Alzheimer's Research & Therapy最新文献

{"title":"Brain derived β-interferon is a potential player in Alzheimer's disease pathogenesis and cognitive impairment.","authors":"Qiong Wang, Shufen Yuan, Chenxi Wang, Duntao Huang, Mengguo Zhang, Yaxi Zhan, Feng Gao, Jiong Shi, Allan I Levey, Yong Shen","doi":"10.1186/s13195-024-01644-z","DOIUrl":"https://doi.org/10.1186/s13195-024-01644-z","url":null,"abstract":"<p><strong>Background: </strong>Recent research has postulated that the activation of cGAS-STING-interferon signalling pathways could be implicated in the pathogenesis of Alzheimer's disease (AD). However, the precise types of interferons and related cytokines, both from the brain and periphery, responsible for cognitive impairment in patients with AD remain unclear.</p><p><strong>Methods: </strong>A total of 131 participants (78 [59.5%] female and 53 [40.5%] male; mean [SD] age, 61.5 [7.6] years) with normal cognition and cognitive impairment from the China Aging and Neurodegenerative Initiative cohort were included. CSF and serum IFNα-2a, IFN-β, IFN-γ, TNF-α, IL-6, IL-10, MCP-1and CXCL-10 were tested. The correlation between these interferons and related cytokines with AD core biomarkers in the CSF and plasma, cognition performance, and brain MRI measures were analysed.</p><p><strong>Results: </strong>We found that only CSF IFN-β levels were significantly elevated in Alzheimer's disease compared to normal cognition. Furthermore, CSF IFN-β levels were significantly associated with AD core biomarkers (CSF P-tau and Aβ42/Aβ40 ratio) and cognitive performance (MMSE and CDR score). Additionally, the CSF IFN-β levels were significantly correlated with the typical pattern of brain atrophy in AD (such as hippocampus, amygdala, and precuneus). In contrast, CSF IL-6 levels were significantly elevated in non-AD cognitively impaired patients compared to other groups. Moreover, CSF IL-6 levels were significantly associated with cognitive performance in non-AD individuals and correlated with the vascular cognitive impairment-related MRI markers (such as white matter hyperintensity).</p><p><strong>Conclusion: </strong>Our findings demonstrate that distinct inflammatory molecules are associated with different cognitive disorders. Notably, CSF IFN-β levels are significantly linked to the pathology and cognitive performance of AD, identifying this interferon as a potential target for AD therapy.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"271"},"PeriodicalIF":7.9,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142870817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cognitive decline profiles associated with lewy pathology in the context of Alzheimer's disease neuropathologic change.","authors":"Jon B Toledo, David P Salmon, Melissa J Armstrong, Douglas Galasko","doi":"10.1186/s13195-024-01628-z","DOIUrl":"https://doi.org/10.1186/s13195-024-01628-z","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease neuropathologic change (ADNC) and Lewy pathology (LP) often coexist in cognitively impaired individuals. These pathologies' relative distribution and severity may modify these individuals' clinical presentation, cognitive profile, and prognosis. Therefore, we examined the contributions of LP and concomitant ADNC to disease survival and profiles of cognitive decline in preclinical and clinical stages in a large neuropathologically diagnosed group.</p><p><strong>Methods: </strong>We evaluated 597 participants with LP and 491 participants with intermediate/high ADNC in the absence of LP from the National Alzheimer Coordinating Center (NACC) database. At baseline, 237 participants were cognitively normal (CN), 255 were diagnosed with mild cognitive impairment (MCI), and 596 with dementia. Cognition was assessed using three cognitive domain scores (i.e., Memory, Executive, and Language) from the NACC Uniform Dataset (UDS) neuropsychological test battery, MMSE, and Clinical Dementia Rating (CDR). Multivariate adaptive regression splines were used to evaluate associations between baseline cognitive scores and mean annual rate of change over two years. The likelihood of progression to MCI or dementia was assessed using Cox hazard models.