bluuebunny/crossref_metadata_2025_split huggingface dataset:
Elucidating Multi‐Stage Progression of Neuro‐degeneration Process in Alzheimer’s Disease
Authors: Ma Haixu , Liu Yufeng , Wu Guorong 
Published: December 2022

AbstractBackgroundMounting evidence shows that an individual’s neurodegeneration process exhibits wide heterogeneity in clinical manifestation. Since early symptomatic interventions may ultimately constitute the best long‐term therapeutic strategy, it is vital to disentangle the diverse neurodegeneration process into several distinct progression stages and understand the stage‐specific interaction between AD biomarkers and risk factors.MethodWe aim to understand the pathophysiological mechanism of multi‐stage disease progression as well as the role of risk factors that contribute to the diversities of neurodegeneration in the development of AD. Our statistical inference is performed on 2,352subjects with amyloid‐PET scans, 836 subjects with tau‐PET scans, 2,546 subjects with FDG‐PET scans. The cognitive decline is measured by MMSE score.Result(1) Both amyloid and tau pathologies contribute to cognitive decline at a constant pace in the APOE4 carrier cohort. In contrast, APOE4 non‐carriers show more diversities in the time course of the neurodegenerative process. The multi‐stage cognitive decline in APOE4 non‐carrier populations suggests the necessity of adjusting treatment as the disease progresses. (2) The decline pattern with respect to tau pathology shows more diversity in terms of progression stages (three transition points have been detected) than amyloid pathology (no transition has been detected) in the aging population. As the neurodegenerative process is most likely non‐linear, this result provides lateral evidence that measuring the tau level in a longitudinal manner is more beneficial than using the amyloid biomarker in tracking cognitive decline. (3) We find the pathological process that AD pathology (measured by CSF tau/Aβ ratio) leads to the reduction of metabolism level exhibits three progression stages. In addition, such multi‐stage progression pattern of pathology‐to‐neurodegeneration relationship only exists in males instead of females. (4) We find APOE4 status is a predominant risk factor deeply involved in the critical transition points of disease progression. Regarding the modifiable variable, education level plays a significant role in modulating the disease progression in AD.ConclusionWe disentangle the heterogeneous temporal behavior of pathophysiological mechanisms in AD, which allows us to advance our understanding of disease diversity in AD. These findings provide a new window to manage the priority of risk factors more effectively in AD treatment.
Resistance training improves white matter structural connectivity in older adults at‐risk for cognitive decline
Authors: Lien Ryu , Furlano Joyla , Nagamatsu Lindsay ,   Exercise, Mobility, and Brain Health Lab
Published: December 2022

AbstractBackgroundDiabetes is a global health concern that impacts 415 million people worldwide. Individuals who are at‐risk for diabetes (characterized by high blood glucose and/or being overweight) have white matter atrophy, decreased cognitive function, and an increased risk of Alzheimer’s disease (AD). Recently, resistance training (RT) has been shown to lower white matter atrophy and white matter lesion volume. However, investigating changes in white matter tracts is complex, hence previous findings remain inconclusive. Diffusion tensor imaging (DTI) serves as a highly sensitive tool that enables visualization and characterization of white matter tracts and has the potential to combat this complexity. The study aimed to measure the effects of RT on structural connectivity in older adults at‐risk for cognitive decline using DTI.MethodWe conducted a 6‐month, thrice‐weekly randomized controlled trial. Twenty‐four participants (aged 60‐80 years, sedentary; body mass index ≥25) were randomized into one of two groups: 1) progressive resistance (weight) training (RT), or 2) balance and tone (BAT; control group). High resolution DTI images were obtained using a 3T Siemens MRI scanner at both baseline and endpoint for 17 (RT:11, BAT:6) participants. Images were analyzed using FSL’s tract based spatial statistics (TBSS) to evaluate structural connectivity between groups based on fractional anisotropy (FA), a measure reflecting fiber density, axonal diameter, and myelination in white matter tracts.ResultsSix months of RT led to higher FA values in the splenium of the corpus callosum, right posterior thalamic radiation, right and left superior corona radiata (+0.56%, +0.90%, +0.64% and +0.66%, respectively) compared to BAT (+0.16%, ‐0.72%, ‐0.28% and ‐0.24%).ConclusionThese findings suggest that RT is associated with improvements in WM fiber microstructural integrity related to motor functions and visual short term memory capacity (vSTM). Thus, resistance training may be a promising intervention for patients with AD as the literature suggests that motor function deficits and vSTM dysfunction are early markers of AD pathology.
