Current Alzheimer research最新文献

{"title":"Childhood Maltreatment and Dementia Risk Factors in Midlife: A Prospective Investigation.","authors":"Cathy S Widom, Hang H Do, Kristin S Lynch, Jennifer J Manly","doi":"10.2174/0115672050281539231222071355","DOIUrl":"10.2174/0115672050281539231222071355","url":null,"abstract":"<p><strong>Background: </strong>Previous studies have linked childhood adversities to dementia risk, yet most studies are cross-sectional in design and utilize retrospective self-reports to assess childhood experiences. These design characteristics make it difficult to establish temporal order and draw firm conclusions.</p><p><strong>Objectives: </strong>Using a longitudinal design, we sought to determine whether childhood maltreatment predicts dementia risk factors in middle adulthood.</p><p><strong>Methods: </strong>Data have been obtained from a prospective cohort design study of children with documented cases of childhood maltreatment (ages 0-11 years at case identification) and demographically matched controls who were followed up and interviewed in middle adulthood. Outcomes were assessed through a medical examination and interview, and 807 of the cases that included blood collection at mean age 41. Dementia risk were investigated using 11 potentially modifiable risk factors.</p><p><strong>Results: </strong>Compared to controls, individuals with histories of childhood maltreatment had a higher risk of low educational attainment, low social contact, smoking, and clinical depression, and a higher total number of dementia risk factors. In general, childhood maltreatment predicted a higher risk of dementia for females, males, and Black and White participants. Black maltreated participants had a greater risk for traumatic brain injury compared to Black controls. Physical abuse, sexual abuse, and neglect, each predicted a higher number of dementia risk factors in mid-life.</p><p><strong>Conclusion: </strong>These findings provide evidence that childhood maltreatment increases the risk for dementia in mid-life and has a demonstrable impact lasting over 30 years. Reducing the prevalence of mid-life dementia risk factors could reduce the risk of later-life dementia.</p>","PeriodicalId":94309,"journal":{"name":"Current Alzheimer research","volume":" ","pages":"636-647"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139059402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and Optimization of a Target Engagement Model of Brain IDO Inhibition for Alzheimer's Disease.","authors":"Kurt R Stover, Paul M Stafford, Andreea C Damian, Jagadeesh P Pasangulapati, Jake Goodwin-Tindall, Lucía M López Vásquez, Sanghyun Lee, Seung-Pil Yang, Mark A Reed, Christopher J Barden, Donald F Weaver","doi":"10.2174/0115672050283199240111111801","DOIUrl":"10.2174/0115672050283199240111111801","url":null,"abstract":"<p><strong>Background: </strong>Indoleamine 2,3-dioxygenase (IDO1) inhibition is a promising target as an Alzheimer's disease (AD) Disease-modifying therapy capable of downregulating immunopathic neuroinflammatory processes.</p><p><strong>Methods: </strong>To aid in the development of IDO inhibitors as potential AD therapeutics, we optimized a lipopolysaccharide (LPS) based mouse model of brain IDO1 inhibition by examining the dosedependent and time-course of the brain kynurenine:tryptophan (K:T) ratio to LPS via intraperitoneal dosing.</p><p><strong>Results: </strong>We determined the optimal LPS dose to increase IDO1 activity in the brain, and the ideal time point to quantify the brain K:T ratio after LPS administration. We then used a brain penetrant tool compound, EOS200271, to validate the model, determine the optimal dosing profile and found that a complete rescue of the K:T ratio was possible with the tool compound.</p><p><strong>Conclusion: </strong>This LPS-based model of IDO1 target engagement is a useful tool that can be used in the development of brain penetrant IDO1 inhibitors for AD. A limitation of the present study is the lack of quantification of potential clinically relevant biomarkers in this model, which could be addressed in future studies.