bluuebunny/crossref_metadata_2025_split huggingface dataset:
Using Oligodendrocytes for studies in Alzheimer disease
Authors: Ramirez Aura M , Shepherd Jihanne J , Simon Shaina A , Oron Oded , Vasquez Marina Lipkin , Moura Ana Sofia , Muniz Maria , Rajabli Farid , Wang Liyong , Liu Xiaoxiao , Jin Fulai , Kunkle Brian W. , Nuytemans Karen , Griswold Anthony J. , Young Juan J , Vance Jeffery M. , Dykxhoorn Derek M. ,   Hussman Institute for Human Genomics
Published: December 2022

AbstractBackgroundGenomic regulatory architecture (GRA) has been primarily studied in European ancestry. As part of the functional Consortium of the Alzheimer Disease Sequencing Project, we are determining the GRA in African and Amerindian ancestries. Oligodendrocytes (OLs) are the largest glial population in the adult central nervous system. While their main role is to support neuronal metabolism and connectivity, few studies have examined their importance in Alzheimer’s disease (AD), despite reports of low numbers of oligodendrocytes and reduced myelin in the early stages of AD and a demonstrated role of myelinating oligodendrocytes in learning and memory. Several studies have reported the derivation of OLs from pluripotent cells, such as induced pluripotent stem cells (iPSC) to be challenging. Here, we optimized a protocol to derive oligodendrocytes from iPSC for studies in AD patients with different ancestries and how ancestry‐specific genomic differences drive the onset and pathogenesis of AD.MethodiPSC lines derived from AD patients were cultured and differentiated into oligodendrocytes using different induction media, as well as different seeding densities. The cells in each treatment were compared at multiple time points using immunocytochemistry (ICC) and qRT‐PCR for oligodendroglia lineage markers with the goal of identifying the culture conditions that increase the yield of O4+ cells and myelinating oligodendrocytes.ResultOur results showed that increasing the initial seeding density positively correlates with the number of Olig2+ cells that subsequently transitioned into mature O4+ cells capable of producing myelin. Additionally, we showed that the addition of N2 supplement to the induction media was necessary to maintain the cell viability during the initial stage of differentiation.ConclusionWe have optimized a protocol to derive OLs from human iPSC lines. We determined that both the seeding density and the media supplements used during the initial stage of differentiation directly influence viability and, consequently the amount Olig2+ cells that could be obtained to be terminally differentiated into O4+ and myelinating cells. Our optimized protocol will be used to evaluate the GRA and functionality of potential GWAS driving loci in cultured oligodendrocytes from individuals of African and Amerindian ancestries.
Lower CSF ApoE glycosylation associates with measures of Alzheimer's disease biomarkers
Authors: Nedelkov Dobrin , Meuret Cristiana , Martinez Ashley , Hu Yueming , Smadi Sabrina , Yassine Hussein N. 
Published: December 2022

AbstractBackgroundThe mechanisms of how APOE4 allele (APOE4) increases the risk of Alzheimer’s disease (AD) pathology have not been fully elucidated. In cerebrospinal fluid (CSF), apoE is heavily glycosylated but its contribution to AD pathology is not known. The objective of this study was to determine the impact of APOE genotype and cognitive status on the relative abundance of apoE protein isoforms and their specific glycosylation patterns in CSF and plasma.MethodTotal glycosylation and ApoE isoform‐specific glycosylation were analyzed in plasma and CSF from a group of older individuals (n = 106) from the USC ADRC cohort, grouped into cognitively normal, with mild cognitive impairment, and with AD dementia. We used a new mass spectrometric immunoassay that simultaneously detects the apoE isoforms and glycoforms (O‐linked GalNAc(‐Sia)‐Gal‐Sia, and various combinations thereof).ResultIn heterozygous individuals, the apoE3/E2, E4/E2, and E4/E3 isoform ratios were all significantly lower in plasma compared to CSF. For all individuals, a single O‐linked glycan was observed in plasma, while two glycans (of the same type) per apoE were observed in CSF. The ratio of glycosylated to total apoE was greater in CSF compared to plasma for all apoE isoforms. In CSF, ApoE4 was 35% and 25% less glycosylated (P<0.001) than ApoE2 and ApoE3 carriers respectively. The % of secondary glycosylation was positively correlated with CSF Aβ42 levels (R=0.55, p<0.001) and negatively correlated with CSF total Tau (R=‐0.38, p=0.001). Patients with AD dementia had lower % glycosylation than individuals with MCI (p=0.008).ConclusionCSF glycosylation is lower in CSF apoE4 isoform and in those with dementia, and correlate with markers of AD pathology. Ongoing experiments are delineating the effects of ApoE glycosylation on its functions. ApoE4 glycosylation may represent a newer target of treatment in AD.
