bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proteomics identifies CSF biomarker panels reflective of pathological networks in the Alzheimer's disease brain
Authors: Higginbotham Lenora A , Ping Lingyan , Dammer Eric B , Duong Duc , Zhou Maotian , Gearing Marla , Johnson Erik CB , Hajjar Ihab , Lah James J , Levey Allan I , Seyfried Nicholas T 
Published: December 2020

AbstractBackgroundThe repeated failures of amyloid‐targeting therapies have underscored the need for additional biomarkers of Alzheimer’s disease (AD) that reflect its complex multi‐network dysfunction. Using a network‐based proteomic approach, we previously defined a wide range of protein system alterations in the AD brain. In this study, we integrated these brain networks with proteomic analysis of cerebrospinal fluid (CSF), resulting in the identification of CSF biomarker panels reflective of diverse pathophysiology within the AD brain.MethodsUsing quantitative liquid chromatography coupled to tandem mass spectrometry (LC‐MS/MS), we comparatively analyzed the CSF proteomes of 40 samples (20 controls, 20 AD). Differential expression analysis resolved CSF proteins significantly altered in AD. These CSF biomarkers were mapped to proteomic networks derived from 48 postmortem brain tissues comprising control, asymptomatic AD (AsymAD), AD, and other neurodegenerative diseases. Validation was performed in an independent CSF cohort of 96 control, AsymAD, and AD samples using high‐throughput proteomic methods.ResultsWe identified >3,500 proteins across the initial 40 CSF samples and >12,000 proteins across the 48 postmortem brain tissues. Co‐expression network analysis of the brain tissues yielded 44 protein modules, nearly half of which correlated significantly to AD neuropathology. Fifteen modules robustly overlapped with proteins quantified in the CSF, including 271 CSF markers highly altered in AD. These 15 overlapping modules were collapsed into five panels of brain‐linked fluid markers representing a variety of cortical functions. Neuron‐enriched synaptic and metabolic panels demonstrated decreased levels in the AD brain but increased levels in diseased CSF. Conversely, glial‐enriched myelination and immunity panels were highly increased in both the brain and CSF. Validation of these findings in an independent CSF cohort of control, AsymAD, and AD samples remarkably demonstrated panel alterations in the early, asymptomatic stages of disease. In fact, several panel markers appeared to stratify subpopulations within this preclinical cohort.ConclusionThese brain‐linked CSF biomarker panels represent a promising step toward a comprehensive physiological tool that could enhance the therapeutic management of AD.
Effect of apolipoprotein‐E Ε4 genotype on amyloid‐β and tau accumulation in Alzheimer’s disease
Authors: Baek Min Seok , Cho Hanna , Lee Jae Hoon , Ryu Young Hoon , Lyoo Chul Hyoung 
Published: December 2020

AbstractBackgroundWe investigated effects of apolipoprotein E (ApoE) ε4 genotype on Aβ and tau burden and their longitudinal changes in Alzheimer’s disease spectrum.MethodAmong 272 individuals who underwent PET scans (18F‐florbetaben for Aβ and 18F‐flortaucipir for tau), and ApoE genotyping, 187 individuals completed 2‐year follow up PET scans. After correcting for partial‐volume effect, we compared the SUV ratio (SUVR) for Aβ and tau burden between ε4+ and ε4‐ groups. By using a linear mixed‐effect model, we measured the changes in SUVR in ApoE ε4+ and ε4‐ groups.Resultε4+ group showed greater baseline Aβ burden in diffuse cortical regions, and greater tau burden in lateral, and medial temporal, cingulate, and insula cortices. An annual accumulation rates of tau was higher in parietal, occipital, lateral and medial temporal cortices in ε4+ group. However, the accumulation of Aβ was not significantly different between ε4+ and ε4‐ groups. In Aβ+ individuals, baseline tau burden was higher in medial temporal cortex, while Aβ burden was conversely greater in ε4‐ group than ε4+ group in the global cortex, sensorimotor, and parietal cortices. Baseline Aβ burden showed decreasing trend and tau burden showed increasing trend associated with the number of ε4 alleles in dose‐dependent manner in Aβ+ individuals.ConclusionProgressive tau accumulation occurs in ε4 carriers in AD spectrum especially in medial and lateral temporal cortices. Existence of ε4 may modulate Aβ and tau burden differently based on the amount of existing amyloidosis.
The role of calbindin‐D28k in a mouse model of Down syndrome‐related Alzheimer's disease
Authors: Hamlett Eric D. , Carroll Steven L. , Granholm Ann‐Charlotte 
Published: December 2020

