bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic Relationship between Alzheimer’s Disease and Schizophrenia
Authors: Chen Jingchun , Lu Yimei , Cue Joan Manuel , Patel Neel , Zheng Jennifer J. , Cummings Melika J. , Do Jenifer 
Published: December 2022

AbstractBackgroundLarge genome‐wide association studies (GWASs) have demonstrated that common genetic variation contributes to the heritability of brain disorders, including Alzheimer’s disease and schizophrenia. Patients with Alzheimer’s disease and schizophrenia often have similar symptoms such as cognitive decline and hallucinations. Excessive synaptic pruning resulting from neuroinflammation and microglial activation are considered to play an important role in the development of both diseases. However, the genetic correlation between Alzheimer’s disease and schizophrenia is unclear.MethodIn this study, we used genotyping data of Alzheimer’s disease and schizophrenia to examine the genetic relationship between the two diseases. We calculated polygenic risk scores (PRSs) at multiple thresholds for both diseases and tested their relationship using logistic and linear regression.ResultWe found that schizophrenia PRSs were negatively associated with Alzheimer’s disease at multiple thresholds. The most significant association (p = 2.24 x 10‐9) was obtained at GWAS threshold p = 0.5. Vice versa, Alzheimer’s disease PRSs were positively associated with schizophrenia. The most significant signal (p = 4.10 x 10‐8) was obtained at GWAS threshold p = 0.1. Logic regression showed there was a strong correlation between the best schizophrenia PRSs and diagnosis of Alzheimer’s disease. The same held with the best Alzheimer’s disease PRSs and diagnosis of schizophrenia. Further, we found that there was a significant linear correction between the best PRSs of Alzheimer’s disease and schizophrenia in the Alzheimer’s disease dataset (R = 0.27, p < 2.2 x 10‐16).ConclusionOur study indicated that there is a strong genetic correlation between Alzheimer’s disease and schizophrenia, suggesting GWAS data from each disease might help to build a better risk prediction model for clinical risk assessment. Further studies on the shared risk variants/genes/pathways may help to better understand the mechanisms behind the two diseases for earlier disease prediction, diagnosis, and prevention.
Altered levels of plasma kallikrein‐7 in prodromal Alzheimer’s disease
Authors: Roberts Blaine Russell , Roberts Anne M , Cortes Laura , Fowler Christopher , Villemagne Victor L , Masters Colin L. , Ryan Timothy M 
Published: December 2022

AbstractBackgroundThe accumulation of Aβ is thought to be dependent on imbalances in production or clearance of the peptide. At the core of the production and the breakdown of Aβ are changes in the activity of proteases. Several studies have suggested that the level and activity of brain proteases involved in the clearance pathway are perturbed in the disease. Given that AD is essentially a protease disease, we sought to determine if key proteases were altered in the blood plasma fraction, reflecting changes that are occur in the brain.MethodWe used a fast commercial tool to investigate the level of 34 proteases in plasma between healthy controls and AD patients. Next we used an ELISA and western blot assays to validate results from the discovery assay.ResultWe discovered that the protease kallikrein‐7 (KLK7) was significantly elevated in AD plasma. We then asked how early in the disease time course is KLK7 elevated. We used plasma from cognitively normal cases (n=120) with either high or low levels of brain amyloid based on PET imaging and found that KLK7 leaves are decreased.ConclusionThese results suggest that the plasma level of Kallikrein‐7 may be an important tool in detecting elevated levels of brain amyloid before symptoms of AD become apparent.
Biofluid biomarkers in an ethnoracially diverse population and their association with AD
Authors: Hall James , Petersen Melissa , Johnson Leigh , O'Bryant Sid E. 
Published: December 2022