Parental SES buffers the effect of plasma pTau181 on memory among non‐Latinx White, Latinx, and non‐Latinx Black middle‐aged adults
Authors: Manly Jennifer J , Starks Tiara M. , Simoes Sabrina , Turney Indira C , Lao Patrick J. , Banjoko Michael B. , Brickman Adam M. 
Published: December 2022

AbstractBackgroundInclusive ADRD research should consider social and structural forces as potential sources of cognitive reserve and resilience. Characterization of neuropathology is critical for cognitive reserve research, but few cohorts have AD biomarker data in concert with sufficient sample size, population representativeness, and multi‐level, lifecourse measurement of determinants that is necessary to contribute substantial or novel evidence for when and where to intervene. We partnered with participants in a population‐representative intergenerational study in NYC to determine whether parental socioeconomic status (PSES) buffers the association of plasma pTau181 concentrations with memory among middle aged adults, and whether moderation of neuropathology is similar across racialized and ethnic groups.MethodOffspring participants were 1038 adult children (56±11‐years‐old range: 28‐88, 68% women, 12.6±4 years education, 48% Latinx tested in Spanish, 24% Latinx tested in English, 21% non‐Latinx Black, 7% non‐Latinx White) of 694 parents in a longitudinal community‐based study of Northern Manhattan residents age 65+. Blood collected from Offspring determined pTau181 concentration (Quanterix Simoa) and APOE genotype, and memory was tested with the Selective Reminding Test. PSES was measured with years of school collected directly from parents. Regression models examined associations of pTau181 concentration with memory, tested PSES as an effect modifier, and determined whether relationships differed by racial and ethnic group.ResultIn an unadjusted model, higher pTau181 concentrations predicted lower delayed recall (β = ‐0.438, 95% CI:‐0.662,‐0.214,p<0.001), and this was robust to addition of offspring age, sex/gender, years of education, racial and ethnic classification, APOE status, parental age, and PSES into the model (β = ‐0.332, 95% CI:‐0.542,‐0.122,p<0.001). pTau181 concentrations had a weaker relationship to delayed recall among offspring with higher PSES (β = ‐0.291, 95% CI: ‐0.540,‐0.043,p<0.022) than among those with lower PSES (β = ‐0.477, 95% CI:‐0.875,‐0.078,p = 0.019), and this effect modification was similar in all race and ethnicity groups.ConclusionEvidence from a multiethnic intergenerational study suggests that early life socioeconomic conditions promote cognitive reserve against AD neuropathology. The buffering effect of parental SES was present in all groups, but because racial and ethnic minoritized groups have disproportionate exposure to low SES in childhood, interventions that reduce childhood poverty could narrow ADRD disparities.
Changes in neighborhood disadvantage over 18 years contributes to racial disparities in later‐life cognition
Authors: Sol Ketlyne , Esposito Michael , Clarke Philippa , Zahodne Laura B. 
