bluuebunny/crossref_metadata_2025_split huggingface dataset:
PRX012 induces microglia‐mediated clearance of pyroglutamate‐modified Aβ in Alzheimer’s Disease brain tissue
Authors: Tam Stephen , Zhang Gang , Li Lauri , Elmaarouf Abderrahman , Skov Michael , Dolan Philip , Kinney Gene G , Campbell Brian , Zago Wagner M 
Published: December 2021

AbstractBackgroundAlzheimer’s disease (AD) is a devastating neurodegenerative disorder featuring hallmark Aβ plaques that spread throughout the brain as the disease progresses. Removal of these plaques has been a focal point of research toward developing treatments for AD, and outcomes from multiple development programs support the prediction that monoclonal antibodies (mAbs) that reduce Aβ plaques meaningfully slow clinical decline in AD patients (e.g., aducanumab, donanemab, lecanemab). Donanemab, which specifically targets pyroglutamate‐modified Aβ, was recently reported to reduce Alzheimer’s‐related cognitive decline in a phase 2 clinical trial. PRX012 is a high‐potency IgG1 mAb targeting the N‐terminus of Aβ with ∼70pM affinity (KD) for Aβ fibrils. In the current study, we assessed whether PRX012, an N‐terminal Aβ targeting IgG1 antibody, stimulates microglial‐mediated clearance of Aβ species, including pyroglutamate‐modified Aβ (AβpE3‐42), in amyloid plaque‐bearing AD brain tissue.MethodThe impact of PRX012, and other Prothena N‐terminal anti‐Aβ antibodies, on microglia‐mediated phagocytic clearance of Aβ plaque species was assessed ex vivo using cryostat sections of human AD brain. Test antibodies or isotype control were applied to plaque‐bearing AD tissue samples, which were then incubated with murine microglia for 72 hours. Determination of total Aβ (Aβ1‐42) and AβpE3‐42 levels were assessed by enhanced chemiluminescent detection and ELISA.ResultPRX012 and other Prothena N‐terminal anti‐Aβ antibodies promoted rapid and robust microglia‐mediated clearance of Aβ species associated with plaques in human AD tissue. Compared to isotype control, PRX012 significantly reduced both Aβ1‐42 levels as well as pyroglutamate‐modified Aβ species.ConclusionPRX012, an N‐terminal‐targeted anti‐Aβ antibody, facilitated abundant microglia‐mediated clearance of Aβ plaque species, including pyroglutamate‐modified Aβ, in brain tissue from AD patients. These data support further development of PRX012 as a potential subcutaneous next‐generation, best‐in‐class Aβ immunotherapy for AD.
Concerns of older adults during second COVID wave in India
Authors: Chopra Meenakshi , Dasgupta Jayashree 
Published: December 2021

AbstractBackgroundA second wave of COVID infections in India, lockdown, restriction on services, and strain on an unprepared health system has had significant impact on older adults. It is important to examine impact of the lockdown on the elderly and their caregivers, useful coping strategies and requirements for support going forwards.MethodAs part of an ongoing community engagement initiative with older adults, an online survey was conducted in 2020 during the first wave of the pandemic investigating mental health and wellbeing of older adults. Participants who shared details were contacted one year later to understand impact of the second COIVD wave on their wellbeing and coping. An in‐depth telephonic interview was conducted and General Health Questionnaire 5 item were used for data collection. Audio consent was taken prior to interviews which were recorded and transcribed for thematic analysis.ResultOut of 58 participants who shared contact details, 16 % (N=9) agreed to participate in the interview. about 40 % refused mentioning they were unwell/ too busy/or agreed to speak at a later date. One female and 8 males participated in the interview between the ages of 36 to 83 years. All participants held post graduate/ professional degrees. 33 % (N=3) participants obtained a GHQ score of 2 and above on the five item General Health Questionnaire indicating presence of depressive features. As compared to the first lockdown, older adults found the second lockdown more stressful due to deaths of close friends and family members. Increased fears about family members with comorbidities contracting the virus, difficulties managing emotional wellbeing, and challenges helping younger family members manage their routines and follow basic COVID protocols were key concerns. Coping strategies found useful were remaining active and engaged at home, attending online mental wellness sessions, practicing yoga/ meditation and spending time with friends/family. Older adults highlighted a need for more emotional support through creation of social media networks and online platforms.ConclusionPreliminary findings from this study emphasize a need for leveraging technology to support emotional wellbeing of older adults during lockdown and COVID restrictions.