AbstractBackgroundCalbindin‐D28k (CB) is a calcium‐binding/buffering protein that plays critical roles in preventing neuronal death as well as maintaining calcium homeostasis. Marked reductions in neuronal CB expression have been previously observed in individuals suffering from Alzheimer’s disease (AD) and recently observed in individuals with Down syndrome (DS) who develop early‐onset AD in the mid‐40s. The Ts65Dn mouse model of DS develops neurodegenerative patterns in the basal forebrain, the locus coeruleus and in the hippocampal perforant path. We hypothesized that neuronal expression of the mouse CB‐homologue, calbindin 1, may also be reduced in Ts65Dn mice and associated with cognitive deficits and neurodegeneration.MethodMale Ts65Dn mice (n = 24) and euploid control mice (n = 26) were obtained from Jackson Laboratory (Bar Harbor, ME). Mouse cohorts were either 4‐5 months of age (pre‐neurodegeneration) or 8‐10 months of age (post‐neurodegeneration). A behavioral battery was administered to quantify spontaneous activity (SA), novel object recognition(NORT), and spatial memory (WRAM). We performed immunostaining and immunoblotting of the CB‐homologue (calbindin 1) in cortical areas and in the hippocampal formation. performed two‐way ANOVAs to test for differences between the groups (karyotype x treatment), followed by Tukey’s post hoc analyses. Correlations and linear regressions were performed between calbindin 1 and cognitive performance measures. All statistical tests were performed with GraphPad Prism 7.03 (GraphPad Software, La Jolla, CA).ResultIn the adult hippocampus and in cortical areas, calbindin 1 expression was observed in specific principal neurons and subsets of interneurons for all mice. Ts65Dn mice were found to have significant reductions (15‐30% ) of calbindin 1 at 4 months of age. However, loss of calbindin 1‐positive principal neurons in the CA1 was more prominent at 8‐10 months of age in Ts65Dn mice. Calbindin 1 expression in the hippocampus and parietal cortex (but not frontal cortex) significantly correlated with SA and WRAM. Linear regression confirmed the goodness of fit and non‐deviation from linearity for all correlations.ConclusionEarly calbindin 1 depletion contributes to neuronal deficits and cognitive dysfunction in the Ts65Dn mouse model of DS mouse models. These results may be highly translatable to DS‐AD, where a similar CB phenotype also occurs.
PSEN1 M139L mutation in a Chinese pedigree with early‐onset familial Alzheimer's disease
Authors: Li Runzhi , Xu Jun , Suen Mengfan 
Published: December 2020

AbstractBackgroundpresenilin 1(PSEN1) is the most common gene associated with familial Alzheimer's disease. we reported a case with M139L mutation of PSEN1 which was reported as pathogenic mutation in February 2019.Methodchose an early‐onset Alzheimer's patient (proband) and her family (I‐V generation) as the research object. clinical and imaging data of the proband and her family members were collected. High throughput second generation exon sequencing and sanger method was used to analyze the gene of the proband.Result1. Proband clinical characteristic: The proband (IV8) started to progressive memory loss, especially short‐term memory at 38 years old. She can't work because of memory problem. Now she lives on her own, can use mobile phone and APP, drive, remember familiar roads, but cannot shop, take bus to new place, handle own finances. The MMSE score was 27/30, and the MOCA score was 20/30 (delayed recall, time orientation, visuospatial disfunction, calculation) (Figure 1). Brain Magnetic Resonance Imaging suggested hippocampal atrophy (Figure 2). 2. Family phenotypic distribution (Figure 3): The onset age of Alzheimer's disease in this family was early, starting between 38 and 55 years old. The first and prominent clinical manifestations were memory loss, followed by orientation and executive function impairment. Movement disorder appears later or does not appear. It may have mild anxiety or depression. 3. Gene results (Figure 4): a heterozygotic mutation was found in the exon region of the PSEN1 gene: c.415A>T (adenine > thymine), resulting in an amino acid change of p.139l (methionine > leucine).ConclusionWe reported the early onset familial Alzheimer's disease caused by M139L mutation of PSEN1 in Han Chinese family which was helpful to enrich the clinical phenotypic characteristics of early onset familial Alzheimer's disease associated with PSEN1 mutation.
The relationship between VEGF and cerebral vascular territory glucose metabolism is modified by cardiovascular risk in Alzheimer's disease
Authors: Tubi Meral A , Matsiyevskiy Elizabeth , Hapenney Matthew N , Riedel Brandalyn C , Mack Wendy J , King Kevin , Thompson Paul M , Braskie Meredith N 
Published: December 2020

