bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessing the Role of PLCG2*M28L Risk In A Novel Mouse Model Late‐Onset Alzheimer’s Disease
Authors: Territo Paul R , Oblak Adrian L , Persohn Scott C , Bedwell Amanda A , Eldridge Kierra , Kotredes Kevin P , Pandey Ravi S , Rizzo Stacey J Sukoff , Carter Gregory W , Sasner Michael , Howell Gareth R , Lamb Bruce T 
Published: December 2023

AbstractBackgroundMODEL‐AD has developed and characterized novel mouse models that aim to better phenocopy human LOAD for preclinical testing. More than 40 different models carrying combinations of LOAD risk factors have been created and assessed for relevance to LOAD. In this study, we aim to determine the mechanisms by which variations in the phospholipase C gamma 2 (PLCG2) gene increase risk for LOAD.MethodsThe M28L variant in PLCG2 (PLCG2*M28L) was prioritized as a LOAD risk factor. Mice were generated by CRISPR/CAS9 introduction of Plcg2*M28L variant on to LOAD1 (B6.APOE4.Trem2*R47H) and transcriptional profiling of brain hemispheres from 12 months old mice was used to evaluate molecular effects of Plcg2*M28L. To evaluate the contribution of Plcg2*M28L to LOAD risk, mice where placed on control or high fat diet (HFD) to serve as an environmental driver of neuroinflammation. Female and male LOAD1.Plcg2*M28L and LOAD1 control mice are being characterized at 4 and 12 mos through the MODEL‐AD phenotyping pipeline, which includes in vivo imaging of brain perfusion and glycolytic metabolism, multi‐omics, fluid biomarkers, cognition, and neuropathology.ResultsLOAD1.Plcg2*M28L mice showed brain transcriptomic alignment at 12 mos to human LOAD, and was prioritized for deep phenotyping. LOAD1 mice on HFD showed significant regional reductions in brain glycolysis and increased perfusion relative to controls yielding an uncoupled phenotype. By contrast, LOAD1.Plcg2*M28L mice showed a little to no regional changes in brain glycolysis or perfusion and few uncoupled regions. Multi‐resolution connectomics revealed a decrease in cluster number and organization in LOAD1 but not LOAD1.Plcg2*M28L for both sexes fed HFD compared with control diets. By 12 mos, male and female LOAD1.Plcg2*M28L mice on HFD showed opposite changes in clustering coefficient, network degree, and network density, with males showing a decrease and females an increase relative to controls. Mice carrying Plcg2*M28L variants are also being phenotyping at 18 and 24 mos.ConclusionsData collected to date reveal Plcg2*M28L on a LOAD1 background showed fewer sex‐dependent change in metabolism, perfusion and uncoupling on HFD when compared to LOAD1. These data suggest that the Plcg2*M28L risk variant on the LOAD1 background may result in an attenuated TREM2 signaling.
Accelerated cerebral amyloid angiopathy and vascular alterations in a mixed mouse model of Alzheimer’s disease and cerebral small vessel disease
Authors: Choi Sang‐Ho , Letica Leila , Brinson Lovisa Ljungqvist , Park Jung Eun , Silva Afonso C 
Published: December 2023

