normal aging and Alzheimer’s dementia
Authors: Sangha Oshin , MaLeePopuri DaSieunKarteek , Beg Mirza Faisal 
Published: December 2020

AbstractBackgroundIn normal aging, a thinner cortex in males has been reported by various studies. Longitudinal trends in cortical thinning in males and females in healthy aging and in Alzheimer’s Dementia (AD) have yet to explored. In addition, CSF biomarkers also play an important role in detecting AD. In this study, we explored the differences in cortical thinning and CSF biomarkers between males and females in both healthy and AD subjects.MethodBaseline differences and differences up to two‐ years were studied using the data from two publicly available datasets ‐ Alzheimer's Disease Neuroimaging Initiative (ADNI) [Baseline scans‐ healthy control (HC): 423, AD: 330; follow up scans ‐ HC: 1191, AD: 536] and Australian Imaging Biomarkers and Lifestyle Study of Ageing (AIBL) [Baseline scans only ‐ HC: 319, AD: 72.] Only stable subjects (diagnosis does not change in the follow up scans) healthy controls and AD subjects were used. Generalized linear regression models were used to control the effect for age, intracranial volume, and scanner effects. For analyzing the differences between CSF biomarker levels, only age was controlled.ResultIn the Healthy control group, males showed a thinner cortex than females at baseline. Both males and females showed significant cortical thinning in different regions over two years. In the AD group, males showed a thinner cortex than females at baseline and over two years; however, the number of regions showing a significantly thinner cortex in males compared to females were less as opposed to the case in the control group. On the other hand, no significant differences were observed in the level of CSF biomarkers between males and females at either baseline and follow up measurements for both control and AD groups.ConclusionIn AD, females appear to experience greater cortical thinning than males such that the sex difference was less evident in AD than in controls. In the AD group, the sex difference in cortex continued to decrease through the two‐year study period. For CSF biomarkers, no significant difference was observed for males and females. This result suggests that neuro‐imaging is more sensitive to male and female differences than CSF biomarkers.
Vascular dysfunction in CAA in the presence of cardiovascular risk factors: The role of the mitochondria and therapeutic approaches
Authors: Parodi‐Rullan Rebecca M. , Sone Je Yeong , Fossati Silvia 
Published: December 2020

AbstractBackgroundThe accumulation of amyloid‐β (Aβ) on the brain vasculature, known as Cerebral Amyloid Angiopathy (CAA), induces vascular dysfunction contributing to neurodegeneration. Cardiovascular (CV) risk factors, which are also mediators of vascular dysfunction and may increase the risk for developing Alzheimer’s Disease and dementia, may potentiate CAA‐mediated neurovascular pathology. Mitochondria are key cellular organelles that have a dual role as mediators of cell survival and death and have an important role in disease pathogenesis. However, the role of brain endothelial mitochondria in vascular amyloidosis complicated with CV risk factors is unknown. The carbonic anhydrase inhibitors (CAi) methazolamide and acetazolamide were able to reduce amyloid‐induced cell death and mitochondrial dysfunction. Our work focuses on understanding the mechanisms of vascular dysfunction induced by Aβ complicated with CV risk factors. We aim to understand the protective role of CAi in preventing the pathological changes associated to neurovascular dysfunction and neurodegeneration.MethodImmortalized human cerebral microvascular endothelial cells (ECs) were used to study the molecular changes that occur in the cerebral vasculature during amyloid challenge complicated with CV risk factors, such as hyperhomocysteinemia (HHC). We then tested CAi and their potential to prevent cell death and mitochondrial dysfunction in ECs challenged with Aβ in the presence or absence of CV risk factors such as HHC.ResultAβ and HHC increased EC barrier permeability and that the presence of HHC worsened amyloid‐induced barrier permeability. Aβ‐induced EC apoptosis was reduced by treatment with CAi. We further demonstrate that both Aβ and HHC decrease mitochondrial basal respiration. The presence of Aβ induces cytochrome‐c release, mitochondrial membrane potential loss, and ROS production which were reduced by treatment with CAi.ConclusionHHC and Aβ induce brain microvascular EC dysfunction and increase permeability of the EC barrier. Aβ induces cell death and mitochondrial dysfunction, which are both prevented by CAi. We also demonstrate that CV risk factors, specifically HHC, induce mitochondrial dysfunction on brain ECs which could further contribute to neurovascular dysfunction and neurodegeneration observed in CAA. Our studies suggest that CAi could serve as a novel therapeutic strategy towards vascular dysfunction during CAA complicated with CV risk factors.