Olfactory dysfunction and chronic cognitive impairment following SARS‐CoV‐2 infection in a sample of older adults from the Andes mountains of Argentina
Authors: Zamponi Hernan P. , Juarez‐Aguaysol Leonardo , Kukoc Gabriela , Dominguez Maria Eugenia , Pini Belén , Padilla Eduardo G , Calvó Maria , Molina‐Rangeon Silvia Beatriz , Guerrero Gonzalo , Figueredo‐Aguiar Mariana , Fumagalli Emiliano , Yécora Agustín , Brugha Traolach S , Seshadri Sudha , Snyder Heather M. , de Erausquin Gabriel A. , Gonzalez‐Aleman Gabriela ,   Alzheimer's Association CNS SARS‐CoV‐2 Consortium
Published: December 2021

AbstractBackgroundCOVID‐19 has affected more than 150 million people. The causal coronavirus, SARS‐CoV‐2 has infected twice as many individuals who have remained asymptomatic. COVID‐19 includes central nervous system (CNS) manifestations and may result in chronic neuropsychiatric sequelae. Risk factors for COVID‐19 sequelae overlap with those for Alzheimer’s disease (AD), particularly older age and ApoE4 status. The Alzheimer’s Association Consortium on Chronic Neuropsychiatric Sequelae of SARS‐CoV‐2 infection (CNS SC2) established harmonized definitions, ascertainment and assessment methodologies to evaluate and longitudinally follow up cohorts of older adults with variable exposure to COVID‐19. We present preliminary data from CNS SC2 in a prospective cohort of 234 older adult Amerindians from Argentina.MethodParticipants are ≥ 60 years recruited from the health registry of the Province of Jujuy containing all SARS‐CoV‐2 testing data (regardless of clinical status and of the result of the testing). We randomly invite older adults stratified by testing status regardless of symptom severity, a minimum of 3 months after clinical recovery (maximum 6 months); refusal to participate is <45%. Assessment includes interview with the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) and Clinical Dementia Rating scale; neurocognitive assessment; emotional reactivity scale; and neurological assessment including semiquantitative olfactory function test, motor function, coordination and gait. We present here the results of olfactory testing and cognitive assessments.ResultWe assessed 233 infected participants and 64 controls. Average duration of formal learning is 9.35 ± 2.6 years and mean age is 66.7 ± 5.13 years. Normative data for the local population were available for Word list, Corsi Blocks, Oral Trails and Five Digit Tests and were used to normalize Z‐scores and categorize the sample in 3 groups: normal cognition (NC,44.6%); memory only impairment (MOI,21%); and multiple domain impairment (MDI,34.4%). Individuals with MDI presented severe alterations in short‐term memory; semantic memory; naming; executive function and attention compared to NC or MO groups (Table 1). Severity of cognitive impairment was significantly correlated with severity of olfactory dysfunction (χ2 = 13.82; p= 0.003) but not severity of acute COVID‐19.ConclusionOlder adults frequently suffer persistent cognitive impairment after recovery from SARS‐CoV‐2 infection; cognitive impairment is correlated with persistent anosmia.