</p><p><strong>Results: </strong>Neocortical LP, independent of the clinical diagnosis, was associated with lower Executive and higher Language and Memory scores at baseline, whereas Braak V-VI neurofibrillary tangle pathology was associated with lower Memory and Language scores. Similarly, neocortical LP was associated with faster Executive decline, whereas Braak V-VI neurofibrillary tangle pathology was associated with faster Memory and Language decline. A clinical diagnosis of Lewy Body Dementia (i.e., a strong LP phenotype) was associated with the LP cognitive profile and shorter disease duration. Progression to incident MCI or dementia was primarily associated with the degree of tau pathology; neocortical LP or a diagnosis of Lewy Body Dementia only predicted progression when those with intermediate/high ADNC were excluded.</p><p><strong>Conclusions: </strong>LP and ADNC differentially affected cross-sectional and longitudinal cognitive profiles in a large autopsy sample. Concomitant Braak V-VI neurofibrillary tangle pathology had a strong impact on clinical progression in those with LP, regardless of the initial stage. Thus, LB and ADNC co-pathology interact to affect cognitive domains that may be used to track Lewy Body disease longitudinally and as outcome measures in therapeutic trials.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"270"},"PeriodicalIF":7.9,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142870853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of critically short telomeres with brain and blood markers of ageing and Alzheimer's disease in older adults.","authors":"Asrar Lehodey, Perla Kaliman, Cassandre Palix, Robin de Florès, Edelweiss Touron, Anne-Laure Turpin, Séverine Fauvel, Florence Mézenge, Brigitte Landeau, Anne Chocat, Agathe Vrillon, Claire Paquet, Denis Vivien, Vincent de La Sayette, Gaël Chételat, Géraldine Poisnel","doi":"10.1186/s13195-024-01635-0","DOIUrl":"10.1186/s13195-024-01635-0","url":null,"abstract":"<p><strong>Background: </strong>Accumulation of critically short telomeres (CST) is implicated in decreased tissular regenerative capacity and increased susceptibility to degenerative diseases such as Alzheimer's disease (AD). Telomere shortening has also been associated with age-related brain changes. However, it remains unclear whether CST accumulation is directly associated with AD markers or instead amplifies age-related effects, potentially increasing susceptibility of developing AD in cognitively healthy older adults.</p><p><strong>Methods: </strong>This cross-sectional study used baseline data of 129 community-dwelling cognitively healthy older adults from the Age-Well trial (NCT02977819), aged 65 years and older enrolled between 2016 and 2018, in France. Using linear regressions, we analyzed the relationship between an innovative marker of telomere shortening, the percentage of CST (%CST), structural, functional and molecular neuroimaging outcomes, and multiple blood-based biomarkers related to AD pathophysiology. The effect of apolipoprotein E ε4 genotype (APOE4) was assessed on these relationships using interaction analysis.</p><p><strong>Results: </strong>A higher %CST was associated with lower global kurtosis fractional anisotropy (β = -.230; P = .010), particularly in frontal and temporal regions. A higher %CST was also related to higher plasma levels of Neurofilament light chain (β = .195; P = .020) and a lower subiculum volume (β = -.206; P = .020), although these associations did not meet the threshold for multiple comparisons. %CST was not associated with AD-related neuroimaging markers, including the AD-sensitive gray matter pattern (β = -.060; P = .441), glucose metabolism pattern (β = -.099; P = .372), brain perfusion pattern (β = -.106; P = .694) or hippocampus volume (β = -.106; P = .194). In APOE4 carriers, higher %CST was associated with lower subiculum (β = -.423; P = 0.003), DG (β = -.410; P = 0.018) and CA1 volumes (β = -.373; P = 0.024), even though associations with DG and CA1 volumes did not survive multiple comparison.</p><p><strong>Conclusions: </strong>Although an increase in %CST does not appear to be directly linked to the pathophysiology of AD in cognitively healthy older adults, it could heighten the susceptibility of APOE4 carriers to develop AD plausibly due to greater vulnerability to age-related effects. However, longitudinal studies would be necessary to determine whether %CST influences the development and progression of AD later in life.