bluuebunny/crossref_metadata_2025 huggingface dataset:
Smoking behavior, sleep quality, and physical activity level are associated with cerebral amyloid pathology in non‐demented persons: The Amyloid Biomarker Study
Authors: Oomens Julie Elisabeth , Jansen Willemijn J. , Janssen Olin , Maserejian Nancy Nairi , Verhey Frans R.J. , Vos Stephanie J. B. , Visser Pieter Jelle ,   the Amyloid Biomarker Study Group
Published: December 2022

Background

The relationship between lifestyle factors and Alzheimer’s disease pathophysiology is not well understood. The aim of this study was to assess the cross‐sectional association between lifestyle factors and amyloid abnormality in individuals with normal cognition (NC) and mild cognitive impairment (MCI).

Method

We selected 39 cohorts from the Amyloid Biomarker Study. Self‐reported lifestyle data were available for 8924 participants with NC and 2403 participants with MCI. Amyloid abnormality was determined with amyloid‐PET (center‐specific cutoffs) or with aß42 level in CSF (data‐driven or center‐specific cutoffs). Lifestyle data was harmonized across cohorts and dichotomized into ever smoked yes/no, current alcohol consumption yes/no, currently physically active yes/no and current sleep problems yes/no. Education was dichotomized into ‘high’ or ‘low’ at the median of 16 years. Generalized estimating equations with amyloid abnormality as outcome and single lifestyle factors as predictors were used. Interactions with age, sex, education, cognitive status and APOE‐e4 carrier status were assessed and these variables were added as covariates to all models.

Result

Thirty‐one percent of participants were amyloid positive, 37% were ApoE‐4 carrier, and 55% were female. The mean age was 68.7 (SD8.7). Twenty‐five percent of participants smoked, 54% consumed alcohol, 30% experienced sleep problems and 25% were physically inactive. Overall, smoking was associated with a slightly increased prevalence of amyloid abnormality (2%; p = 0.03). In NC, sleep problems were unrelated to the prevalence of amyloid abnormality while in MCI, sleep problems were associated with a lower prevalence (15.3%; p<0.001). Physical activity was related to higher prevalence of amyloid abnormality in APOE‐e4 carriers (5.9%; p<0.001) while this association was not found in noncarriers. Age, sex and educational level did not modify the identified associations between lifestyle factors and amyloid abnormality. Alcohol consumption was unrelated to amyloid abnormality.

Conclusion

Smoking behavior, sleep quality, and physical activity were associated with amyloid abnormality depending on cognitive and APOE‐e4 status. A better understanding of the associations between lifestyle factors and cerebral amyloid pathology in different subgroups will aid in identifying those at risk and contribute to the development of targeted intervention strategies.
Molecular docking study and ADMET prediction of phytoconstituents of Withania Somniferra Flem. in Alzheimer’s disease: an insilico explorative study
Authors: Medhi Bikash , Prajapat Manisha ,   Insilico‐Study
Published: December 2022

Background

Withania somniferra Flem. (brahmi) is known for its neuroprotective property and protective action against AD. Among different phytochemicals of WS, which phytoconstituents is responsible for this neuroprotection in AD is unknown.

Method

Protein Preparation, Ligand Preparation, Molecular Docking on PDB structure of target proteins GSK‐3 beta, CDK‐5, NMDA,SORLA/SORL1,P2×7R, beta catenin, sTLR5 from protein data bank were performed using Schrodinger maestro 12

Ligand preparation: Compound was retrieved from pubchem Withaferin‐A and withanolide‐A.

Molecular Docking: All in silico calculations and procedures were carried out using Schrödinger software Maestro suite 2019, on an Acer predator laptop with an operating system consisting Linux Ubuntu OS 18.04.02 LTS platform.