</p>","PeriodicalId":94309,"journal":{"name":"Current Alzheimer research","volume":" ","pages":"705-714"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139577200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Follow-up Comparisons of Two Plasma Biomarkers of Alzheimer's Disease, Neurofilament Light Chain, and Oligomeric Aβ: A Pilot Study.","authors":"YongSoo Shim","doi":"10.2174/0115672050284054240119101834","DOIUrl":"10.2174/0115672050284054240119101834","url":null,"abstract":"<p><strong>Background and objective: </strong>Recent evidence suggests that blood-based biomarkers might be useful for Alzheimer's disease (AD). Among them, we intend to investigate whether neurofilament light (NfL) and multimer detection system-oligomeric Aβ (MDS-OAβ) values can be useful in screening, predicting, and monitoring disease progression and how the relationship between NfL and MDS-OAβ values changes.</p><p><strong>Methods: </strong>Eighty participants with probable AD dementia, 50 with mild cognitive impairment (MCI), and 19 with subjective cognitive decline (SCD) underwent baseline and follow-up evaluations of the Mini-Mental Status Examination (MMSE) and both plasma biomarkers.</p><p><strong>Results: </strong>Baseline MDS-OAß (p = 0.016) and NfL (p = 0.002) plasma concentrations differed significantly among groups, but only NfL correlated with baseline MMSE scores (r = -0.278, p = 0.001). In follow-up, neither correlated with MMSE changes overall. However, in SCD and MCI participants (n = 32), baseline MDS-OAß correlated with follow-up MMSE scores (r = 0.532, p = 0.041). Linear regression revealed a relationship between baseline MDS-OAβ and follow-up MMSE scores. In SCD and MCI participants, plasma NfL changes correlated with MMSE changes (r = 0.564, p = 0.028).</p><p><strong>Conclusion: </strong>This study shows that only in participants with SCD and MCI, not including AD dementia, can MDS-OAß predict the longitudinal cognitive decline measured by follow-up MMSE. Changes of NfL, not MDS-OAß, parallel the changes of MMSE. Further studies with larger samples and longer durations could strengthen these results..</p>","PeriodicalId":94309,"journal":{"name":"Current Alzheimer research","volume":" ","pages":"715-724"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139652503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blood Biomarkers Discriminate Cerebral Amyloid Status and Cognitive Diagnosis when Collected with ACD-A Anticoagulant.","authors":"Zachary D Green, Paul J Kueck, Casey S John, Jeffrey M Burns, Jill K Morris","doi":"10.2174/0115672050271523231111192725","DOIUrl":"10.2174/0115672050271523231111192725","url":null,"abstract":"<p><strong>Background: </strong>The development of biomarkers that are easy to collect, process, and store is a major goal of research on current Alzheimer's Disease (AD) and underlies the growing interest in plasma biomarkers. Biomarkers with these qualities will improve diagnosis and allow for better monitoring of therapeutic interventions. However, blood collection strategies have historically differed between studies. We examined the ability of various ultrasensitive plasma biomarkers to predict cerebral amyloid status in cognitively unimpaired individuals when collected using acid citrate dextrose (ACD). We then examined the ability of these biomarkers to predict cognitive impairment independent of amyloid status.</p><p><strong>Methods: </strong>Using a cross-sectional study design, we measured amyloid beta 42/40 ratio, pTau-181, neurofilament-light, and glial fibrillary acidic protein using the Quanterix Simoa® HD-X platform. To evaluate the discriminative accuracy of these biomarkers in determining cerebral amyloid status, we used both banked plasma and 18F-AV45 PET cerebral amyloid neuroimaging data from 140 cognitively unimpaired participants. We further examined their ability to discriminate cognitive status by leveraging data from 42 cognitively impaired older adults. This study is the first, as per our knowledge, to examine these specific tests using plasma collected using acid citrate dextrose (ACD), as well as the relationship with amyloid PET status.</p><p><strong>Results: </strong>Plasma AB42/40 had the highest AUC (0.833, 95% C.I. 0.767-0.899) at a cut-point of 0.0706 for discriminating between the two cerebral amyloid groups (sensitivity 76%, specificity 78.5%). Plasma NFL at a cut-point of 20.58pg/mL had the highest AUC (0.908, 95% CI 0.851- 0.966) for discriminating cognitive impairment (sensitivity 84.8%, specificity 89.9%). The addition of age and apolipoprotein e4 status did not improve the discriminative accuracy of these biomarkers.</p><p><strong>Conclusion: </strong>Our results suggest that the Aβ42/40 ratio is useful in discriminating clinician-rated elevated cerebral amyloid status and that NFL is useful for discriminating cognitive impairment status. These findings reinforce the growing body of evidence regarding the general utility of these biomarkers and extend their utility to plasma collected in a non-traditional anticoagulant.