Primary care for people with a newly diagnosed dementia in hospital after discharge
Authors: Hegerath Flora‐Marie , Giehl Chantal , Otte Ina , Vollmar Horst Christian 
Published: December 2022

AbstractBackgroundOlder people with cognitive impairment usually live at home. Possible deficits can be compensated there, often with the help of relatives. Therefore, the diagnosis of dementia is often delayed. It can lead to a first dementia diagnosis being made during an acute hospital stay. As a result, hospital discharge and subsequent care pose challenges for those involved. The aim of this study was to assess existing barriers and facilitating factors in the care of patients with a newly diagnosed dementia after hospitalization in the general practitioner (GP) setting. The study is funded by the German Alzheimer Society.MethodSixteen semi‐structured interviews with GPs from Germany were conducted from July to December 2021. Data were analysed according to the qualitative content analysis from Kuckartz.ResultTheoretical saturation regarding the research question was reached within the qualitative interviews. The analysis showed that GPs identify communication deficits on the part of the hospitals as a barrier to provide adequate care for their patients. A conversation is rarely initiated with the GPs to ensure continued outpatient care.GPs use different strategies to provide care for their patients. Special importance is given to the communication with people with dementia and their relatives in a first consultation after hospital discharge to obtain detailed information, e.g., about the hospital stay or third‐party anamnesis. This first consultation is focused on organizing the care of patients in their own homes. Managing medication from the hospital is a critical issue for GPs, as patients are often prescribed many new medications.ConclusionSince the acute reason for hospitalization is not dementia, there is usually no comprehensive assessment. It is therefore important for those affected that the diagnosis is verified after discharge and that appropriate measures are initiated. Based on the study results, practice‐oriented recommendations for the GP setting are going to be developed, which, for example, highlight the sensitive communication with those involved. For better initial care of their patients, GPs need adequate communication from the side of the hospital. Here, additional professional groups (e.g., care managers) and better digital networking can have a positive impact on care.
Effects of Oral ALZ‐801, an Amyloid Oligomer Inhibitor, on Plasma Biomarkers in APOE4 Carriers with Early Alzheimer’s Disease: Results of Six‐month Interim Analysis from a Phase 2 Biomarker Study
Authors: Abushakra Susan , Hey John , Blennow Kaj , Scheltens Philip , Reiman Eric M. , Hort Jakub , Sheardova Katerina , Rutgers Sterre M. , Prins Niels D. , Dautzenberg Paul , Pazdera Ladislav , Power Aidan , Tolar Martin 
Published: December 2022

AbstractBackgroundALZ‐801, an oral, brain‐penetrant small molecule inhibitor of amyloid oligomer formation is being evaluated as a disease‐modifying treatment in APOLLOE4, a Phase 3 trial in APOE4/4 homozygotes with Early Alzheimer’s disease (AD). A concurrent Phase 2 study is in progress to study its effects on core AD biomarkers, beta‐amyloid (Aβ) and hyperphosphorylated tau (p‐tau) in APOE4 carriers with Early AD.MethodThe Phase 2 study in Czech Republic and Netherlands enrolled APOE4/4 and APOE3/4 subjects with MMSE 22‐30 (CDR‐G 0.5 or 1), who receive ALZ‐801 265 mg tablets BID for 104 weeks. Subjects were amyloid‐PET positive or A+/T+ on CSF assays (ratio of Aβ42/40×10 < 0.61, and p‐tau181 > 61 pg/ml). CSF is evaluated at 52 and 104 weeks, and plasma biomarkers at every visit. Memory tests include the Rey Auditory Verbal Learning Test (RAVLT). Primary outcome is CSF p‐tau181 reduction at 104 weeks; interim analysis on plasma was conducted when all subjects completed 26 weeks. Dr. Blennow’s laboratory (Mölndal, Sweden) performed biomarker analyses blinded to clinical data, using Lumipulse (Fujirebio) for CSF and Simoa assays for plasma. Change from baseline in observed biomarker values at each visit were analyzed with paired t‐tests (2‐sided p‐values).ResultOf 84 enrolled subjects (mean 69 years, 51% female, MMSE 25.6), 80 completed 26 weeks. Plasma p‐tau181, the interim primary outcome, showed significant 18% and 29% reductions at 13 and 26 weeks (p = 0.038 and p = 0.028). Reductions of p‐tau181/Aβ42 were also significant 21% and 30% at 13 and 26 weeks (p = 0.018 and p = 0.022). RAVLT memory scores (immediate + delayed) improved significantly at 26 weeks (p = 0.002). Most common adverse events were mild nausea with no drug‐ related serious events and no ARIA‐E at 52 weeks.ConclusionInterim Phase 2 plasma biomarker results show significant and robust reductions in plasma p‐tau181 and p‐tau181/Aβ42 at 26 weeks with memory improvement at 26 weeks. These ALZ‐801 effects on core biomarkers confirm target engagement in AD brain, and support disease modification potential of ALZ‐801. The biomarker effects, oral formulation, and favorable safety without ARIA‐E, make ALZ‐801 an attractive potential treatment for APOE4 carriers with AD.
Baseline β‐amyloid and tau predict longitudinal tau accumulation at different stages of Alzheimer’s disease
Authors: Cai Yue , Ma Shaohua , Guo Tengfei ,   Tsinghua Shenzhen International Graduate School (SIGS), Tsinghua University, Shenzhen, China
Published: December 2022

AbstractBackgroundPrevious literatures suggest that β‐amyloid (Aβ) plaques, initial tau levels, age and Klotho‐VS heterozygosity (KL‐VShet) may be related to longitudinal tau accumulation in Alzheimer’s disease (AD), but it is still not fully understood how they predict tau replication in medial temporal cortex and propagations from the medial temporal lobe to inferior/middle temporal cortices at different stages of AD.MethodWe classified 325 Aβ PET positive (A+) ADNI participants into 143 A+/T‐and 182 A+/T+ according to the threshold (≥1.25) of Temporal‐metaROI 18F‐flortaucipir (FTP) standardized uptake value ratio (SUVR). Besides, 162 A‐/T‐ cognitive unimpaired participants without evidence of neurodegeneration were included as the reference group (Ref). We compared baseline and slopes of Aβ Centiloids and FTP SUVRs in 6 regions within Temporal‐metaROI with the Ref, and also investigated the prediction of longitudinal FTP SUVR changes by baseline Aβ Centiloids and FTP SUVRs in A+/T‐ and A+/T+ groups. Furthermore, we determined how age (Age<65 and Age≥65 years) and KL‐VShet haplotype (KL‐VShet+ and KL‐VShet‐) affect these associations.ResultA+/T‐ showed significantly or marginally higher tau and faster tau increases in amygdala, entorhinal and parahippocampus than the Ref (Figure 1). Both baseline Aβ and entorhinal tau predicted faster rates of FTP SUVR increases in amygdala, entorhinal and parahippocampus in A+/T‐. While entorhinal tau predicted faster FTP SUVR increases in all the cortical regions within Temporal‐metaROI in A+/T+, baseline Aβ predicted faster FTP SUVR increases in fusiform, inferior and middle temporal regions (Figure 2). Additionally, younger ages showed faster baseline Aβ‐related whereas older ages had more tau‐related longitudinal FTP SUVR increases in fusiform and inferior temporal regions (Figure 3). KL‐VShet+ individuals exhibited attenuated entorhinal tau‐related FTP SUVR increases in fusiform and inferior temporal regions than the KL‐VShet‐ individuals (Figure 4).ConclusionAβ plaques and initial tau tangles may play different roles in tau replication and propagation in A+/T‐ and A+/T+ individuals, and may interact differently with age at prediction longitudinal tau accumulation. KL‐VShet may attenuated tau accumulation via modulating entorhinal tau‐related tau propagation. These findings may provide novel insights into understanding how tau tangles replicate and propagate in Temporal‐metaROI region at different stages of AD.