Pharmacokinetics properties of ligands: admetSAR server (http://lmmd.ecust.edu.cn:8000/) (19), AMDETlabs server (admet.scbdd.com/) and SwissADME server (www.swissadme.ch/) (21) were used for evaluation of pharmacokinetic properties of the ligands (absorption, distribution, metabolism, excretion and toxicity).

Result

Out of these 30 ligands, Withaferin‐A (binding energy to the inhibitory domain of gsk3 beta and beta catenin is ‐5.135, ‐7.764 respectively and withanolide‐A binding energy to the inhibitory domain of gsk3 beta and beta catenin is ‐4.371, ‐6.946 and Both the ligands showed good binding profile, favorable pharmacokinetic profile, no violation of drug ability rules. Both the ligands showed permeability through blood brain barrier. Both the ligands shown non Ames toxicity, non carcinogen and weak inhibitor of HERG. Phytochemical of WS (Withaferin‐A and withanolide‐A) showed good binding profile against gsk3beta targets in AD.

Conclusion

Phytochemical of WS (Withaferin‐A and withanolide‐A) showed good binding profile against Gsk3beta AND Beta catenin targets in AD. We need further studies to evaluate individual efficacy of these phytochemicals in different settings (in‐vitro and in‐vivo).
Letters of Intent for Pilot Projects Affirm the Heterogeneity of Dementia Family Caregiving
Authors: Hepburn Kenneth , Waldrop Drenna , Song Mi‐Kyung , Clevenger Carolyn K , Aflatoony Leila , Higgins Melinda , Glover Crystal M , Lindauer Allison , Perkins Molly
Published: December 2022

Background

The Emory Roybal Center for Dementia Caregiving Mastery (P30AG064200) supports pilot intervention projects designed to enhance informal caregiving mastery and seeks to further their development, following the NIH Stage Model. The Center’s core assertions are that dementia caregiving is heterogeneous in nature and that caregiving role demands are positioned within a variety of intersections involving dementia stage and type, the nature of care tasks, caregiver‐care recipient relationships, and/or other social determinants including race/ethnicity, culture, class, and geography. Thus, interventions to develop/enhance caregiving mastery must be designed within the context of these intersections. This presentation demonstrates the resonance of the Center’s central theme and illustrates the wide range of caregiving situations/contexts investigators seek to address.

Method

We analyzed the letters of intent (LOI) investigators submitted to the Center In its three years of operation. The LOIs describe context/situation‐specific caregiving mastery interventions investigators seek to develop.

Result

In three years, the Center received 67 LOIs from investigators in 26 U.S. states. Most (85%) were from female investigators; the majority were from early‐stage (Assistant Professor) investigators (52%) and investigators from underrepresented groups (54%). Responses came from 10 different disciplines (including Behavioral Sciences (including Social Work), 14; Nursing, 12; and Medicine, 10). Proposed interventions fell into three broad (sometimes intersecting) categories: specific caregiving populations (e.g., racial/ethnic groups; specific caregiving relationships); specific caregiving challenges (e.g., skilled care tasks, managing delirium or chronic pain, caregiver self‐care); and dementia types (e.g., MCI, Lewy Body Disease (LBD), and Frontotemporal Dementia). To date, the Center has provided support for pilot projects aiming to enhance mastery in caregivers of persons with Primary Progressive Aphasia and with LBD and couples living with MCI, among Native American caregivers and those from the LGBTQ community and rural caregivers, and those faced with skilled care tasks and who needed to develop skills through distance means.