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"269"},"PeriodicalIF":7.9,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142870752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Longitudinal trajectory of plasma p-tau217 in cognitively unimpaired subjects.","authors":"Francisco Martínez-Dubarbie, Armando Guerra-Ruiz, Sara López-García, Carmen Lage, Marta Fernández-Matarrubia, Ana Pozueta-Cantudo, María García-Martínez, Andrea Corrales-Pardo, María Bravo, Marcos López-Hoyos, Juan Irure-Ventura, Enrique Marco de Lucas, Marta Drake-Pérez, María Teresa García-Unzueta, Pascual Sánchez-Juan, Eloy Rodríguez-Rodríguez","doi":"10.1186/s13195-024-01642-1","DOIUrl":"https://doi.org/10.1186/s13195-024-01642-1","url":null,"abstract":"<p><strong>Background: </strong>The advent of Alzheimer's disease-modifying drugs requires accurate biological diagnosis to identify candidates for these therapies. So far, the most promising single plasma biomarker is phosphorylated tau at threonine 217 (p-tau217). To understand its biological features, it is essential to know its longitudinal trajectory and factors influencing it in cognitively unimpaired subjects with no brain pathology.</p><p><strong>Methods: </strong>We analyzed longitudinal plasma p-tau217 values (mean follow-up time = 768.3 days) in a cohort of 209 healthy volunteers. We have studied factors associated with plasma p-tau217 changes by using different linear mixed-effects models.</p><p><strong>Results: </strong>In amyloid-negative cognitively healthy subjects (n = 151) carriers of ApoE ε4 allele had significantly higher p-tau217 values than non-carriers (0.85 pg/mL; p-value < 0.001) and also a greater rate of change (0.01 pg/mL/year; p-value < 0.001). In the overall sample, including subjects with amyloid and tau pathology we have seen that amyloid positive subjects had higher predicted baseline plasma p-tau217 values than amyloid negative subjects (0.16 pg/mL; p-value < 0.001) and a greater rate of change (0.00004 pg/mL/day; p-value < 0.001). Subjects considered tau positive also showed a greater rate of change of p-tau217 with respect to tau negative (0.00005 pg/mL/day; p-value < 0.001). A + T + N + participants showed a higher baseline p-tau217 levels than A-T-N- subjects (0.2 pg/mL; p-value < 0.001) and also a greater rate of change (0.00006 pg/mL/day; p-value = 0.002). ApoE ε4 carriers had a greater rate of change than non-carriers (0.00003 pg/mL/day; p-value = 0.03).</p><p><strong>Conclusion: </strong>In amyloid-negative cognitively unimpaired subjects, ApoE4 status influenced both baseline levels and rate of change of plasma p-tau217. Other factors such as age, sex or glomerular filtration rate have not shown significant influence on plasma p-tau217 levels in this group.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"268"},"PeriodicalIF":7.9,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural and functional alterations of neurons derived from sporadic Alzheimer's disease hiPSCs are associated with downregulation of the LIMK1-cofilin axis.","authors":"Raimondo Sollazzo, Domenica Donatella Li Puma, Giuseppe Aceto, Fabiola Paciello, Claudia Colussi, Maria Gabriella Vita, Guido Maria Giuffrè, Francesco Pastore, Alessia Casamassa, Jessica Rosati, Agnese Novelli, Sabrina Maietta, Francesco Danilo Tiziano, Camillo Marra, Cristian Ripoli, Claudio Grassi","doi":"10.1186/s13195-024-01632-3","DOIUrl":"https://doi.org/10.1186/s13195-024-01632-3","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by the accumulation of pathological proteins and synaptic dysfunction. This study aims to investigate the molecular and functional differences between human induced pluripotent stem cells (hiPSCs) derived from patients with sporadic AD (sAD) and age-matched controls (healthy subjects, HS), focusing on their neuronal differentiation and synaptic properties in order to better understand the cellular and molecular mechanisms underlying AD pathology.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Skin fibroblasts from sAD patients (n = 5) and HS subjects (n = 5) were reprogrammed into hiPSCs using non-integrating Sendai virus vectors. Through karyotyping, we assessed pluripotency markers (OCT4, SOX2, TRA-1-60) and genomic integrity. Neuronal differentiation was evaluated by immunostaining for MAP2 and NEUN. Electrophysiological properties were measured using whole-cell patch-clamp, while protein expression of Aβ, phosphorylated tau, Synapsin-1, Synaptophysin, PSD95, and GluA1 was quantified by western blot. We then focused on PAK1-LIMK1-Cofilin signaling, which plays a key role in regulating synaptic structure and function, both of which are disrupted in neurodegenerative diseases such as AD.