AbstractBackgroundPlasma‐based biomarkers of Alzheimer’s disease are cost‐effective, minimally invasive and highly scalable tools to aid in clinical practice and trials. There remain significant gaps in our understanding of the factors that influence their levels. The majority of fluid biomarker research has been conducted in clinical settings using CSF biomarkers with non‐Hispanic Whites. Although Hispanic and African American communities have higher rates of dementia, there is limited research on blood‐based biomarkers of AD in these communities. The current study of a sample of Mexican Americans, African Americans and Non‐Hispanic Whites investigated the performance of plasma biomarker across the three largest ethnic/racial groups in the US to assess the impact of ethnicity/race on the level of the plasma biomarkers of Aβ40, Aβ42, total tau, ptau 181 and NfL.MethodParticipants were 2200 community dwelling older adults (850 Mexican Americans (MA); 850 Non‐Hispanic Whites (NHW) and 500 African Americans (AA) drawn from The Health & Aging Brain Study – Health Disparities (HABS‐HD) study. Cognitive diagnoses were assigned using an algorithm verified by consensus review. Samples were assayed using Simoa technology. Levels of each biomarker were compared for the three ethnoracial groups across cognitive diagnoses.ResultsSignificant differences were found across the groups at each level of cognitive impairment. For those with normal cognition AA had significantly lower levels of each of the biomarkers and NHW had higher levels of Aβ40, Aβ42 and NFL. MA had the highest level of t tau and p tau 181. MCI group NHW had the highest levels on all the biomarkers and AA had the lowest. NHW and MA has higher levels of Aβ40, Aβ42, total tau, ptau 181 compared to AA. NHW levels of NfL were the highest and MA and AA did not differ. For dementia there was no difference between the groups for Aβ42. NHW had significantly higher levels of Aβ40, t tau, ptau 181 and NfL than AA.ConclusionFindings support the importance of considering ethnoracial background in the clinical use of blood‐based biomarkers and the difficulty of establishing universal cutting points for these biomarkers in the diagnostic process.
Protection of cognitive decline and Alzheimer’s disease progression by a human origin‐probiotic biotherapy
Authors: Wang Shaohua , Prajapati Santosh K , Mishra Sidharth P , Jain Shalini , Yadav Hariom 
Published: December 2022

AbstractBackgroundChronic inflammation is a key risk factor for age‐related progression of cognitive decline and Alzheimer’s disease (AD); however, its etiology remains elusive. Multiple emerging evidence indicates that abnormalities in the gut microbiome (dysbiosis) contribute to the pathology of cognitive decline and Alzheimer’s disease, by elevating gut permeability (leaky gut) which in turn instigates inflammation. However, remedies to mitigate cognitive decline and AD progression are not well known.MethodWe examined the effects of human origin probiotics (containing newly isolated probiotics from infant’s gut) in APP/PS1 mice, with and without leaky gut.Result: We observed that probiotic feeding significantly reduced the burden of AD markers like amyloid‐beta accumulation, inflammation in the brain, along with a lesser cognitive decline in treated mice. These improvements were linked with beneficial changes in the microbiome, increased production of beneficial metabolites, and reduced leakiness in the gut.ConclusionOur results demonstrated that a human origin probiotic cocktail reduced the progression of age‐related cognitive decline and AD by reducing abnormalities in the microbiome‐metabolites‐leaky gut axis. Thus, microbial biotherapies like probiotics ameliorating leaky gut can be beneficial in protecting cognitive decline and AD.
IMPACT OF THE COVID‐19 PANDEMIC IN ADRD PATIENTS AND CAREGIVERS IN A LATIN‐AMERICAN COUNTRY
Authors: Custodio Nilton , Malaga Diego , Chambergo‐Michilot Diego , Ore‐Gomez Maria Fernanda , RIVERA‐FERNANDEZ CLAUDIA , Soto‐Añari Marcio , Reyes‐Dumeyer Dolly , Failoc‐Rojas Virgilio E , Casavilca‐Zambrano Sandro , Montesinos Rosa , Tosto Giuseppe 
Published: December 2022