The interplay between functional MRI measures of episodic memory and CSF measures of tau in healthy adults at risk of Alzheimer’s Disease
Authors: Molloy Eóin N. , Binette Alexa Pichet , Marquardt Jonas , Remz Jordana , Kreißl Michael C. , Rosa‐Neto Pedro , Poirier Judes , Rajah Natasha , Villeneuve Sylvia , Maass Anne ,   Pre‐symptomatic Evaluation of Experimental or Novel Treatments for Alzheimer’s Disease (PREVENT‐AD) Research Group
Published: December 2022

AbstractBackgroundNeural changes occur early in Alzheimer’s disease (AD). Longitudinal data on the relationship between AD pathology and brain activity, however, are sparse. Using an established cohort of cognitively unimpaired older adults (PREVENT‐AD) at risk of AD (due to familial incidence), we assessed the relationship between functional magnetic resonance imaging (fMRI) activity during episodic memory retrieval and cerebrospinal fluid (CSF) markers of tau and β‐amyloid. We aimed to test whether baseline fMRI signal predicts changes in CSF markers and vice versa.MethodThree‐hundred and three participants (64.7±8.3yrs, 82 male) underwent task‐based fMRI of associative episodic memory retrieval at baseline, with longitudinal fMRI data for up to five timepoints with a 3, 12, 24, and 48‐month follow‐up. Region of Interest (ROI) analysis assessed retrieval activity (Fig.1A; t‐contrast differentiating hits for old stimuli from the correct rejection of new stimuli) in the bilateral precuneus and medial temporal lobe (MTL, Fig.1B‐1C). In a subset of participants (n = 117, 30 male), CSF was sampled to quantify t‐tau, p‐tau 181, and the ratio of β‐amyloid 1‐42 to p‐tau 181 (with another measurement 36‐months post‐baseline). Data were analyzed with random‐intercept linear mixed models, assessing changes in ROI activity and CSF markers over time. We tested whether baseline ROI activity predicted change in CSF markers and whether baseline CSF measures predicted change in ROI activity over time.ResultResults indicate a significant decrease in precuneus activity over time, but not MTL, and an increase in t‐tau and p‐tau 181 (Fig.2A‐2D). No change was observed for β‐amyloid/p‐tau 181 ratio. We also observed a significant time by baseline MTL activity interaction on t‐tau (Fig.3) with higher baseline activity being associated with lower t‐tau in CSF over time. We observed no relationship between baseline CSF markers and functional activity.ConclusionWhile preliminary, these results suggest that baseline MTL retrieval activity may predict t‐tau (a marker of neurodegeneration) accumulation in the CSF of healthy adults at risk of AD. Further analyses of whole‐brain episodic memory responses, episodic memory task‐performance over time, and of positron emission tomography (PET) measures of regional tau and β‐amyloid, are critical to extend these findings further.