IL‐1 beta and TNF‐alpha play an essential role in modulating the risk of both periodontitis and Alzheimer’s disease
Authors: Wang Rachel Pei‐Hsuan , Leung Wai‐Keung , Goto Tetsuya , Ho Janice Yuen‐Shan , Chang Raymond Chuen‐Chung 
Published: December 2021

AbstractBackgroundPeriodontitis, a chronic systemic inflammatory disease, is a common health problem in the elderly. With increasing recognition that inflammation plays a key role in the pathophysiology of Alzheimer's disease (AD), our research team has been studying how systemic inflammation affects the brain immune responses. Aging is a major risk factor for both periodontitis and AD. As aging causes dysregulation of immune responses, we aimed to define the roles of cytokines in the pathogenesis of periodontitis and AD.MethodsTo induce experimental periodontitis, female WT mice were injected with heat‐killed P. gingivalis into their buccal mucosa three times per week every other week for a total of 5 weeks. Another group of mice were injected with IL‐1b and TNF‐a following the same timeline as above. Sickness Behavior and cognitive functions were assessed through open field and puzzle box test. Mandibular jaws were harvested for Micro‐CT scan. Different brain regions were harvested for biochemical analysis.ResultsMice injected with heat‐killed bacteria had worsened long‐term memory functions. It also significantly increased periodontal bone loss, which was accompanied by increased gene expression levels of IL‐1b and TNF‐a in the gums. Significant elevated levels of pro‐inflammatory cytokines in the liver as well as different brain regions were also observed. Immunostaining revealed increased levels of phospho‐tau in WT mice injected with heat‐killed bacteria, suggesting that elevated systemic cytokine levels caused by the injection of heat‐killed bacteria can lead to the appearance of AD pathology. Another group of mice injected with IL‐1b and TNF‐a displayed hyperactivity and worsened short‐term memory functions. Injections of cytokines also induced periodontal bone loss, which was accompanied by elevated levels of inflammatory cytokines in the liver as well as different brain regions.ConclusionTaken together, our study revealed that increased cytokine immune response in the gums led to periodontal bone loss, brain inflammation and modulated the cognitive functions of WT mice. This research demonstrated that cytokines play a crucial role in the pathogenesis of both periodontitis and AD.Acknowledgement: The study is supported by Health and Medical Research Fund (HMRF 04151216) to RCCC. RPHW is awarded by Hong Kong PhD Fellowship.
Alterations of plasma endocannabinoid levels in MCI and dementia patients
Authors: Kaur Daman Preet , Finn David P , Bucholc Magda , Todd Stephen , Wong‐Lin KongFatt , McClean Paula L 
Published: December 2021

AbstractBackgroundThere is growing evidence that alterations in the endocannabinoid system (ECS) co‐occur with dementia pathophysiology. Currently, limited literature is available on components of the peripheral ECS as diagnostic markers for dementia.MethodsIn the present study we analysed the concentrations of the endocannabinoids (eCBs) anandamide (AEA) and 2‐Arachidonoylglycerol (2‐AG), and their lipid congeners N‐palmitoylethanolamide (PEA) and N‐oleoylethanolamide (OEA) in plasma and serum using LC‐MS/MS. Samples were collected from healthy controls, participants with mild cognitive impairment (MCI), Alzheimer’s disease (AD) and other dementia subtypes (OD).ResultsStatistical analysis revealed significantly lower concentrations of plasma AEA (p: 0.0017), PEA (p: 0.0056) and OEA (p: 0.0015) in MCI vs. OD groups, and lower OEA levels in MCI vs. healthy controls (p: 0.0099). Plasma PEA levels in AD patients were lower compared to healthy controls (p: 0.0409) and OD groups (p: 0.0307). Additionally, plasma 2‐AG levels correlated positively with age and body mass index (p<0.0001), and negatively with ACE‐III scores (p<0.0011).ConclusionsThese results suggest that peripheral levels of eCBs vary with age and cognitive decline, and may be beneficial in differential diagnosis of dementia. Further, plasma eCB levels may be indicative of early stages of cognitive impairment like MCI, which currently is difficult to diagnose.