AbstractBackgroundAlzheimer Disease and Related Dementia (ADRD) patients and caregivers have been significantly affected by the coronavirus disease 2019 (COVID‐19) pandemic and have seen their access to healthcare disrupted. ADRD has emerged as a key comorbidity of COVID‐19. Little is known about the impact of the pandemic in ADRD patients living in countries with reduced vaccinations rates. Our objective was to assess the impact of the pandemic in ADRD patients and caregivers in Peru, which has one of the world’s highest COVID‐19 death rate.MethodAs part of the Genetics of Alzheimer’s disease In Peruvian Populations (GAPP) study, we performed a cross‐sectional study in ADRD patients and caregivers. We employed the National Alzheimer Coordination Center COVID‐19 survey to evaluate the impact of the pandemic in our cohort. We also considered the severity of cognitive impairment, measured by the Cognitive Dementia Rating Scale (CDR).Resultthe GAPP cohort had 52 ADRD cases and 213 controls. The median age was 72 (54‐95 IQR 12), and 68.68% were females. A third of patients reported COVID‐19 symptoms; of those, 2.71% were hospitalized in the Intensive Care Unit (1 patient needed respirator). Over 50% of participants reported at least some cognitive or behavioral changes (with memory being the most predominant), with no difference between cases and controls. Overall, participants felt moderately concerned with infection and social distancing, with no differences between groups. Caregivers reported higher degrees of concern, especially for ADRD participants. 25% of caregivers reported being affected significantly by the pandemic, mainly because of decreased takeover by family or friends, especially among those looking after ADRD participants. Over 50% considered their income reduced. Finally, their willingness to participate in research projects was not impacted significantly.ConclusionThe COVID‐19 pandemic has impacted ADRD patients (especially those with higher CDR) and their caregivers, reducing their financial income and their caregiving ability. These results could help in developing COVID‐19 public health policies that include specific needs for ADRD patients.
Quantitative analysis of 6,150 real‐world amyloid Positron Emission Tomography (PET) scans from the Imaging Dementia–Evidence for Amyloid Scanning (IDEAS) study
Authors: Zeltzer Ehud , Mundada Nidhi S. , La Joie Renaud , Apgar Charles , Gatsonis Constantine , Carrillo Maria C. , Hanna Lucy , Hillner Bruce E , Koeppe Robert , March Andrew , Siegel Barry A , Smith Karen , Whitmer Rachel A. , Windon Charles , Iaccarino Leonardo , Rabinovici Gil D. 
Published: December 2022

AbstractBackgroundAmyloid‐PET had been widely used and validated in research settings, using highly selected samples, harmonized acquisition protocols, co‐registration with MRI, and central interpretation by highly experienced experts. In contrast, in clinical settings, more heterogeneous acquisition, reconstruction, and interpretation may compromise the accuracy of the imaging. We quantitatively analyzed real‐world amyloid‐PET scans to assess their validity.MethodIDEAS acquired 18,295 amyloid PET scans at 343 PET facilities in patients with MCI or dementia using 18F‐florbetapir, 18F‐florbetaben, or 18F‐flutemetamol. Scans were visually interpreted at each site as either negative or positive for cortical tracer retention. Scans from consenting patients were archived. As of December 1, 2021, amyloid‐PET scans from 6,263 unique participants were available for analysis. Exclusion for lack of valid images or clinical data and failure of quality checks resulted in 6,150 (98.2%) valid scans. We analyzed the scans using a recently validated PET‐only processing pipeline designed to process heterogeneous amyloid‐PET scans (Iaccarino et al, 2022) and quantified cortical uptake in Centiloid (CL) units. A previously established neuropathology‐based threshold of 24.4 CL was used to define amyloid‐PET positivity independent of visual reads.ResultMean CL was higher in dementia (mean±SD = 53±51) than in MCI (40±48) (mean difference: 13; 95%CI: 10‐15). Mean CL of visually negative scans (3±27) was very close to 0, as expected for patients without amyloid accumulation, and significantly lower than visually positive scans (72±41) (mean difference: 69; 95%CI: 67‐70) (table 1). High concordance was found between local visual reads and CL‐based positivity (86.5%, Cohen’s κ=0.72, figure 1). CL exhibited a bimodal distribution, with most scans clearly positive or negative, and a minority of visual‐quantitative discordant scans surrounding the positivity threshold (figure 2). CL negatively correlated with MMSE (r=‐0.19, p<.001, figure 3). CL further correlated with the level of confidence in the diagnosis of Alzheimer’s Disease (AD), as was indicated by clinicians before the performance of PET (r=0.13, p<.001, figure 4).ConclusionA large heterogeneous dataset of real‐world amyloid‐PET scans analyzed quantitatively, shows high concordance with visual reads, and expected relationships with clinical and neuropsychological measures of AD.
Lecanemab (BAN2401) Infusion Reactions and Immunogenicity: Results from Randomized Phase 2 Study and an Open‐Label Extension (OLE).
Authors: Landry Ishani , Kanekiyo Michio , Aluri Jagadeesh , Li David JianJun , Hussein Ziad , Reyderman Larisa , Dhadda Shobha , Swanson Chad J , Irizarry Michael C , Kramer Lynn D 
Published: December 2022