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;sAD and HS hiPSCs displayed similar stemness features and genomic stability. However, they differed in neuronal differentiation and function. sAD-derived neurons (sAD-hNs) displayed increased levels of AD-related proteins, including Aβ and phosphorylated tau. Electrophysiological analyses revealed that while both sAD- and HS-hNs generated action potentials, sAD-hNs exhibited decreased spontaneous synaptic activity. Significant reductions in the expression of synaptic proteins such as Synapsin-1, Synaptophysin, PSD95, and GluA1 were found in sAD-hNs, which are also characterized by reduced neurite length, indicating impaired differentiation. Notably, sAD-hNs demonstrated a marked reduction in LIMK1 phosphorylation, which could be the underlying cause for the changes in cytoskeletal dynamics that we found, leading to the morphological and functional modifications observed in sAD-hNs. To further investigate the involvement of the LIMK1 pathway in the morphological and functional changes observed in sAD neurons, we conducted perturbation experiments using the specific LIMK1 inhibitor, BMS-5. Neurons obtained from healthy subjects treated with the inhibitor showed similar morphological changes to those observed in sAD neurons, confirming that LIMK1 activity is crucial for maintaining normal neuronal structure. Furthermore, administration of the inhibitor to sAD neurons did not exacerbate the morphological alterations, suggesting that LIMK1 activity is already compromised in these cells.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;Our findings demonstrate that although sAD- and HS-hiPSCs are similar in their stemness and genomic stability, sAD-hNs exhibit dis","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"267"},"PeriodicalIF":7.9,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of gender on the willingness to participate in clinical trials and undergo related procedures in individuals from an Alzheimer's prevention research cohort.","authors":"Lidia Canals-Gispert, Alba Cañas-Martínez, Gema Huesa, Marc Suárez-Calvet Alomà, Marta Milà-Alomà, Eider Arenaza-Urquijo, Davide Cirillo, Annemarie Schumacher Dimech, Maria Florencia Iulita, Julie Novakova Martinkova, Maria Carmela Tartaglia, Frances-Catherine Quevenco, Antonella Santuccione Chadha, Gonzalo Sánchez-Benavides, Carolina Minguillón, Maria Teresa Ferretti, Karine Fauria, Anna Brugulat-Serrat","doi":"10.1186/s13195-024-01626-1","DOIUrl":"https://doi.org/10.1186/s13195-024-01626-1","url":null,"abstract":"<p><strong>Background: </strong>Although there is growing evidence of the association between gender and early diagnosis of preclinical Alzheimer's disease, little attention has been given to the enrolment ratio of men and women in clinical trials and data reporting.</p><p><strong>Methods: </strong>This study aims to analyze gender differences in sociodemographic factors associated with the willingness to participate in clinical trials and undergo specific procedures in the context of an Alzheimer's disease prevention research cohort. 2544 cognitively unimpaired participants from the ALFA parent cohort (age 45-75 years) of the Barcelonaβeta Brain Research Center were contacted through a structured phone call to determine their willingness to participate in Alzheimer's disease clinical trials and undergo trial-related procedures (magnetic resonance imaging, lumbar puncture, positron emission tomography, and cognitive assessment). Sociodemographic data on education, occupational attainment, civil and caregiver status were gathered. Stepwise logistic regression models were performed in order to study the interaction between gender and sociodemographic factors in the willingness to participate in clinical trials and to undergo clinical trial-related procedures.</p><p><strong>Results: </strong>1,606 out of the 2,544 participants were women (63.1%). Women were significantly younger and had lower educational attainment compared with men. In addition, women were more likely to be caregivers, single and unemployed. Women showed a significantly lower willingness than men to participate in a clinical trial (p = 0.003) and to undergo a lumbar puncture (p < 0.001). Single women were less willing to participate in clinical trials than single men (p = 0.041). Regarding clinical trial-related procedures, women with higher years of education were significantly less willing to undergo a lumbar puncture (p = 0.031).