Published: December 2022

AbstractBackgroundNeighborhood disadvantage (NDis) is a well‐studied contextual and local indicator of Black‐White health disparities, including cognitive health. Trajectories of NDis are less commonly studied but may be important for understanding how investment and disinvestment in neighborhoods with predominately Black residents may contribute to disparities in cognitive aging. This study characterizes 18‐year trajectories of NDis and examines whether trajectories of NDis mediate Black‐White disparities in cognitive function.MethodThis study of 480 non‐Hispanic Black (NHB) and White (NHW) older adults (Mage = 63.9; 55% Black) were drawn from the Michigan Cognitive Aging Project (MCAP), a regionally‐representative, prospective longitudinal study of older adults in the Detroit metropolitan area. Participants’ current addresses were geocoded and linked to historical neighborhood data from the National Neighborhood Data Archive (NaNDA). Yearly measures of NDis from 2000 to 2017 reflect a composite of four indicators of disadvantage (proportions of: female headed families with children; households with public assistance; families below the federal poverty level; adults unemployed). First, a latent class growth analysis (LCGA) was used to determine distinct types of 18‐year NDis trajectories across 1,344 census tracts in the six counties represented in the sample. Next, path analysis was used to quantify the extent to which the identified classes of NDis trajectory mediated the association between race and global cognition, which was operationalized as a composite of five cognitive domain factor scores (i.e., episodic memory, executive function, processing speed, language, and visuospatial ability). Mediation models adjusted for age, sex/gender, and education.ResultLCGA indicated three classes of NDis trajectories: persistently high disadvantage (PHD: 9%), high and increasing disadvantage (HID; 16%), and persistently low disadvantage (PLD; 75%). NHB participants were more likely to live in PHD or HID neighborhoods, which were each associated with worse global cognition. NDis trajectories explained 12% of the Black‐White disparity in global cognition. HID was a stronger mediator of cognitive disparities than PHD.ConclusionDisinvestment in neighborhoods may contribute to racial disparities in global cognition among adults transitioning to late life. This study highlights the value of examining risk and resilience factors at the neighborhood level in research on ADRD inequalities.
Characterizing Amyloid Responsive Microglia in a Cognitively Resilient Patient with Alzheimer’s Disease Neuropathologic Change: A Case Report
Authors: Nguyen Aivi T. , Przybelski Scott A. , Lesnick Timothy G. , Ramanan Vijay K , Petersen Ronald C. , Graff‐Radford Jonathan , Knopman David S. , Jack Clifford R. , Dickson Dennis W. , Van Deerlin Vivianna M , Lee Eddie B , Reichard Ross R. , Vemuri Prashanthi 
Published: December 2022

AbstractBackgroundCognitive resilience, the discrepancy observed in individuals with high Alzheimer’s disease (AD) neuropathology and near‐normal cognition, is a growing area of study, wherein multiple factors are responsible. Currently, the role of the microglial activation in cognitive resilience is unknown. Herein described is a case report characterizing the amyloid responsive microglia (ARM) in an 88‐year‐old male decedent homozygous for APOE E4, clinically cognitively intact, and found to have AD neuropathologic change (ADNC) upon autopsy.MethodThe participant was enrolled in the Mayo Clinic Study of Aging (MCSA) and continuously followed for 14 years from 73‐ to 87‐years‐old, wherein serial MRI and clinical assessments were obtained. An autopsy was performed upon death, and routine neuropathologic sections were taken. Formalin‐fixed, paraffin‐embedded sections were stained with H&E, and single immunohistochemistry was performed using antibodies against tau (AT8), beta‐amyloid (6F3D), alpha‐synuclein (LB509), TDP‐43 (pS409/410), and CD163 (10D6). Digital image analysis was performed on dorsolateral prefrontal cortex sections scanned at 40x (Leica GT450). ARM (CD163% area) and beta‐amyloid (% area) measurements were obtained using QuPath threshold classifiers. Descriptive statistics were performed (Graphpad).ResultThe decedent was an 88‐year‐old male, homozygous for APOE E4, with a history of three cardiovascular and metabolic conditions, and lifelong smoking. His MMSE (average 28/30) and global cognition (average ‐0.51) were relatively stable (Figure 1), with no clinical concerns for cognitive impairment. Cortical thickness was normal (temporal meta‐ROI>3 mm) on four serial MRIs. The participant reported high cognitive, physical activities, and education‐occupation scores (upper quartile for the 70+ population). Neuropathologic evaluation was notable for severe cerebral amyloid angiopathy, high ADNC (A3B3C3), and remote microinfarcts. CD163‐positive ARM were observed in the neocortices and perivascular spaces, and the ARM:beta‐amyloid ratio was 0.26 (Figure 1). This ARM:beta‐amyloid ratio trended upwards (>90th percentile) compared to APOE E4/E4‐matched‐ and age‐matched controls provided from the University of Pennsylvania.ConclusionThis case report demonstrates a cognitively resilient individual with an elevated ARM:amyloid ratio. Conversely, lower ARM ratios were observed in a cognitively impaired cohort, raising the possibility ARM may associate with cognition. ARM may represent a protective and phagocytic population, and further studies correlating microglia, cognition, and putative mechanism are required.