AbstractBackgroundTreatment with 10 mg/kg lecanemab (BAN2401), a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species, has been shown to reduce amyloid PET standard uptake value ratio (SUVr) and slow clinical decline in an 18‐month, phase 2 proof‐of‐concept study (Study 201 Core) in early Alzheimer’s disease with an OLE. The present analysis aimed to review infusion related reactions from Study 201 and the results of immunogenicity assessments from the completed lecanemab clinical trial.MethodsInfusion related reactions were summarized by treatment group using descriptive statistics. All adverse events were coded using MedDRA version 24.0 and graded based on CTCAE guidelines.Analysis of anti‐drug antibodies (ADA) and its impact on pharmacokinetics, pharmacodynamics, efficacy, and safety during Study 201 were undertaken. All ADA and NAb assays were developed and validated in accordance with FDA guidance and industry best practice and were performed using a tiered approach.ResultsIn Study 201 Core, 854 treated subjects (lecanemab:609; placebo:245) were randomized across 6 treatment groups. In the OLE phase a total of 180 subjects were treated with lecanemab 10 mg/kg biweekly (LEC10BW). Infusion‐related reactions were the most common adverse event associated with LEC10BW treatment, with 19.9% (32/161) of subjects compared to 3.3% (8/245) of placebo subjects. All events were mild/moderate in severity, most occurred with the first infusion, resulted in a low rate of discontinuations (LEC10BW:2.5%; placebo:0.8%). Over 70% of patients who initially experienced infusion‐related reactions had no further reactions with preventative medications. Infusion reaction data from the OLE were consistent with the Core study. The incidences of ADA for LEC10BW in the Core and OLE were 40.9% and 11.1% (Core placebo‐treated subjects), respectively; titers were very low (most ≤125). Detailed analysis of lecanemab ADA demonstrated no meaningful impact of ADA on pharmacokinetics, pharmacodynamics, efficacy, and safety.ConclusionsIn the lecanemab Study 201 Core and OLE, infusion‐related reactions were the most common adverse event, however were readily manageable with preventative medication, were of low severity, and resulted in minimal discontinuations. Lecanemab is a low‐risk molecule for immunogenicity based on ADA profile and minimal impact of ADA on pharmacokinetics, pharmacodynamics, efficacy, and safety.
Brain‐Wide Cellular Resolution Regional Quantification of Microglia and Amyloid in 5xFAD mice
Authors: Guanzon Nathaniel , Murry Alexandria , May Emily , Wells Alicia , Gallegos Yessenia , Redd Chase , Azevedo Ricardo , Shamloo Mehrdad , Gandho Sunil , Wheeler Damian G. 
Published: December 2022

AbstractBackgroundRecent advances in optical clearing and light sheet imaging have opened an exciting new avenue for brain‐wide, cellular resolution immunostaining at the forefront of a dimensional shift from 2D to 3D histology. Traditional histological methods have been a mainstay of neuroscience research dating back more than 100 years. Yet, despite great advances in tissue labeling and imaging technology, until very recently imaging more than a few hundred microns into a tissue has required slicing and mounting on slides. When looking for read‐outs of genetic or pharmacological manipulations that affect the entire brain, this traditional focused approach is lacking, forcing researchers to look at specific brain regions of interest.MethodTo help solve this issue, we have developed an optimized iDISCO‐based tissue clearing method and with our Mesoscale Imaging System for ZEISS Lightsheet microscopes, we can image cellular‐resolution immunoreactivity across entire intact mouse brains in ∼25 min. Further, our machine learning‐enabled 3TK software identifies individual immunostained cells and objects throughout the brain and aligns them to the Allen Reference Atlas to produce an unbiased, regionalized read‐out of cellular patterns across 100’s brain areas. We have applied this technology to quantify microglia and β‐amyloid plaques in the 5xFAD mouse model of Alzheimer’s Disease.ResultUsing antibodies targeting the microglial protein Iba1, we can identify microglia throughout the entire brain. We have developed two machine learning‐enabled workflows; one counts the microglia and the other measures microglial shape. We have also validated methods for labeling β‐amyloid throughout the brain and have used machine learning to differentially quantify immunoreactivity in plaques vs neuronal cell bodies in the same fluorescence channel. In 5xFAD Tg mice, rather than displaying the ramified morphology seen in WT mice, microglia become condensed and colocalize with β‐amyloid plaques. Our automated methods can identify and count plaques and plaque‐associated microglia (PAM) throughout the brain.ConclusionThese new methods for whole‐brain, next generation 3D immunohistochemistry are ideally suited to pre‐clinical studies for unbiased, complete and anatomically precise mapping of the efficacy of CNS therapeutics affecting amyloid deposition and neuroinflammation. We thank NIMH for Grant R43MH122070.
PET tracer SMBT‐1 discriminates between BU99008 and Deprenyl binding sites on reactive astrocytes in Alzheimer's disease brains
Authors: Fontana Igor C. , Kumar Amit , Okamura Nobuyuki , Nordberg Agneta K 
Published: December 2022