The role of lycopene on the hippocampus of rat model of lipopolysaccharide‐induced Alzheimer's disease
Authors: Temitope Saula Rofiat 
Published: December 2021

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disorder that is the sixth leading cause of dementia worldwide. According to AD hypothesis, the progression of AD begins following the accumulation of these proteins, leading to eventual synapse loss and neuronal cell death. Over the last few decades, significant advances have been made in our understanding of AD by investigating the mechanisms of the two proteins: amyloid beta and tau pathology. There are yet unanswered questions regarding the aetiology and progression of the disease.This study was designed to investigate the role of lycopene on hippocampus in lipopolysaccharide‐ induced Alzheimer’s disease.MethodsFifty (50) adult Wistar rats were divided into five (5) groups. Group A (The control group were given equal volume of water), Group B Lipopolysaccharides (LPS) only; given 150mg/kg body weight), Group C (curative group, given 150mg/kg of LPS followed by 15mg/kg body weight of lycopene (LYC), Group D (preventive, given 15mg/kg of LYC followed by 150mg/kg body weight of LPS), Group E (LYC only). The rats were subjected to neurobehavioral protocols. After sacrifice, the brain sections were processed and stained for H&E, Silver, LUXOL‐FAST BLUE, and Masson Trichrome stains.ResultsThe results revealed that LPS induced significant reduction in body and brain weights, reference memory and neuronal parameters. There was significant histologically lesions, demyelination and increased neuroinflammation.Conclusionsthe study demonstrated that Lycopene exhibited neuroprotective effects by mitigating oxidative stress, suppressing production of inflammatory cytokines, and attenuating the pathologic lesions associated with LPS AD modelin the hippocampus.
mRNA‐Binding Protein DJ‐1 as a pivotal protein in AD pathology
Authors: Uneri Ayse , Niere Farr , Macauley Shannon L , Ma Tao , Keene C. Dirk , Craft Suzanne , Raab‐Graham Kimberly F 
Published: December 2021

AbstractBackgroundAlzheimer’s Disease (AD) is a complex neurodegenerative disorder of the synapse, characterized by the accumulation of amyloid beta plaques and neurofibrillary tangles. We have recently shown that Parkinson Protein 7, DJ‐1, is upregulated by mTORC1 activity, and is a translational hub that is predicted to coordinate the expression of a population of synaptic proteins (Niere et al., 2016). This cellular function of DJ‐1 is mediated through its RNA‐binding properties, yet many of its target mRNAs are unidentified, and the effects of this protein‐mRNA association are not well‐defined.MethodSynaptically increased DJ‐1 expression was determined by Western blotting of synaptoneurosomes from AD patients (Niere et al., 2020), and APP/PS1 and P301S mouse models of AD. DJ‐1 target mRNAs were first bioinformatically identified using a modified consensus sequence of DJ‐1 protein (van der Brug et al., 2008), and confirmed via RNA‐immunoprecipitation of DJ‐1 from WT mouse cortices. FMR1KO mouse cortices were used as a negative control.ResultSynaptic DJ‐1 expression is increased in a preclinical mouse model of AD exhibiting plaque pathology, and AD patients. Interestingly, there is no change in synaptic DJ‐1 levels in the P301S mouse model, which presents neurofibrillary tangles. We bioinformatically identified that mRNA coding for the RNA‐binding protein FMRP, and tau‐tubulin kinase 1 (TTBK1), known for phosphorylating pathogenic tau, as potential targets for DJ‐1, and confirmed it via RNA‐immunoprecipitation. Furthermore, the protein levels of FMRP is significantly decreased in the synapses of AD patients and APP/PS1 mice, while there is no change in the P301S model consistent with no change in DJ‐1 expression.ConclusionDecrease in FMRP in AD synapses where DJ‐1 expression is high suggests that DJ‐1 is a translational repressor of FMRP. FMRP binds to the mRNA of amyloid precursor protein (APP), the building block of amyloid beta plaques. Therefore, DJ‐1’s capacity to bind both Fmr1, coding for a protein which is known as a translational suppressor of APP mRNA (Borreca et al., 2016), and Ttbk1, a tau kinase involved in tau phosphorylation and aggregation (Sato et al., 2006) suggests that DJ‐1 might be at the crossroads of both AD hallmark pathologies.