Reliability of BBB water exchange rate assessed by diffusion‐prepared pseudo‐continuous ASL (DP‐pCASL): Preliminary results from the Cognitive Recovery After Elective Surgery (CREATES) Study
Authors: Shao Xingfeng , Wang Danny JJ , Boxerman Jerrold , Schlett Wesley J , Cosgriff Mads P , Daiello Lori A 
Published: December 2022

AbstractBackgroundImpaired blood‐brain barrier (BBB) function is hypothesized to be an important mechanism in the development of perioperative neurocognitive disorders (postoperative delirium and postoperative cognitive impairment), as well as in the onset and progression of Alzheimer’s (AD) and cerebrovascular disease. Non‐contrast neuroimaging methods have shown promise for detecting subtle alterations in BBB permeability; however, test‐retest reliability has not been well‐established. Here we report preliminary results for BBB water exchange rate (kw ) values from a novel diffusion‐prepared 3D pseudo‐continuous arterial spin labeling (DP‐pCASL) protocol with two different post‐labeling delays (PLD), and compared test‐retest reliability results with the original approach with a single PLD.MethodThe DP‐pCASL pulse sequence (resolution=3.5x3.5x8mm3, 10 slices) has been previously described (Shao X, et al., 2019). kw was calculated from the ratio of intra‐ and extra‐vascular perfusion signals using the original protocol with 1‐PLD [1.8 sec]; and the new protocol with 2‐PLDs [1.8 and 2.1 sec]. Total scan time was 15 minutes.Participants were healthy older adult controls enrolled in Cognitive Recovery After Elective Surgery (CREATES) study, a longitudinal study of relationships between BBB dysfunction and perioperative neurocognitive disorders following major elective surgery. Seventeen participants (11 females, age=78.5±5.4 yrs) underwent test‐retest MRI scans (∼30 days apart) on a Siemens 3T Prisma Fit system (Erlangen, Germany). kw maps were normalized into the MNI space, and regional analysis was performed for cortical gray/white matter, frontal/temporal/parietal areas, and nine subcortical brain regions. Test‐retest reliability was evaluated by intra‐class correlation coefficients (ICC).ResultWhole brain and regional kw values were calculated for the two protocols (Table 1). Test‐retest reliability increased using the 2‐PLD protocol. Whole brain kw ICC was 0.7 (good reliability; reference range, 0.5‐0.74) vs. 0.87 (excellent reliability; reference range, ≥ 0.75) for 1‐PLD and 2‐PLD protocols, respectively (Figure 1). ICC values increased across all brain regions with the 2‐PLD protocol (Figure 2).ConclusionIn a modest sample of cognitively healthy older adults, we found that measurement reliability of whole brain and regional kw values was notably improved by using the 2‐PLD DP‐pCASL protocol. These preliminary findings warrant confirmation in larger cohorts with and without late‐life cognitive disorders.
Establishing a Type 2 Diabetes phenotype in APPxhQC transgenic mice expressing N‐terminally modified pGlu Aβ peptides.