Conclusion

The Center has supported pilot projects that illustrate the importance of appreciating the heterogeneity of dementia caregiving. The voluminous response to the LOI call demonstrates the salience of the heterogeneity theme and underscores the need for additional work to enhance dementia caregiving mastery in its many contexts.
CSF tau phosphorylation at sites 217 and 181 are associated with preclinical and biphasic alterations in resting‐state functional connectivity in Autosomal Dominant AD
Authors: Meeker Karin L. , Barthélemy Nicolas R. , Gordon Brian A. , McDade Eric , Karch Celeste M. , Fagan Anne M. , Strain Jeremy F. , Luckett Patrick H , Benzinger Tammie L.S. , Bateman Randall J. , Holtzman David M. , Ances Beau M ,   the Dominantly Inherited Alzheimer Network (DIAN)
Published: December 2022

Background

In autosomal dominant AD (ADAD), elevated cerebrospinal fluid (CSF) soluble phosphorylated tau (pT181) increases shortly after amyloid positron emission tomography. Recent advancements have identified additional phosphorylated tau sites, such as phosphorylated tau 217 and 205 (pT217 and pT205), which are associated with amyloid deposition and neuronal dysfunction, respectively. Degradation of cortical brain network resting‐state functional connectivity (RS‐FC) is typically observed at the onset of cognitive impairment and is most prevalent in regions where amyloid and tau accumulate. However, it is unknown how specific phosphorylated tau sites are associated with alterations in brain networks and contribute to the transition from asymptomatic to symptomatic AD.

Method

CSF tau phosphorylation occupancy on 217, 181 and 205 residues and RS‐FC were measured in 93 individuals from the Dominantly Inherited Alzheimer Network (amyloid‐negative asymptomatic mutation carrier [(aMCA‐); n=26]; amyloid‐positive asymptomatic mutation carriers [a(MCA+); n=36]; and amyloid‐positive symptomatic mutation carriers [(sMCA+); n=31]). Regression models were used to determine within‐group associations between CSF phosphorylated tau sites and within‐network RS‐FC measures.

Result

P‐tau associated RS‐FC alterations began during preclinical stages and continuously changed throughout disease progression. Specifically, within aMCA‐, pT217, pT181, and pT205 were associated with decreased RS‐FC in salience and ventral attention networks, while in aMCA+, pT217 and pT181 were associated with increased RS‐FC in the fronto‐parietal network. In sMCSA+ elevated p‐tau sites were associated with decreased RS‐FC in the cingulo‐opercular, dorsal attention, default mode, and memory networks.

Conclusion

Elevated phosphorylation at specific tau sites is associated with a biphasic pattern of RS‐FC which begins during asymptomatic stages. P‐tau‐ associated RS‐FC alterations were consistent with proposed models of cascading network failure and AD pathophysiology. These results suggest that in ADAD, phosphorylation of tau is associated with widespread and dynamic RS‐FC alterations which begin before the transition to symptomatic AD.
Default Mode Network failure is associated with increased tau PET uptake
Authors: Scott David , Bracoud Luc , Adamczuk Katarzyna , Ingalhalikar Madhura , Conklin Chris , Rousset Olivier , Suhy Joyce
Published: December 2022

Background

The accumulation of neurofibrillary tangles contributes to a neurodegenerative cascade toward Alzheimer’s disease. Focal tau deposition may impair signal integrity within a broader network of functionally connected brain regions. 18F‐Flortaucipir PET allows visualization of tau pathology in vivo, and functional compensation between Default Mode Network (DMN) subsystems is an fMRI‐based biomarker of network failure. We sought to characterize the relationship between network failure in the DMN and tau burden throughout the brain.

Method

620 ADNI3 subject visits with concurrent fMRI and flortaucipir PET scans were selected from the database (http://adni.loni.ucla.edu) for analysis. ADNI PET core PVC values referencing inferior cerebellar cortex were used to index SUVR across the entire FreeSurfer parcellation, and the ADNI MRI core Network Failure Quotient (NFQ) was used as a summary metric of fMRI connectivity strength in the DMN. Linear partial correlation coefficients were calculated for NFQ and SUVR in each brain region, controlling for age. Lasso logistic regression also returned penalized maximum‐likelihood fitted coefficients for a generalized linear model estimating NFQ from regional SUVR; regions with non‐zero coefficients in the sparsest model were included in a composite. A subset of 131 subjects with paired visits at one year follow‐up were included in longitudinal analysis.