Focus Ultrasound‐Induced Blood‐Brain Barrier opening enhances anti‐pGlu3 Aβ mAb delivery and amyloid‐beta plaque clearance
Authors: Bathini Praveen , Sun Tao , Shi Qiaoqiao , Zhang Yongzhi , Taudte Nadine , Schenk Mathias , Hettmann Thore , Schilling Stephan , McDannold Nathan , Lemere Cynthia A 
Published: December 2021

AbstractBackgroundAlzheimer’s Disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid plaques and hyperphosphorylated tau in the brain. Currently, therapeutic agents targeting amyloid appear promising for AD, however, delivery to the CNS is limited due to the blood‐brain‐barrier (BBB). Focused ultrasound (FUS) is a method to induce a temporary opening of the BBB to enhance delivery of therapeutic agents to CNS. Our lab has shown that an mAb (07/2a), targeting N‐terminally truncated and modified toxic Aβ species, reduced pGlu3 Aβ and general Aβ cerebral plaques in aged APP/PS1dE9 mice. Here, we asked whether FUS‐induced BBB opening enhances the delivery of 07/2a mAb and whether it has any additive effect on cognition or plaque clearance.MethodsFirst, 24 mo‐old APP/PS1dE9 mice were i.v. infused with a single dose of 300 µg 07/2a with or without hippocampal FUS sonication (n=5/group) with i.v. infused Optison microbubbles and euthanized 4 or 72 h later; brain levels of antibodies were measured by ELISA. Next, 16 mo‐old APP/PS1dE9 mice were treated weekly for 3 weeks with PBS (n=9), 500 µg 07/2a alone (n=9), FUS alone (n=7) or 07/2a + FUS combination (n=6). Behavioral testing in the Water T Maze (WTM) was performed 1‐2 weeks later followed by euthanasia.ResultsFUS treatment increased 07/2a mAb levels in brain by 5.9‐fold 4 hr (41.7 pg/mg for mAb alone, vs. 244 pg/mg mAb+FUS; t=3.48, p<0.005) and 5.5‐fold (mean=31.5 pg/mg for mAb alone, vs. 173 pg/mg for mAb+FUS; t=2.9, p<0.05) 72 hr post‐treatment. Immunohistochemistry confirmed a significant increase in IgG2a mAb staining in the mAb+FUS treated mice at 4 hr (p=0.007) and a strong trend in the mAb+FUS treated mice at 72 hr after treatment compared to mAb alone. Three weekly treatments of 07/2a improved cognition however, when combined with FUS, this improvement occurred faster and in a higher percentage of mice and led to reduced hippocampal plaque load compared to PBS control mice.ConclusionsTransient opening of the BBB by FUS increased 07/2a delivery to the brain, improved cognition, and enhanced Ab clearance in aged APP/PS1dE9 mice, suggesting that FUS increased efficacy of the 07/2a mAb.
Defining the role of PLD3 in Alzheimer’s disease pathology
Authors: Rosene Matthew J , Hsu Simon , Martinez Rita , Norton Joanne , Yan Ping , Cirrito John R , Lee Jin‐Moo , Cuervo Ana Maria , Goate Alison M. , Cruchaga Carlos , Karch Celeste M. 