AbstractBackgroundAstrocytes are the homeostatic cells of the mammalian brain. We recently proposed a “two‐wave” hypothetical model in which reactive astrocytes (RA) are early‐responders to Alzheimer’s disease (AD) pathology and may support a perpetual brain inflammatory state1. Advances in positron emission tomography (PET) imaging biomarkers allow for detecting RA in the early stages of AD (e.g., [11C]‐L‐Deprenyl and [11C]BU99008, which target MAO‐B and the imidazole binding sites 2 – I2Bs, respectively). However, RA assume multiple states, thus, a very heterogenous population of RA exist. Based on a recent consensus, the development of novel PET‐tracers targeting different RA populations is a priority in the field. [18F]‐SMBT‐1, a selective MAO‐B PET‐tracer, was recently designed as an alternative to detect RA in the human brain. However, further studies using [18F]‐SMBT‐1 are needed to evaluate its sensitivity to image RA in AD. We aimed at evaluating the binding properties of SMBT‐1 versus two PET‐tracers targeting RA ‐ [3H]‐L‐Deprenyl and [3H]‐BU99008 ‐ using in vitro human brain techniques.MethodCompetition binding assays for [3H]‐L‐Deprenyl and [3H]‐BU99008 versus SMBT‐1 were performed in postmortem temporal cortex brain homogenate. The number of binding sites and their affinities (IC50 ; half‐maximal inhibitory concentration) as well as percentage were calculated in AD and control brainsResultOur competition binding assays in temporal cortex tissue revealed that SMBT‐1 competes for a single binding site versus [3H]‐L‐Deprenyl in AD (IC50 = 1.141 x 10‐8) and control (IC50 = 1.93 x 10‐8) human brains. Remarkably, SMBT‐1 also competes for [3H]‐BU99008 binding sites in both AD (IC50 = 1.09 x 10‐13 and IC50 = 3.36 x 10‐8, 31% in the high fraction) and control (IC50 = 3.51 x 10‐13 and IC50 = 1.06 x 10‐6, 30% in the high fraction) cases.ConclusionSMBT‐1 competes with [3H]‐L‐Deprenyl for the high affinity MAO‐B binding site and displaces [3H]‐BU99008 binding to the I2Bs. The presence of I2Bs in the entrance channel of MAO‐B may explain this behavior, as SMBT‐1 potentially causes steric hinderance, affecting the availability of this binding site.
Cannabinoids as a potent therapeutic target for Alzheimer’s disease
Authors: Brugal Gemma Navarro , Rivas‐Santisteban Rafael , Marquez Alejandro Lillo , Jové Jaume Lillo , Franco Rafael 
Published: December 2022

AbstractBackgroundThe NMDA receptor plays a central role in the CNS excitatory neurotransmission, being also a therapeutic target to combat AD. Receptor function deregulation is, at least in part, responsible for the progression of the disease. In this regard it would be interesting to discover membrane proteins capable of interacting with NMDA receptors, and being able to modulate their function to slow the onset of symptoms and the progressive neurodegeneration.MethodCB2‐NMDA complexes were identified in heterologous system by BRET technique and in primary cultures of control or APP Sw/Ind AD mice model by PLA. cAMP and MAPK signalling pathways were evaluated. Protein propagation was analyzed by microfluidic devices.ResultIn a heterologous system we identified CB2‐NMDA complexes with a particular heteromer print consisting of impairment by cannabinoids of NMDA receptor function. The print was detected in activated primary microglia treated with lipopolysaccharide and interferon‐γ. CB2R activation blunted NMDA receptor‐mediated signaling in primary hippocampal neurons from APPSw/Ind mice. Furthermore, imaging studies showed that primary cells (microglia or neurons) from APPSw/Ind mice displayed a marked overexpression of macromolecular CB2‐NMDA receptor complexes thus becoming a tool to modulate excessive glutamate input using cannabinoids. The expression of the CB2‐NMDA Hets increases in both microglia and neurons from the APP Sw/Ind transgenic mice, compared with levels in WT mice.ConclusionThe results indicate a negative cross‐talk in CB2‐NMDA complexes function, where cannabinoiods become an important neuroptotecting target by their own action and also by blocking NMDA signaling.