Differential brain expression of 3R and 4R Tau isoforms in aging wild‐type and young genetically engineered PSEN1 mutant marmosets
Authors: Rizzo Stacey J Sukoff , Choi Sang‐Ho , Huhe Hasi , Kofler Julia , Schaeffer David , Murai Takeshi , Hachem Stephanie , Karavolis Marlena , Mou Yongshan , Ha Seung‐Kwon , Carter Gregory W , Park Jung Eun , Homanics Gregg E , Strick Peter L , Silva Afonso C 
Published: December 2022

AbstractBackgroundThe common marmoset (Callithrix jacchus) has emerged as an important model for studying Alzheimer’s disease (AD). Several previous publications reported the natural and spontaneous accumulation of Aβ aggregates in aging marmosets. However, the presentation of tau in aging marmosets has been understudied. A recent report investigated the expression of different tau isoforms and concluded that only 4R tau is expressed throughout adulthood (Sharma et al., J. Biol. Chem. 2019). Here, we investigated the presence of amyloid and tau aggregates in aged wild‐type marmosets and in young adult individuals genetically engineered with knock‐in (KI) point mutations in the PSEN1 gene that cause early‐onset AD.MethodWe used standard IHC protocols and western blotting techniques with validated antibodies for amyloid (NAB228) and tau (RD3, 3T3, PHF‐1) to investigate the presence and localization of AD aggregates in the brains of 5 marmosets (n = 3 wild‐type and 2 PSEN1 KI mutants).ResultWe observed the natural accumulation of amyloid aggregates with the anti‐amyloid antibody NAB228 in a 10‐year male marmoset that confirms this subject’s previous in vivo evaluation with 11C‐PiB PET imaging. Interestingly, this aged marmoset showed positive 3R and 4R tau staining with the anti‐tau antibodies RD3 and 3T3, respectively (Figure 1) in the hippocampus. In agreement with Sharma et al., 2019, tau staining in the hippocampus was much more abundant for the 4R than the 3R tau isoform, with substantial phosphorylation at Ser‐396 and Ser‐404. We detected no tau staining in the entorhinal cortex of this animal and no amyloid nor tau in the brain of a one‐year‐old juvenile. We observed similar results of significant amyloid accumulation and RD3 and 3T3 labeling in the brains of two young (18 months) PSEN1 KI mutants. Separately, we confirmed by western blot 3R and 4R tau isoforms in homogenates from the hippocampus and entorhinal cortex of three individual marmosets (aged 1‐7 years).ConclusionOur genetically diverse marmoset population of aging and PSEN1 mutation carriers present both 3R and 4R isoforms across the lifespan. These data further support marmosets as an ideal species for translational studies of AD. Studies in larger sample sizes are ongoing.
The expression levels of pro‐inflammatory and anti‐inflammatory cytokines and chemokines in blood serum of Alzheimer’s dementia patients: report from a pilot study in Kazakhstan
Authors: Kaiyrlykyzy Aiym , Zholdasbekova Gulnaz , Alzhanova Dinara , Olzhayev Farkhad , Baibulatova Aida , Tsoy Andrey , Askarova Sholpan 
Published: December 2022

AbstractBackgroundChronic peripheral inflammation is one of the critical factors contributing significantly to the development and progression of Alzheimer’s disease (AD). Human and animal studies strongly suggest that systemic inflammation, marked by changes in the peripheral profile of blood immune cells and blood levels of circulating pro‐inflammatory and anti‐inflammatory cytokines, can promote or even precede pro‐inflammatory conditions in the CNS. It has been reported that the levels of circulating pro‐inflammatory cytokines are increased while the levels of anti‐inflammatory cytokines are decreased in AD patients. However, despite increasing data supporting the association between abnormal peripheral inflammation and AD, no well‐established inflammatory biomarkers are currently available for AD. In this regards, we have studied an expanded spectrum of pro‐inflammatory and anti‐inflammatory cytokines and chemokines in the serum samples of the patients diagnosed with AD and compared them to those without cognitive impairment matched on age and gender.MethodsWe have simultaneously assayed cytokines and chemokines in the serum of AD patients (n=40) and normal controls (n=46) using MILLIPLEX Map Human Cytokine/Chemokine Magnetic Beas Panel on the Luminex xMAP technology according to the manufacturer’s protocol. The kit included the following 41 human cytokines and chemokines: EGF, IL‐12P70, IL‐13, IL‐15, IL‐17A, IL1RA, IP‐10, MCP‐1, MIP‐1α, MIP‐1β, RANTES, VEGF, FGF‐2, TGF‐α, FIT‐3L, Fractalkine, GRO, MCP‐3, MDC, PDGF‐AA, PDGF‐AB/BB, sCD40L, IL‐1α, IL‐1β, TNFα, G‐CSF, IFNγ, TNFβ, IL‐10, IL‐2, GM‐CSF, IL‐3, IL‐4, IL‐5, IL‐6, IL‐7, IL‐8, IL‐9, Eotaxin, IFNα2, and IL‐12P40.ResultsWe have found IL‐12P40, IL‐9, IL‐7, GM‐CSF, IL‐10, IFNγ, IL‐1α, MCP‐3, FIT‐3L, IL‐17A, IL‐13, IL‐15, and IL‐12P70 were significantly higher in Alzheimer’s patients compared to controls. At the same time, cognitively healthy controls had higher concentrations of PDGF‐AB/BB, PDGF‐AA, RANTES, and FGF‐2 in the peripheral blood. We observed significant positive correlation between C‐reactive protein and IP‐10 (r=0.5), IL1RA (r=0.3), PDGF‐AA (r=0.3), IL‐10 (r=0.3), GRO (r=0.4), GCSF (r=0.3), PDGF‐AB/BB (r=0.3).ConclusionStudying the expression levels of pro‐inflammatory and anti‐inflammatory cytokines and chemokines in the blood serum of Alzheimer’s dementia patients is of considerable interest since it can potentially contribute to the discovery of new blood‐based biomarkers for earlier diagnosis of AD and development of the personalized treatment strategies.