Published: December 2021

AbstractBackgroundAlzheimer’s disease (AD) is characterized by the accumulation of amyloid‐β (Aβ) in the brain. We recently identified coding variants in the phospholipase D3 (PLD3) gene that double the risk for late onset AD.MethodWe examined the impact of PLD3 risk variants on PLD3 and Aβ metabolism using CRISPR/Cas9 in induced pluripotent stem cells (iPSC). We then modeled the PLD3 expression patterns observed in AD brains in immortalized cell and AD mouse models. Lysosomal function was assessed in human brain tissue.ResultPLD3 A442A disrupts a splicing enhancer binding site and reduces PLD3 splicing in human brains. Differentiation of PLD3 A442A and isogenic control iPSCs into cortical neurons produced cells that were morphologically similar. At the molecular level, PLD3 A442A neurons displayed a similar defect in PLD3 splicing as was observed in human brains and a significant increase in Aβ42/Aβ40 compared with isogenic control lines. Thus, PLD3 A442A is sufficient to alter PLD3 splicing and Aβ metabolism. PLD3 expression was significantly lower in AD brains compared with controls, and PLD3 expression was highly correlated with expression of lysosomal genes. Thus, we sought to determine whether PLD3 contributes to Aβ accumulation in AD via disrupted Aβ metabolism. We found that overexpression of PLD3 in immortalized cells decreased Aβ levels while shRNA silencing of Pld3 increased Aβ levels. In an AD mouse model, overexpression of PLD3 in hippocampal neurons produced decreased interstitial fluid (ISF) Aβ levels and accelerated Aβ turnover. Conversely, knocking out Pld3 increased ISF Aβ, reduced Aβ turnover, and increased APP protein levels. Knocking out Pld3 overtime lead to altered amyloid morphology. To begin to determine whether PLD3 influences Aβ turnover via the lysosome, we isolated lysosomal fractions from human AD and control brains. PLD3 was enriched in lysosomal subfractions and PLD3 distribution in these subfractions was altered in AD. Furthermore, PLD3 stability in the lysosomal fractions was disrupted in AD brains.ConclusionTogether, our findings demonstrate that PLD3 promotes Aβ clearance through pathways involving lysosomal degradation.
Subcortical Volumes as Early Predictors of Fatigue in Multiple Sclerosis
Authors: Fleischer Vinzenz , Ciolac Dumitru , Gonzalez‐Escamilla Gabriel , Grothe Matthias , Strauss Sebastian , Molina Galindo Lara S. , Radetz Angela , Salmen Anke , Lukas Carsten , Klotz Luisa , Meuth Sven G. , Bayas Antonios , Paul Friedemann , Hartung Hans‐Peter , Heesen Christoph , Stangel Martin , Wildemann Brigitte , Then Bergh Florian , Tackenberg Björn , Kümpfel Tania , Zettl Uwe K. , Knop Matthias , Tumani Hayrettin , Wiendl Heinz , Gold Ralf , Bittner Stefan , Zipp Frauke , Groppa Sergiu , Muthuraman Muthuraman ,   the German Competence Network Multiple Sclerosis (KKNMS)
Published: December 2021

ObjectiveFatigue is a frequent and severe symptom in multiple sclerosis (MS), but its pathophysiological origin remains incompletely understood. We aimed to examine the predictive value of subcortical gray matter volumes for fatigue severity at disease onset and after 4 years by applying structural equation modeling (SEM).MethodsThis multicenter cohort study included 601 treatment‐naive patients with MS after the first demyelinating event. All patients underwent a standardized 3T magnetic resonance imaging (MRI) protocol. A subgroup of 230 patients with available clinical follow‐up data after 4 years was also analyzed. Associations of subcortical volumes (included into SEM) with MS‐related fatigue were studied regarding their predictive value. In addition, subcortical regions that have a central role in the brain network (hubs) were determined through structural covariance network (SCN) analysis.ResultsPredictive causal modeling identified volumes of the caudate (s [standardized path coefficient] = 0.763, p = 0.003 [left]; s = 0.755, p = 0.006 [right]), putamen (s = 0.614, p = 0.002 [left]; s = 0.606, p = 0.003 [right]) and pallidum (s = 0.606, p = 0.012 [left]; s = 0.606, p = 0.012 [right]) as prognostic factors for fatigue severity in the cross‐sectional cohort. Moreover, the volume of the pons was additionally predictive for fatigue severity in the longitudinal cohort (s = 0.605, p = 0.013). In the SCN analysis, network hubs in patients with fatigue worsening were detected in the putamen (p = 0.008 [left]; p = 0.007 [right]) and pons (p = 0.0001).InterpretationWe unveiled predictive associations of specific subcortical gray matter volumes with fatigue in an early and initially untreated MS cohort. The colocalization of these subcortical structures with network hubs suggests an early role of these brain regions in terms of fatigue evolution. ANN NEUROL 2022;91:192–202