Result

A significant age‐corrected association was observed between higher NFQ, reflecting worsening DMN failure, and higher flortaucipir SUVR in Braak 1 (p < 0.02) and meta‐temporal composite ROIs (p < 0.03). Age‐corrected partial correlations achieved marginal significance (p < 0.05) in bilateral entorhinal, inferior and middle temporal, superior parietal and caudal middle frontal cortices, left posterior cingulate and right isthmus cingulate. Lasso regression revealed a subset of non‐zero coefficients including frontal, temporal, cingulate and subcortical brain regions. In the longitudinal analysis, age‐corrected baseline tau load in Braak 5/6 and a set of frontoparietal subregions was marginally significantly associated with change in NFQ after 1 year.

Conclusion

Functional network failure in the DMN is associated with greater tau burden inside and outside the network. These results suggest the NFQ is a viable fMRI‐based biomarker for tau pathophysiology and disease state.
Gantenerumab treatment increases plasma beta‐amyloid(1–42) and decreases plasma pTau
Authors: Bittner Tobias , Scelsi Marzia A. , Kollmorgen Gwendlyn , Jethwa Alexander , Kerchner Geoffrey A. , Fontoura Paulo , Baudler Monika , Doody Rachelle S.
Published: December 2022

Background

Gantenerumab, a human monoclonal antibody targeting aggregated beta‐amyloid (Abeta), is a potential disease‐modifying treatment for early (prodromal‐to‐mild) Alzheimer’s disease (AD). SCarlet RoAD (NCT01224106) and Marguerite RoAD (NCT02051608) were two Phase III trials which assessed the efficacy and safety of subcutaneous, low‐dose gantenerumab in participants with prodromal and mild AD, respectively, for up to 2 years. Following a gap period gantenerumab treatment was continued with uptitration to a dose of 1,200 mg monthly in open‐label extensions (OLE), which demonstrated substantial Abeta removal by positron emission tomography without new or unexpected safety findings. The aim of this work is to investigate the pharmacodynamic effects of gantenerumab on plasma markers for amyloid and tau during both double‐blind and OLE periods.

Method

We evaluated the pharmacodynamic effects of subcutaneous gantenerumab on blood‐based biomarkers for amyloid and tau proteins in plasma samples collected once every year from participants who completed the double‐blind periods of SCarlet RoAD and Marguerite RoAD and participated in the OLE for up to 3 years. We measured Abeta(1–42) and phosphorylated Tau (pTau) in plasma samples using prototype Elecsys® immunoassays from Roche Diagnostics.

Result

Plasma Abeta(1–42) increases by 106% (95% confidence interval [CI]: 48% to 163%) in SCarlet RoAD and 63% (95% CI: 49% to 77%) in Marguerite RoAD after 3 years of OLE treatment. Plasma pTau decreases by 24% (95% CI: –44% to –4%) in SCarlet RoAD and 11% (95% CI: –23% to +2%) in Marguerite RoAD after 3 years of OLE treatment.

Conclusion

Chronic treatment with 1,200 mg subcutaneous injections of gantenerumab every 4 weeks increases levels of plasma Abeta(1–42) and decreases levels of plasma pTau consistently across both studies.
Implementation of Blood‐Based Biomarker Assays to Deliver Consistent and Comparable Data
Authors: Russ Kristen A , Stecker Mara , Olson Chelsea , Foroud Tatiana M. , Dage Jeffrey L.
Published: December 2022

Background

Implementing biomarkers for Alzheimer’s Disease (AD) is an important area of research that will enhance the ability to accurately characterize the disease with the goal of earlier detection and treatment. Analytical validation is the first step to determine the measuring range, specificity, precision, and matrix effects of biomarker assays. Studies on analyte stability and performance bridging when key reagents are changed are critical to deliver reliable and consistent data over time. The goal of these studies is to demonstrate the performance of the assays implemented in the NCRAD Biomarker Assay Laboratory (BAL).