AbstractBackgroundWhile aging is the primary risk factor for Alzheimer’s disease (AD), emerging evidence suggests that vascular dysfunction, present in cerebral small vessel diseases (CSVD) such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), is also a major contributor for disease progression. Indeed, several studies have provided clinical evidence for a close synergistic relationship between AD and CSVD in cases where both diseases coexist. CSVD can elicit amyloid pathology, while Alzheimer’s‐associated cerebral amyloid angiopathy (CAA) and Ab plaque deposition may lead to concomitant vascular damage. Mutations in genes such as APP, PSEN1, and PSEN2 are not limited to AD, as APP mutations can also cause CAA, while PSEN1 and PSEN2 are involved in Notch3 signaling, a process known to be dysregulated in CADASIL. Here, we aimed to investigate the additive or synergistic effects of amyloid pathology and CADASIL‐related vascular damage on disease progression.MethodTo explore alterations in amyloid and vascular pathology when AD and CADASIL‐related CSVD coexist, we used PET/CT and histology to analyze over time the amyloid deposition in the form of plaques and CAA in a relevant mouse model of AD (5xFAD) carrying the Notch3 C456R mutation that causes CADASIL. Methoxy‐X04, Thioflavin‐S, or 6E10 were used to visualize amyloid accumulation in fixed brain tissues. The progression of microvascular dysfunction and neuroinflammation were assessed by immunofluorescence staining, Western blotting, RNA sequencing, and real‐time PCR.ResultAdult 5xFAD‐Notch3C456R mice showed accelerated parenchymal and vascular amyloid deposition compared to 5xFAD mice. Progressive gliosis and microvascular damage were concomitant to parenchymal and vascular amyloid accumulation. These changes were associated with blood‐brain barrier disruption and reduction in pericyte coverage of cerebral capillaries.ConclusionWe found accelerated amyloid plaque deposition, CAA, gliosis, and vascular damage in a mixed murine model of AD and CADASIL, suggesting that CSVD‐associated vascular changes directly contribute to AD pathology. This model offers novel opportunities to investigate the intricate interplay between CSVD and AD. This research was funded by NIH/NINDS grant RF1NS117486.
Oligomeric tau enters brain vascular endothelial cells and induces cellular senescence and brain microvascular dysfunction in tauopathy
Authors: Hussong Stacy A , Banh Andy Q , Van Skike Candice E , Dorigatti Angela O , Hernandez Stephen F , Hart Matthew J , Ferran Beatriz , Makhlouf Haneen , Gaczynska Maria , Osmulski Pawel , McAllen Salome , Dineley Kelly T , Ungvari Zoltan , Perez Viviana , Kayed Rakez , Galvan Veronica 
Published: December 2023

AbstractBackgroundVascular mechanisms of Alzheimer’s disease (AD) may constitute the most therapeutically addressable biological pathway underlying dementia. Soluble pathogenic forms of tau (tau oligomers) accumulate in brain microvasculature of AD and other tauopathies, particularly in microvascular endothelial cells.MethodsPrimary human brain microvascular endothelial cells (HBEC) were exposed to tau oligomers. Microtubule stability, eNOS activation, and markers of senescence were measured. Mice expressing P301S‐mutant human tau (P301S(PS19) mice), a model of tauopathy, were given immunotherapy to selectively remove tau oligomers, or non‐specific IgGs. After measurements of vascular reactivity, eNOS activity and markers of senescence were measured in microvasculature purified from brain.ResultOligomeric tau significantly decreased microtubule stability and eNOS activity, and induced cellular senescence in primary HBECs. Microtubule destabilization, reduced eNOS activity, and increased markers of cellular senescence in brain microvasculature of P301S(PS19) mice were associated with impaired vascular reactivity, and the latter was negated by immunotherapy that specifically removed oligomeric tau from brain.ConclusionBrain microvascular deficits in P301S(PS19) mice modeling tauopathy, mediated by tau oligomers, may arise from endothelial cell senescence and eNOS dysfunction triggered by internalization of tau oligomers. Pathogenic tau oligomers and senescent brain microvascular endothelial cells may thus be targets for intervention in AD and other tauopathies.
Cognitive impairment among sexual and gender minority groups: A scoping review of the literature
Authors: Romanelli Robert 
Published: December 2023