AbstractBackgroundVascular endothelial growth factor (VEGF) regulates angiogenesis, neurogenesis, and glucose transport. Cardiovascular risk factors promote atherosclerosis and disrupt vascular integrity, possibly interfering with VEGF function. Variability in cardiovascular dysfunction severity may explain an inconsistent neuroprotective effect of VEGF across Alzheimer’s disease (AD) studies. Atherosclerosis in the middle and posterior cerebral arteries is associated with AD. We hypothesize that a higher Framingham Risk Score (FRS), a proxy for atherosclerosis severity, will moderate the association between VEGF and glucose metabolism in brain regions supplied by the MCA and PCA.MethodIn 158 participants (age: 55‐90 years; 39 normal, 80 MCI, 39 AD; 105M/53F) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), we evaluated whether CSF VEGF levels were associated with bilateral glucose metabolism (FDG‐PET) in gray matter vascular territories supplied by the anterior (ACA), middle (MCA), and posterior cerebral arteries (PCA), each defined by the vascular territory MNI template (Figure‐1, Figure‐2). We evaluated whether FRS modified the regional relationship between VEGF (Figure‐3) and FDG‐PET across all participants and within each diagnostic group. We used a mixed effects linear regression model (covarying for age, sex, education, APOE4 carrier status, CSF T‐tau, and diagnosis; random effect=site). All p‐values presented are false discovery rate (FDR) corrected at FDR <5%.ResultHigher VEGF was associated with higher FDG‐PET MCA‐SUVR (β=0.170, p=0.043), nominally associated with higher PCA‐SUVR (β=0.129, p=0.078), and not associated with ACA‐SUVR (β=0.092, p=0.244). In all participants, FRS nominally modified the association between VEGF and ACA‐SUVR (VEGF‐FRS interaction β=‐0.040, p=0.066) and MCA‐SUVR (VEGF‐FRS interaction β=‐0.032, p=0.066). In MCI participants alone, FRS significantly modified the association between VEGF and both ACA‐SUVR (VEGF‐FRS interaction β=‐0.078, p=0.014) and MCA‐SUVR (VEGF‐FRS interaction β=‐0.068, p=0.014).ConclusionThe region‐specific negative interaction of FRS with CSF VEGF suggests that higher VEGF levels were associated with greater MCA territory glucose metabolism in persons with lower FRS. Greater cardiovascular dysfunction may dampen VEGF’s neuroprotective effects, particularly in MCA‐supplied brain regions and in populations at risk for AD.
Ability of elderly women with cognitive decline in food preparation and related factors
Authors: Eguchi Yoko , Matsuda Yukiko , Matsuoka Teruyuki , Kato Yuka , Ueno Daisuke , Mimura Masaru , Narumoto Jin 
Published: December 2020

AbstractBackgroundFood preparation is an instrumental activity of daily living (IADL) affected by even mild cognitive decline. People with cognitive decline may perform some tasks of food preparation if done routinely and with prior proficiency. In Japan, women commonly prepare food owing to the cultural background, but few studies have investigated the impact of dementia in women on food preparation. The aim of the present study was to investigate the relationship between dietary abilities and cognitive and physical decline in the elderly women suspected with dementia.MethodThe subjects were 220 women, aged 65 years or older, who visited a hospital with signs of dementia in the period from February 1, 2017 to April 30, 2019. Information on the social background, ability to prepare food (higher IADL stage indicating worse performance), cognitive function, and physical status (body mass index, nutritional status) was obtained from clinical records.ResultThe mean age of the subjects was 79.6 ± 6.3 years, and 72.6% of them prepared food (including delivery) at least once a day. Regarding the ability of food preparation, 96, 30, 43, 32, and 19 people were in stages 1 (plans, prepares, and serves adequate meals independently), 2, 3, 4 (needs to have meals prepared and served), and unknown, respectively. The total Mini‐Mental State Exam (MMSE) scores for stages 1, 2, 3, and 4 were 23.2 ± 4.1, 20.3 ± 3.5, 19.4 ± 5.1, and 15.9 ± 5.5, respectively. Of the patients in stage 1, 51.0% had cognitive decline. The analysis of variance revealed significant differences in MMSE, Alzheimer’s Disease Assessment Scale scores and serum albumin levels among food preparation stages (F (3, 197) = 23.1; F (3, 194) = 23.18; F (3, 190) = 8.1; p ≤0.001).ConclusionHigher food preparation ability is associated with higher cognitive function and better nutritional status. While approximately half of the women with reduced cognitive function sustain their food preparation ability, some women, despite good cognitive function, do not. Therefore, individualized interventions are necessary in food preparation.
Peripapillary retinal nerve fiber layer thickness measured using optical coherence tomography as a marker of Alzheimer's disease
Authors: Wang Xin , Jiao Bin , Liao Xinxin , Liu Hui , Shen Lu 
Published: December 2020