Method

Samples were collected from patients with AD (N=14) and from healthy control subjects (N=19) by the Indiana Biobank. Samples were assayed on the Quanterix Simoa HD‐X platform using the Simoa Nf‐light Advantage Kit and P‐tau181v2 Advantage Kit to determine neurofilament light chain and P‐tau 181 concentrations. Five samples were chosen to span high, medium, and low concentrations for the validation method. Sets of 3 plates were run on two separate days using kits of the same lot number and same 5 samples. Validation assessed precision, parallelism, protein recovery, dilutional linearity, and sensitivity. In addition, our validation method allowed assessment of intra and inter batch variability. Euroimmun Beta‐Amyloid 1‐40 and 1‐42 ELISA kits were also assessed.

Result

The Nf‐Light Advantage Kit precision data coefficient of variation (CV) was less than 7% within plates and less than 8% percent within batches. The CV for precision between the runs on both days was less than 10%. The P‐tau181v2 Advantage assay precision data CV was less than 7% within plates and less than 10% within batches. The CV for total precision between runs on both days was less than 10%. Dilutional linearity, protein recovery, sensitivity, and parallelism were within acceptable levels.

Conclusion

The validation studies of the commercially available Simoa Nf‐light and P‐tau181v2 Advantage Kits demonstrate the performance of these assays as implemented within the NCRAD BAL. The stability and bridging studies illustrate how the assays will be kept performing over time to deliver consistent and reliable data for researchers submitting samples for analysis. Supported by U24 AG021886 and UL1TR002529.
Baseline risk factors for developing ARIA‐E from the SCarlet RoAD and Marguerite RoAD open‐label extension studies
Authors: Lyons Marco , Neve Anuja , Huang Zhiyue , Das Bibha , Wojtowicz Jakub , Bullain Szofia
Published: December 2022

Introduction

Treatment‐induced Amyloid‐Related Imaging Abnormalities‐Edema (ARIA‐E) are identified risks of N‐terminus anti‐amyloid antibodies, with reported overall incidence in Alzheimer’s disease (AD) trial participants of up to 40%. Known risk factors for developing ARIA‐E include apolipoprotein‐E‐e4 (APOE e4) carrier status, higher anti‐amyloid antibody dose, and baseline microhemorrhage burden.

Background

SCarlet RoAD (SR) (NCT01224106) and Marguerite RoAD (MR) (NCT02051608) open‐label extensions were designed to investigate the long‐term safety and biomarker impact of gantenerumab 1,200mg q4w. To generate safety data that would inform future pivotal study design (GRADUATE trials [NCT03444870, NCT03443973]), five titration regimens were studied (Figure 1). ARIA‐E incidence varied across treatment arms; here we investigated potential baseline risk factors for ARIA‐E.

Methods

Baseline risk factors were selected for analysis based on those previously reported in the literature as potential individual characteristics. Univariate logistic analysis was used to identify baseline risk factors and multivariate logistic analysis to assess the independence of identified risk factors.

Results

In univariate logistic analysis, identified baseline risk factors for ARIA‐E in both studies were APOE e4 carrier status and presence of one or more microhemorrhages (Tables 1 and 2). Homozygous APOE e4 carriers were at higher risk than heterozygotes (Tables 1 and 2). Multivariate logistic analysis showed that presence of APOE e4 alleles, or one or more microhemorrhages at baseline were independent risk factors (Tables 3 and 4). Participants with both risk factors had a higher ARIA‐E onset risk than those with one or none. Age, race, sex, and body mass index were not identified as baseline risk factors for ARIA‐E (Tables 1 and 2).