</p>","PeriodicalId":94309,"journal":{"name":"Current Alzheimer research","volume":" ","pages":"557-566"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10792989/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138479958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Online Shared Decision-making Intervention for Dementia Prevention: A Parallel-group Randomized Pilot Study.","authors":"Raymond L Ownby, Rosemary Davenport","doi":"10.2174/0115672050274126231120112158","DOIUrl":"10.2174/0115672050274126231120112158","url":null,"abstract":"<p><strong>Objectives: </strong>Evaluate the acceptability and efficacy of an online dementia prevention intervention based on a cognitive behavioral shared decision-making model.</p><p><strong>Materials and methods: </strong>This was an unblinded pilot study in which participants were randomly assigned to one of two treatment groups. This study was carried out remotely via telephone, video conferencing, and online data collection. Eighteen English-speaking persons 40 years of age and older interested in developing more brain-healthy lifestyles. Both groups received 12 weekly sessions on lifestyle factors related to cognitive decline. The treatment-as-usual (TAU) group received the information and was encouraged to make lifestyle changes. The cognitive behavioral shared decision- making model (CBSDM) group received structured weekly sessions with support for evidence- informed personal goal choices and behavior change strategies. Primary outcome measures were the Alzheimer's Disease Risk Inventory and the Memory Self-Efficacy and Dementia Knowledge Assessment Scales. Participants reported brain health activities during the first, sixth, and 12th weeks of the study.</p><p><strong>Results: </strong>No significant between-group changes were seen in the three primary outcome measures. The intervention was viewed positively by participants, who all said they would participate in it again. Participants in the CBSDM group showed increases in knowledge of dementia risk factors and exercise. Other outcomes were consistent with moderate to large effect sizes for both groups.</p><p><strong>Conclusion: </strong>An online intervention providing psychoeducation and behavior change support was viewed positively by older adults. Results provide preliminary support for the CBSDM intervention's efficacy in promoting brain health in older adults.</p><p><strong>Clinical trial registration number: </strong>NCT04822129.</p>","PeriodicalId":94309,"journal":{"name":"Current Alzheimer research","volume":" ","pages":"577-587"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138479957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microglia <i>PTK2B</i>/Pyk2 in the Pathogenesis of Alzheimer's Disease.","authors":"Yun Guo, Cheng-Kun Sun, Lian Tang, Meng-Shan Tan","doi":"10.2174/0115672050299004240129051655","DOIUrl":"10.2174/0115672050299004240129051655","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a highly hereditary disease with complex genetic susceptibility factors. Extensive genome-wide association studies have established a distinct susceptibility link between the protein tyrosine kinase 2β (<i>PTK2B</i>) gene and late-onset Alzheimer's disease (LOAD), but the specific pathogenic mechanisms remain incompletely understood. <i>PTK2B</i> is known to be expressed in neurons, and recent research has revealed its more important significance in microglia. Elucidating the role of <i>PTK2B</i> high expression in microglia in AD's progression is crucial for uncovering novel pathogenic mechanisms of the disease. Our review of existing studies suggests a close relationship between <i>PTK2B</i>/proline-rich tyrosine kinase 2 (Pyk2) and tau pathology, and this process might be β-amyloid (Aβ) dependence. Pyk2 is hypothesized as a pivotal target linking Aβ and tau pathologies. Concurrently, Aβ-activated Pyk2 participates in the regulation of microglial activation and its proinflammatory functions. Consequently, it is reasonable to presume that Pyk2 in microglia contributes to amyloid-induced tau pathology in AD via a neuroinflammatory pathway. Furthermore, many things remain unclear, such as identifying the specific pathways that lead to the release of downstream inflammatory factors due to Pyk2 phosphorylation and whether all types of inflammatory factors can activate neuronal kinase pathways. Additionally, further in vivo experiments are essential to validate this hypothesized pathway. Considering <i>PTK2B</i>/Pyk2's potential role in AD pathogenesis, targeting this pathway may offer innovative and promising therapeutic approaches for AD.