AbstractBackgroundSexual and gender minority (SGM) groups tend to have a higher prevalence of risk factors for cognitive impairment and/or dementia. However, the relationship between sexual orientation and gender identity (SOGI) status and cognitive impairment/dementia is currently unclear. We conducted a scoping review to examine the current state of evidence for this relationship.MethodA scoping review of the literature was conducted. Five databases (PubMed/Medline, CINAHL, Web of Science, PsycInfo, and Embase) were searched for primary articles published in English to compare incidence or prevalence of cognitive impairment among sexual and gender minority (SMG) groups versus non‐SGM groups. Two reviewers independent screened articles and conducted risk‐of‐bias assessment of eligible articles based on study design, handling of confounding, and measurement of exposure/outcomes.ResultFifteen primary studies published from 2007‐2022 were eligible. Most studies (n = 13) were cross‐sectional, with moderate to critical risk of bias. Among eight studies using subjective cognitive impairment (SCI), seven reported a higher prevalence among some SGM groups versus non‐SGM groups. Among seven studies using objective measures of cognitive impairment, three examined prevalence of clinician‐documented diagnosis of dementia, of which two reported a higher prevalence specifically among transgender versus cisgender individuals. Among the other four studies, two reported poorer cognitive performance or memory for SGM versus non‐SGM groups, one reported better performance and another reported no difference in performance. Comparisons across studies are complicated due to inconsistencies in how SOGI status and cognitive impairment were operationalised, as well as the factors used for statistical adjustment; some studies adjusted for putative intermediary factors that potentially drive differences in cognitive impairment.ConclusionWhereas most studies have identified a relationship between SOGI status and SCI, evidence is rather mixed with regard to objective measures of impairment. Well‐designed longitudinal, observational studies using objective measures of cognitive impairment are needed, with careful consideration of confounding versus intermediary risk factors.
Clinical profile of Early‐Onset Alzheimer’s disease in Peru: Case Series from a Neurological Care Center
Authors: Castro‐Suarez Sheila , Guevara‐Silva Erik Alberto , Alvarez‐Toledo Kelvin , Caparo‐Zamalloa Cesar , Cornejo‐Olivas Mario , Meza‐Vega Maria 
Published: December 2023

AbstractBackgroundEarly‐onset Alzheimer’s disease (EOAD) is a rare and devasting form of Alzheimer disease that represents 5.5% of the total number of Alzheimer cases. The clinical presentation is heterogeneous, the amnestic variant is the most frequent, followed by atypical phenotypes including visual (8‐13%), language (7‐9%) and executive/behavioral (2%) variants. Clinical aspects of EOAD in Admixed Latin American population are lacking in the literature.MethodWe reviewed medical records of patients diagnosed as probable EOAD during January‐December 2022. All patients were evaluated by trained neurologists from a dementia outpatient clinic at a tertiary neurologic center in Lima, Peru. Relevant information about neurocognitive, neuropsychiatric, and functional assessments were extracted from medical records with further descriptive analysis. IRB approval from local institution was obtained for this study.ResultA total of 20 EOAD patients (65% female, age at onset = 55±7.5 years) met the selection criteria. Fourteen cases (70%) were categorized as amnestic variant, 4 cases (20%) of executive/behavioral variant, and 1 case of visual and language variant (5%). The average of education was 10±4.3 years. The delay for diagnosis in this group was from 3 to 5 years. A first‐degree relative with dementia was present in 10% of patients. Clinical and cognitive assessment profile included: MMSE average score was 14.9±4.9 with memory loss and dysexecutive dysfunction predominance for amnestic variant. Based on NPI the most frequent neuropsychiatric symptoms were irritability (62%), depression (53%) and aberrant motor activity (39%) in the group of amnestic variant and irritability (100%), apathy and appetite/eating abnormalities (75%) in executive/behavioral variant. Severity of dementia were assessed by CDR (CDR = 3 for 10.5%, CDR = 2 for 26.3%, CDR = 1 for 57.9% and CDR = 0.5 for 5.3%).ConclusionThe clinical features of our Peruvian EOAD cohort are mostly consistent with previous reports. There is a significant delay of EOAD diagnosis. The second most frequent variant of EOAD in our series was executive/behavioral variant. Implementing training strategies for clinicians, neurologists, and no‐neurologists, will improve a timely and accurate diagnosis of EOAD. Further prospective and longitudinal studies for EOAD are required to assess disease progression and evolution of symptoms.
Establishing the Trial Ready Registry and Dementia Platform Korea system to advance AD research in Korea
Authors: Kim Haeng Jun , Mook‐Jung Inhee , Kim Ki Woong , Seo Sang Won , Lee Jong‐Min , Jung Sun Jae , Bae Hyunjung , Lee Jihyun ,   TRR Research Group
Published: December 2023