AbstractBackgroundOptical coherence tomography (OCT), is an advanced, noninvasive technology that can provide the images of retinal structure, including peripapillary retinal nerve fiber layer (pRNFL), macular retinal thickness (MRT), as well as macular volume (MV). However, whether the retinal structure varied in Alzheimer's disease (AD) patients was still unclear. This study aims to detect the retinal changes of AD patients and explore their correction with severity of disease and classic biomarker.Method78 AD patients and 188 HC matched with age and sex were enrolled in this study. The pRNFL thickness, MRT and MV were assessed using OCT. In addition, Aβ42, Aβ40 and tau protein in plasma were detected using Simoa technology.ResultThe results showed that the pRNFL thickness of AD patients was significantly thinner than HC (96.76±10.44 vs 101.4±17.74, p=0.023). Compared with HC, MRT and MV were reduced in AD patients, but the differences were not significant(p>0.05). Furthermore, the pRNFL thickness was significantly negatively correlated with MMSE (r=‐0.362, p=0.005) and disease duration (r=‐0.295, p=0.002); In addition, the pRNFL thickness was positively correlated with t‐tau protein in plasma(r=0.409, p=0.002); while negatively correlated with Aβ42/40 in plasma(r=‐0.277, p=0.041). However, there was no significant correction between neither MRT nor MV and MMSE, disease duration, Aβ42, Aβ40 and tau protein in plasma (p>0.05).ConclusionThese results supported that pRNFL thickness measured using OCT may serve as a useful predictor of AD.
The difference of long‐term outcome according to baseline dementia severity in Korean Alzheimer’s disease patients treated with anti‐dementia medications
Authors: Kim Jeong Lan , Lee Miji , Park Yuri , Seo Heewon 
Published: December 2020

AbstractBackgroundTo describe the difference of long‐term outcome in Alzheimer’s disease (AD) according to initial dementia severity at the time of diagnosis in the clinical setting.MethodWe carried out retrospective chart review of patients who were diagnosed with Alzheimer’s disease on dementia clinic at an University Hospital in Korea from 2012 to 2019. Participants had been treated with donepezil or donepezil and memantine combination. We dichotomized participants into three groups by initial Clinical Dementia Rating (CDR); very mild group for CDR 0.5, mild group for CDR 1, and moderate group for CDR 2. The observation period was four years. All participants were assessed cognitive function, neuropsychiatric symptoms and severity of dementia by the Consortium to Establish a Registry for Alzheimer’s Disease Neuropsychological assessment battery (CERAD‐NP) including CDR, Minimal Mental Status Exam (MMSE), and Neuropsychiatric Inventory (NPI). The annual change of CDR‐SB(CDR‐sum of box), MMSE score, total score of CERAD‐NP, and total score of NPI were analyzed with general linear model multivariate analysis by SPSS version 22.ResultTwo hundred nine patients were finally enrolled. There were 73 participants in very mild group (mean age 80.11±6.99), 109 in mild group (mean age 80.42±7.27) and 27 in moderate group (mean age 83.15±8.29). The annual changes of CDR‐SB, MMSE score, and total score of CERAD‐NP were showed significant difference among three groups (moderate group > mild group > very mild group), except the total score of NPI. The declining rate of the total score of CERAD‐NP and MMSE were faster in the order of the moderate group, the mild group, and the very mind group.ConclusionOur result showed that the more advanced cognitive decline when a patient is diagnosed with AD can be associated with faster progression despite of receiving therapy with anti‐dementia medications. It is meaningful that we have studied these long‐term outcome of AD patients in real‐world clinical setting. In conclusion, the earlier treatment of AD, the slower progression of AD.
Ninety‐day ketogenic diet intervention has differential effects on neuronal and astrocytic transcriptional pathways in mouse brain
Authors: Koppel Scott J. , Pei Dong , Wilkins Heather M. , Weidling Ian , Wang Xiaowan , Menta Blaise , Perez‐Ortiz Judit , Kalani Anuradha , Manley Sharon , Koestler Devin C. , Swerdlow Russell H. 
Published: December 2020