</p>","PeriodicalId":94309,"journal":{"name":"Current Alzheimer research","volume":" ","pages":"692-704"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139699223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antipsychotics in Alzheimer's Disease: Current Status and Therapeutic Alternatives.","authors":"Maria Paula Maziero, Natalia P Rocha, Antonio L Teixeira","doi":"10.2174/0115672050287534240215052417","DOIUrl":"10.2174/0115672050287534240215052417","url":null,"abstract":"<p><p>Psychosis and hyperactive behaviors, such as agitation and wandering, affect a significant proportion of patients with Alzheimer's disease (AD). These symptoms are often treated with antipsychotics, usually in an off-label approach. This mini-review provides an updated perspective on the pharmacological approach for the neuropsychiatric symptoms (NPS) in AD. The results of new studies have provided a better understanding of AD-related NPS management, but high-quality evidence still needs to be obtained. Herein, we argue for a more cautious approach to the use of antipsychotics in AD and highlight the importance of exploring alternative treatments for NPS. By doing so, we can ensure that patients with AD receive optimal care that is both effective and safe.</p>","PeriodicalId":94309,"journal":{"name":"Current Alzheimer research","volume":" ","pages":"682-691"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139975344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Accuracy of Telephone-Based Cognitive Screening Tests: Systematic Review and Meta-Analysis","authors":"E. Elliott","doi":"10.2174/15672050mta3qnjgj4","DOIUrl":"https://doi.org/10.2174/15672050mta3qnjgj4","url":null,"abstract":"","PeriodicalId":94309,"journal":{"name":"Current Alzheimer research","volume":" 620","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141218925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Withdrawn: Biomarkers in Alzheimer's Disease-Recent Update.","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Article Withdrawn</p>","PeriodicalId":94309,"journal":{"name":"Current Alzheimer research","volume":" ","pages":"None"},"PeriodicalIF":0.0,"publicationDate":"2017-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139975347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PERK-opathies: An Endoplasmic Reticulum Stress Mechanism Underlying Neurodegeneration.","authors":"Michelle C Bell,&nbsp;Shelby E Meier,&nbsp;Alexandria L Ingram,&nbsp;Jose F Abisambra","doi":"10.2174/1567205013666151218145431","DOIUrl":"https://doi.org/10.2174/1567205013666151218145431","url":null,"abstract":"<p><p>The unfolded protein response (UPR) plays a vital role in maintaining cell homeostasis as a consequence of endoplasmic reticulum (ER) stress. However, prolonged UPR activity leads to cell death. This time-dependent dual functionality of the UPR represents the adaptive and cytotoxic pathways that result from ER stress. Chronic UPR activation in systemic and neurodegenerative diseases has been identified as an early sign of cellular dyshomeostasis. The Protein Kinase R-like ER Kinase (PERK) pathway is one of three major branches in the UPR, and it is the only one to modulate protein synthesis as an adaptive response. The specific identification of prolonged PERK activity has been correlated with the progression of disorders such as diabetes, Alzheimer's disease, and cancer, suggesting that PERK plays a role in the pathology of these disorders. For the first time, the term \"PERK-opathies\" is used to group these diseases in which PERK mediates detriment to the cell culminating in chronic disorders. This article reviews the literature documenting links between systemic disorders with the UPR, but with a specific emphasis on the PERK pathway. Then, articles reporting links between the UPR, and more specifically PERK, and neurodegenerative disorders are presented. Finally, a therapeutic perspective is discussed, where PERK interventions could be potential remedies for cellular dysfunction in chronic neurodegenerative disorders. </p>","PeriodicalId":94309,"journal":{"name":"Current Alzheimer research","volume":"13 2","pages":"150-63"},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542591/pdf/nihms-1025111.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41224631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}