AbstractBackgroundNumerous studies on Alzheimer’s disease (AD) are being undertaken, and there is a plethora of high‐quality clinical data and resources for AD in Korea. However, because the resources and data are not thoroughly standardized, they are challenging to use. The Trial Ready Registry (TRR) and Dementia Platform Korea (DPK) technologies were developed to investigate possible AD therapy targets and biomarkers, as well as to progress the AD research field in Korea by standardizing the dementia dataset in Korea.MethodTo collect human‐derived materials with MCD, we designed the minimum common dataset (MCD), which includes clinical evaluations, cognitive evaluations, magnetic resonance imaging (MRI), Florbetaben (FBB)‐PET, Flutematamol (FMM)‐PET, and blood tests.ResultThe TRR‐DPK system is planned to enroll 3,000 participants in MCD exams, blood tests, and brain imaging by 2028. Since 2020, 942 people had been recruited for the system as of December 2022. We collected human‐derived materials such as plasma, serum, DNA, and PBMCs from participants with the purpose of distributing human‐derived materials matched to their brain imaging and clinical data.ConclusionWe expect that the TRR‐DPK system will improve AD research by giving researchers access to human‐derived materials and a variety of quality‐controlled data.
Multi‐omics approach reveals disturbances in brain phosphatidylcholine metabolism in Alzheimer’s Disease
Authors: Tang Xinyu , Lebrilla Carlito B. , Jin Lee‐Way , Maezawa Izumi , Harvey Danielle J. , Zivkovic Angela M. 
Published: December 2023

AbstractBackgroundLipid dysregulation is implicated in Alzheimer’s disease (AD) pathology, given its involvement in amyloid β processing, myelination, and cell membrane structure. Studies have demonstrated increased phosphatidylcholine (PC) hydrolysis in the brains of AD individuals, but the connections between AD and PC metabolism are not fully understood.MethodTo investigate the alterations in PC metabolism in AD, we analyzed publicly available transcriptomic, metabolomic, and lipidomic data from the ROSMAP study, which included dorsolateral prefrontal cortex (DLPFC) tissue and serum samples. DLPFC and serum samples were classified based on clinical consensus diagnosis of cognitive status at the time of death and the last valid clinical diagnosis, respectively. Concentration differences were determined with a linear model using the Limma R package.ResultAccording to the lipidomic results, the concentration of total PC‐containing glycerophospholipid was significantly decreased in AD DLPFC samples (P < 0.05). Specifically, diacyl‐PC and acyl‐alkyl‐PC, the two most abundant subclasses, were significantly decreased in the brains of AD patients (P < 0.05). The concentration of the PC breakdown product, glycerophosphocholine (GPC), was increased in AD patient brains (P‐value < 0.05). However, GPC phosphodiesterase 1 (GPCPD1), the enzyme that further hydrolyzes GPC to free choline, was downregulated and choline abundance was reduced in AD DLPFC samples (P < 0.05). The expression of phosphatidylethanolamine N‐methyltransferase (PEMT), which converts PE to PC, was reduced as was the abundance of PEMT products (PC 18:2/20:4 and PC 18:0/20:4, P < 0.05). These alterations in the brain were not observed in the serum.ConclusionThese results indicate that PC metabolism is disturbed in the DLPFC of AD patients, with evidence of increased PC breakdown and reduced GPC hydrolysis as well as reduced conversion of PE to PC in AD brains. However, these changes in the brain are not reflected in serum. Further studies are needed to better understand changes in phospholipid metabolism in the brains of AD patients.
Primary etiology and associated medical conditions in Mild Cognitive Impairment Subtypes in the NACC Database
Authors: Elkasaby Mohamed , Appleby Brian , Duffy Charles , Leverenz James B , Malone Joseph , Miller‐Scott Lindsay J , Murphy Tamara B , Ogrocki Paula K. , Pillai Jagan A. , Lerner Alan J. 
Published: December 2023