Modeling CNS neuronal‐glial interactions relevant to Alzheimer’s Disease and ADRD with microglia and neurons derived from human induced pluripotent stem cells
Authors: McDonough Patrick M. , Gordon Kara L. , Basa Ranor C. B. , Rines Christine G. , Rohn Troy T. , Price Jeffrey H. 
Published: December 2022

AbstractBackgroundCNS neurons and microglia participate in neuroimmune pathways linked to Alzheimer’s Disease (AD) and AD Related Dementias (ADRD). However, CNS neurons and microglia cannot be isolated from living people, and primary microglia harvested post‐mortem rapidly de‐differentiate in culture. hiPSC‐neurons and hiPSC‐MG represent a practical alternative for in vitro research, as they are human‐derived, upscalable, and can be made from people with AD/ADRD‐sensitive or ‐resilient genotypes. We are developing high‐throughput assays utilizing hiPSC‐neurons/‐MG, to explore interactions between these cell types and pathways relevant to AD, and to test compounds for beneficial effects on neuronal health.MethodhiPSC‐neurons (excitatory) were purchased from Fujifilm CDI or differentiated in‐house (with kits from Elixirgen). hiPSC‐MG were differentiated in‐house from hiPSCs via a protocol in which yolk sac‐like structures are produced as an intermediary step. Mono‐ or cocultures were prepared in 96‐ or 384‐well dishes. Results were obtained via automated digital microscopy, with cellular structures and biomarkers analyzed via high content analysis (HCA) and cell activity (calcium or voltage transients) analyzed via Kinetic Image Cytometry; in certain experiments, LDH release, a general measure of cytotoxicity, was also assayed.ResultCoculture of hiPSC‐MG with hiPSC‐neurons led to a 2‐fold increase in neurites. hiPSC‐MG also elicited calcium transients in the hiPSC‐neurons via close contact. The APOE‐e4 gene variant confers the greatest risk for late‐onset AD, and proteolysis of ApoE4 may produce neurotoxic fragments. In our hands, a fragment of ApoE4 (ApoECFp17, aa 1‐151) induced LDH release in both hiPSC‐neurons and hiPSC‐MG, indicating cytotoxicity, whereas the corresponding fragment of ApoE3 had no effect; additionally, the toxic effect on hiPSC‐MG was partially blocked by PH002 (an ApoE4 “structure corrector”) and by RAP (a protein that blocks ApoE4 binding to cell‐surface receptors).ConclusionOur data demonstrate that hiPSC‐MG alter neurite expression and calcium transient activity in cocultured hiPSC‐neurons, and that the aa 1‐151 fragment of ApoE4 is toxic to human neurons and microglia, which could potentially play a role in AD etiology. Future research will incorporate hiPSC‐astrocytes into the cultures to further model CNS neuronal‐glial interactions and elucidate pathways relevant to AD/ADRD.