Conclusion

APOE e4 carrier status, in particular homozygous status, and microhemorrhage presence were identified as independent, non‐modifiable, and cumulative baseline risk factors for ARIA‐E. Taking into consideration these non‐modifiable and modifiable (speed of titration) risk factors as well as the convenience of a universal regimen for all participants, an optimized trial design with a single 9‐month titration was selected for GRADUATE trials. This optimized trial design aims to maximize exposure for all participants including individuals at higher ARIA‐E risk while offering a simple regimen for all. Results of GRADUATE trials are expected by end of 2022.
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

Background

Large 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.

Method

In 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.

Result

We 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).

Conclusion

Our 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

Background

The 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.

Method

We 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.

Result

We 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.

Conclusion

These 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

Background

Plasma‐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.

Method

Participants 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.

Results

Significant 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.

Conclusion

Findings 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

Background

Chronic 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.

Method

We 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.

Conclusion

Our 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

Background

Alzheimer 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.

Method

As 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).

Result

the 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.

Conclusion

The 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

Background

Amyloid‐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.

Method

IDEAS 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.

Result

Mean 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).

Conclusion

A 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

Background

Treatment 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.

Methods

Infusion 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.

Results

In 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.

Conclusions

In 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

Background

Recent 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.

Method

To 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.

Result

Using 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.

Conclusion

These 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

Background

Astrocytes 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.

Method

Competition 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 brains

Result

Our 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.

Conclusion

SMBT‐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

Background

The 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.

Method

CB2‐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.

Result

In 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.

Conclusion

The 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.
Cerebral amyloid angiopathy interacts with parenchymal beta‐amyloid to promote tau and cognitive decline
Authors: Rabin Jennifer S. , Nichols Emma , La Joie Renaud , Casaletto Kaitlin B , Palta Priya , Dams‐O'Connor Kristen , Kumar Raj G. , George Kristen M. , Satizabal Claudia L , Schneider Julie A , Pa Judy , Brickman Adam M.
Published: December 2022

Background

Prior work has shown that cerebrovascular disease contributes to Alzheimer’s disease (AD) pathophysiology and progression toward AD dementia. Cerebral amyloid angiopathy (CAA) is a form of cerebrovascular pathology that results from the buildup of β‐amyloid (Aβ) in the vessel walls. CAA commonly co‐occurs with AD pathology and increases the risk of AD dementia. Here, we examined whether CAA influences tau deposition and cognitive decline, independently or synergistically with parenchymal Aβ burden. Secondarily, we examined whether tau burden mediates the association between CAA and cognitive decline.

Method

We included data from autopsied subjects recruited from one of three longitudinal clinical‐pathological cohort studies at Rush University. Participants completed annual cognitive evaluations and underwent brain autopsy. CAA pathology was rated as none, mild, moderate, or severe. We used linear regression and linear mixed models to test independent versus interactive effects of CAA and neuritic plaques on tau burden and cognitive decline. We used causal mediation models to examine whether tau mediates the association between CAA and cognitive decline at low and high neuritic plaque burden.

Result

We included 1722 autopsied subjects (mean age at baseline = 80.2+7.1; mean age at death = 8.9+6.7; 68% women). CAA interacted with neuritic plaques to promote tau burden and cognitive decline, such that those with more severe CAA and higher neuritic plaque burden exhibited greater tau and faster cognitive decline (Figures 1 and 2). Tau mediated the effect of CAA on cognitive decline among participants with high neuritic plaque burden. Specifically, increased tau pathology due to the presence of severe CAA led to a 5‐year decline in cognition that was 0.10 (95% CI: 0.03 ‐ 0.19) SD units greater than those with no CAA. A direct effect of CAA on cognitive decline (i.e., an effect not mediated by tau) was not significant in the low or high neuritic plaque groups (Figure 3).

Conclusion

These results highlight the dynamic interplay between cerebrovascular and AD pathways in the progression of AD. The present findings have implications for AD clinical trials and therapeutic development, and further support the idea that improving and/or preserving the brain’s vasculature might be an effective target for AD prevention