Authors: Babalola Joshua Adekunle , Loeffler Tina , Schilcher Irene , Breznik Livia , Rabl Roland , Sideromenos Spyridon , Flunkert Stefanie , Prokesch Manuela , Hoefler Gerald , Hutter‐Paier Birgit 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is a debilitating neurodegenerative disease characterized by the accumulation of amyloid beta (Aβ) plaques in the brain. Aβ peptides are commonly subjected to post‐translational modifications like truncation known to play pivotal role in Aβ plaque aggregation. N‐terminally truncated Aβ peptides containing pyroglutamatic acid (pGlu) catalyzed by glutaminyl cyclase (QC) e.g., pGlu3‐Aβ (3‐40/42) are the major Aβ peptide fragments within the core of the neuritic plaques and correlate with disease severity and progression. Type 2 diabetes (T2D) is one of the major risk factors associated with AD and compelling evidence supports the notion that insulin resistance, a key feature of T2D, is involved in AD‐type neurodegeneration. Hence, in this study, we aim to establish a T2D phenotype in APPxhQC transgenic using low‐dose Streptozocin injection in combination with high fat diet (HFD).MethodsAPPxhQC mice, crossbreds of APPSL and hQC mice, were used. APPSL mice express human APP751 with the Swedish and the London mutation on a C57Bl/6RccHsd background. hQC mice on B6CBAF1/J background express human glutaminyl cyclase (QC) enzyme. The cross‐breeding results in an increased generation of N‐terminal modified pGlu Aβ peptides. To establish a T2D phenotype, 8‐9 months old APPxhQC transgenic mice were allocated to 4 treatment groups receiving: standard chow diet, HFD, standard chow diet in combination with streptozocin injections and HFD in combination with streptozocin injections. The intraperitoneal glucose tolerance test (ipGTT) and intraperitoneal insulin tolerance test (ipITT) were performed at 6 and 7 weeks after the initiation of the diet, as a relevant parameter of T2D progression.ResultsStreptozocin‐injected mice maintained on HFD had the least tolerance to injected glucose as shown by ipGTT. Impaired glucose clearance was observed at 15, 30, 60 and 120 mins after intraperitoneal glucose injection (2g/kg). Also, impaired glucose clearance at 15 mins after intraperitoneal insulin injection (0.75U/kg) was observed in the same group.ConclusionCombination of high‐fat diet and streptozocin injections leads to the development of robust T2D symptoms in APPxhQC transgenic mice. Current experiments are focusing on combinational effects of T2D and post‐translationally modified amyloid peptides in AD progression and pathophysiology.
The Relationship between Vascular Risk Factors and White Matter Structural and Vascular Imaging Metrics
Authors: Kim Donghoon , Hughes Tim M. , Kim Jeongchul , Harvey Danielle J. , Lockhart Samuel N. , Craft Suzanne , Baker Laura D. , Whitlow Christopher T. , Okonmah‐Obazee Stephanie E. , Hugenschmidt Christina E , Bobinski Matthew , Jung Youngkyoo 
Published: December 2022

AbstractBackgroundVascular risk factors are associated with cerebral small vessel disease and dementia pathology and reduced WM integrity is correlated with the severity of cognitive impairment in dementia. We have investigated if vascular risk factors are related to white matter structural and vascular imaging metrics. Imaging metrics include intracellular volume fraction (ICVF), white matter hyperintensities (WMH), and cerebrovascular measures such as cerebral blood flow (CBF), cerebrovascular reactivity (CVR), and arterial transit time (ATT).MethodSixty‐four subjects (Table 1) enrolled in the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core cohort underwent MRI, including T2 FLAIR, neurite orientation dispersion and density imaging (NODDI), pseudo‐continuous ASL (PCASL). CVR was measured as a percent of increased CBF during a hypercapnic respiratory paradigm. ATT and resting CBF were obtained from a multi‐TI PCASL sequence. ICVF was obtained from NODDI. Head size adjusted WM total lesion volume (TLV) was calculated using SPM12‐LST2 toolbox with T2‐FLAIR image. Linear regression models were performed to examine if CBF, CVR, ATT, ICVF, or TLV are related to the risk factors or cognitive status adjusted covariates: age, sex, and years of education. A covariates adjusted logistic regression estimated weighting factors for each interrelated vascular imaging parameter to create novel cerebrovascular functional composites for each vascular risk group and mild cognitive impairment (MCI) group. The factor score p‐values were also calculated from two‐sample t‐tests with the cerebrovascular composite. The entire analyses were performed within the whole brain WM.ResultIn the whole brain WM, hypertension subjects (p=0.031) showed higher CVR (Figure 1). T2DM subjects (p=0.007) showed higher WM TLV (Figure 2). T2DM and MCI subjects showed lower ICVF than normal subjects did (Figure 3). Based on the weights of each cerebrovascular parameter in the composite (Table 2), the effects of CBF and CVR are stronger in hypertension group while all three cerebrovascular measures had substantial contribution to cognition status.ConclusionEach risk factor and cognitive status differently affected WM structural and vascular dynamic imaging parameters. The findings warrant further investigations of contributions of vascular risk factors to the structural and vascular abnormalities in dementia.