AbstractBackgroundGlucose hypometabolism and mitochondrial dysfunction are early deficits in Alzheimer’s disease (AD) brains. The ketogenic diet (KD) has been suggested as a treatment for AD. The KD is theorized to support the brain through the generation of ketone bodies that serve as an alternative fuel to glucose and possibly through other unknown mechanisms. Historically many studies examine CNS function as though it is a homogenous bioenergetic compartment and under value how different CNS cell populations may respond to metabolic interventions or contribute to disease. Here, we characterized how a 3‐month KD intervention influences transcriptional pathways in enriched mouse neuron and astrocyte isolations through magnetic assisted cell separation and RNAseq analysis.MethodAll protocols were reviewed and approved by the KUMC Institutional Animal Care and Use Committee. 30 C57Bl6/N mice were maintained for 90‐days on either chow or ketogenic diet. Upon completion of the dietary intervention mice were euthanized, whole brains dissected, and single cell suspensions were generated. Neuronally and astrocytically enriched fractions were generated immunologically using cell‐type specific antibodies and magnetic selection. Isolated total single stranded RNA was processed and sequenced using Illumina Novaseq 6000 Genome Sequencer and analyzed statistically for differentially expressed genes.ResultKD increased the number of transcriptional pathways activated in mouse neurons whereas astrocytes were observed to have mainly suppressed transcriptional pathways. Molecular pathways with lowest q‐values activated by KD in neurons included endoplasmic reticulum protein processing, insulin signaling pathway, and oxidative phosphorylation. Top disease associated pathways activated by KD in neurons included Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. Top significant pathways suppressed in astrocytes by KD intervention included axon guidance, glutamatergic synapse, and circadian entrainment.ConclusionNeurons and astrocytes have substantially different responses to KD in terms of their transcriptional pathways. Treatment of neurologic disease with drugs that target molecules common to multiple CNS cell types may have diluted, antagonistic effects. Beneficial effects of KD or other therapies may be improved through the identification and targeting of not only disease relevant pathways, but disease relevant cellular compartmentalization of pathways and in doing so improve our ability to treat AD and other neurodegenerative diseases.
Plasma phospho‐tau217 can detect Alzheimer‐like pathology in Parkinson’s disease with dementia and dementia with Lewy bodies
Authors: Hall Sara , Stomrud Erik , Janelidze Shorena , Londos Elisabet , Dage Jeffrey L. , Hansson Oskar 
Published: December 2020

AbstractBackgroundParkinson’s disease with dementia (PDD) and Dementia with Lewy bodies (DLB) are considered synucleinopathies; however, neuropathology studies have revealed the common occurrence of comorbid Alzheimer’s disease (AD) pathology. Especially AD‐like tau pathology may contribute to cognitive decline in PDD/DLB. In vivo, the presence of co‐pathologies can be detected with PET imaging or CSF testing. However, recent advances in blood biomarkers make it feasible to investigate their utility for identifying AD co‐pathology. In this study we investigate plasma P‐tau217 and P‐tau181 in patients with PDD and DLB.MethodWe included 36 patients with PDD (n = 5) or DLB (n = 31), all part of the BioFINDER 2 study. Plasma was analyzed for P‐tau217 and P‐tau181. Also, CSF was analyzed for P‐tau217, P‐tau181, and Aβ42/Aβ40. 32 patients had undergone [18F]RO940 PET scans to detect AD‐like tau aggregates.ResultPlasma P‐tau217 had significant correlations with plasma P‐tau181 (Rs = 0.683, p < 0.001), CSF P‐tau217 (Rs = 0.678, p < 0.001) and negatively with CSF Aβ42/40 ratio (Rs = ‐0.568, p < 0.001). Both plasma P‐tau217 and plasma P‐tau181 correlated with [18F]RO940 retention in both a temporal meta‐ROI (stage I‐IV) (β= 0.61, p < 0.001 and β = 0.55, p = 0.002) and an extratemporal neocortical meta‐ROI (stage V‐VI) (β = 0.68, p < 0.001 and β = 0.57, p = 0.005). Plasma P‐tau217 predicted [18F]RO940 PET positivity with an AUC = 0.84 using the temporal meta‐ROI (stage I‐IV) and an AUC = 0.92 using the extratemporal neocortical meta‐ROI (stage V‐VI). Furthermore, plasma P‐tau217 predicted [18F]RO940 positivity with a significantly higher accuracy compared with plasma P‐tau181. The performance of plasma P‐tau217 in predicting [18F]RO940 positivity was similar to that of CSF P‐tau217. Additionally, plasma P‐tau217 predicted CSF Aβ positivity with an AUC = 0.91, also with a higher accuracy compared with plasma P‐tau181.ConclusionPlasma P‐tau217 might be a useful marker for AD co‐pathology in PDD and DLB, and may be useful for stratification of patients in clinical trials. Future studies are needed to determine whether plasma P‐tau217 provide important prognostic information in patients with PDD or DLB.