AbstractBackgroundMild cognitive impairment (MCI) reflects cognitive deficits without significant functional decline in activities of daily living (1). MCI subtypes correspond to phenotypic cognitive impairment patterns in memory, attention, language, executive, and visuospatial compared to age‐adjusted norms: Amnestic single domain (ASD) or multi‐domain (AMD), Nonamnestic single domain (NASD), or Nonamnestic multi‐domain (NAMD). Previous studies have suggested nonamnestic subtypes are more likely to represent non‐AD prodromes, but conclusions have been limited by small sample sizes (1).MethodUsing the National Alzheimer’s Coordinating Center (NACC) database (grant U24 AG072122), we selected all initial Uniform Data Set (UDS) assessments diagnosed as MCI with subtyping. The NACC data was collected from 37 participating Alzheimer’s disease Research Centers. Baseline clinical features, primary etiology and associated medical conditions were collected.Results9852 individuals with MCI on baseline UDS visits were analyzed: 45.6% were diagnosed with AD (Table 1). AD was the most common primary etiology in all subtypes, more frequent in amnestic than nonamnestic subtypes (AMD 54.1%; ASD 50.5%; NAMD 20.0%; NASD 18.8%). Overall, 6% were diagnosed with DLB and 3.1% with PD; NAMD and NASD were more frequent than AMD or ASD. The most frequently associated medical conditions were hypercholesterolemia, HTN, depression, anxiety, sleep apnea and diabetes (table 2). The highest percentage of depression and anxiety were in nonamnetsic subtypes. Recent stroke was most frequent in NAMD.ConclusionMCI is a heterogeneous disorder, and its classification by subtypes is essential in understanding prodromal stages and neurodegenerative neuropathology. Dementia risk modulation and prevention is linked to identification and treatment of associated medical conditions including frequent neuropsychiatric comorbidity (2).
Recalling Biobank Participants to Clinical Study of Alzheimer’s Disease – FinnGen Pilot Study
Authors: Julkunen Valtteri , Schwarz Claudia , Kalapudas Juho , Hallikainen Merja , Piironen Aino‐Kaisa , Mannermaa Arto , Kujala Hanna , Laitinen Timo , Kosma Veli‐Matti , Paajanen Teemu , Kälviäinen Reetta , Hiltunen Mikko , Herukka Sanna‐Kaisa , Kärkkäinen Sari , Kokkola Tarja , Urjansson Mia , Perola Markus , Palotie Aarno , Runz Heiko , Vuoksimaa Eero ,   FinnGen
Published: December 2023

AbstractBackgroundPopulation‐based biobanks that comprehensively ascertain health and genetic data hold promise to facilitate identification of Alzheimer’s disease (AD) trial participants. We conducted a pilot study in individuals with mild impairment in cognition or AD to assess the feasibility of recalling biobank participants. We also tested the utility of computer‐ and telephone‐based cognitive assessments as cost‐effective alternatives to in‐person neuropsychological testing and investigated plasma‐based biomarkers.MethodsWe utilized FinnGen, a large population‐based biobank study of up to 500,000 participants representing almost 10% of the Finnish population. Single‐center cross‐sectional study included individuals with ICD‐10 codes for AD (G30) and mild cognitive disorder (MCD; F06.7). Dementia screening instruments were in‐person Mini‐Mental State Examination (MMSE) and telephone interview for dementia (TELE). Episodic memory was assessed with three trial word list tasks in three formats; in‐person, with web‐based tool and with the modified Telephone Interview for Cognitive Status including three learning trials. Each of these yielded immediate and delayed free recall measures. Blood samples were collected to determine plasma‐based biomarkers: amyloid beta (Aβ)1‐40 to Aβ1‐42 ratio, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL) and phosphorylated‐tau181 (pTau‐181).ResultsA total of 78% (110/140) of a pre‐specified FinnGen sub‐cohort were successfully reached. Of those, 39% (43/110) were willing to participate and 19% (N = 27, mean age = 72y, 13 women) completed the study. FinnGen and hospital records largely matched. For 8/12, MCD was due to other reasons than early AD. MMSE and TELE correlated .818 (p< .001). Immediate and delayed recall measures correlated across three formats: from .584 to .679 (p’s<.003) and from .250 to .424 (p’s: .031 ‐ .218), respectively. AD group had higher levels of GFAP (p = .002) and pTau‐181 (p = .020). TELE was negatively correlated with GFAP (p = .011), NfL (p = .001) and pTau‐181 (p = .006). Moreover, p‐Tau181 had negative correlations with episodic memory measures (all r’s< ‐.202) with telephone‐administered immediate recall reaching statistical significance (r = ‐.394, p = .042).ConclusionsInformative, customized clinical recall studies from FinnGen are feasible. Remote testing is a cost‐effective approach in recall studies. Next phase of our study aims to invite cognitively unimpaired FinnGen participants for screening of high AD risk individuals.