</p><p><strong>Conclusion: </strong>We found gender differences regarding the sociodemographic factors that predict the willingness to participate in clinical trials and to undergo clinical trial-related procedures. Our results highlight the urgent need to design recruitment strategies accounting for gender-related factors, particularly those related to marital status and education.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"263"},"PeriodicalIF":7.9,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intracerebral hemorrhage following mild ARIA-H in an APOE ε2 carrier receiving lecanemab.","authors":"Sung Ji, Michael Rosenbloom","doi":"10.1186/s13195-024-01640-3","DOIUrl":"https://doi.org/10.1186/s13195-024-01640-3","url":null,"abstract":"<p><strong>Objective: </strong>Report a case of an apolipoprotein E (APOE)ε2 carrier receiving lecanemab who developed late onset intracerebral hemorrhage (ICH) following amyloid-related imaging abnormalities-hemorrhage (ARIA-H).</p><p><strong>Method: </strong>We detail the history and neuroimaging findings of a 73-year-old male with Alzheimer's disease (APOEε2/ε3 status) who developed ICH after mild ARIA-H and suffering a fall.</p><p><strong>Results: </strong>The patient developed mild ARIA-H after his 13th infusion that was proceeded by left temporo-occipital hemorrhage following his 14th infusion.</p><p><strong>Discussion: </strong>Although APOE ε2 is known to be protective against Alzheimer's disease, it has also been shown to increase risk for hemorrhage with cerebral amyloid angiopathy. This case serves as an opportunity to examine the complex role that APOE ε2 plays in both protection against Alzheimer's disease and contribution to increased hemorrhagic risk with lecanemab.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"265"},"PeriodicalIF":7.9,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response to Schmidt et al.: Lower activity of cholesteryl ester transfer protein (CETP) and the risk of dementia: a Mendelian randomization analysis.","authors":"Emma L Anderson","doi":"10.1186/s13195-024-01631-4","DOIUrl":"https://doi.org/10.1186/s13195-024-01631-4","url":null,"abstract":"<p><p>A recent paper concluded that cholesteryl ester transfer protein (CETP) inhibition may be a viable target to treat dementia, based on human genetic evidence of a protective effect of target inhibition on risk of Lewy body and Parkinson's dementia. Alzheimer's disease, which is by far the most prevalent cause of dementia (around 80% of all dementia cases) was not included as an outcome. Evidence shows CETP inhibition is unlikely to affect Alzheimer's risk and may even potentially modestly increase risk. There is also little evidence to support an effect of CETP inhibition on all-cause or vascular dementia. Thus, CETP inhibition is unlikely to be a viable target to treat the most prevalent causes of dementia.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"264"},"PeriodicalIF":7.9,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analytical and clinical performance of eight Simoa^® and Lumipulse^® assays for automated measurement of plasma p-tau181 and p-tau217.","authors":"Anna L Wojdała, Jeroen Vanbrabant, Sherif Bayoumy, Daniel Antwi-Berko, Nathalie Le Bastard, Wiesje M van der Flier, Andreas Jeromin, Charlotte Lambrechts, Maxime Van Loo, Manu Vandijck, Erik Stoops, Inge M W Verberk, Charlotte E Teunissen","doi":"10.1186/s13195-024-01630-5","DOIUrl":"https://doi.org/10.1186/s13195-024-01630-5","url":null,"abstract":"<p><strong>Background: </strong>Among the Alzheimer's disease (AD) biomarkers measured in blood, phosphorylated forms of tau (p-tau) have been shown to exhibit a particularly high diagnostic potential. Here, we performed a comprehensive method comparison study, followed by evaluation of the diagnostic performance of eight recent plasma p-tau immunoassays targeting different tau phosphorylation sites, different tau fragments, and that are measured by two distinct platforms.</p><p><strong>Methods: </strong>We enrolled a cohort of 40 patients with AD at the stage of dementia (AD-dem) characterized by positive CSF A + T + profile, and a control group of 40 cognitively healthy participants (Control), to conduct a comprehensive method comparison for three plasma p-tau181 and five plasma p-tau217 assays run on the Simoa^® HD-X™ or Lumipulse^® G600II/G1200 platforms. Design of the compared assays differed in regard to: (1) tau phosphorylation site targeted by the capture antibody (T181 or T217), and (2) epitope of the pan-tau detector antibody (N-terminal or mid-region). For each of the assays we determined precision and analytical sensitivity parameters and used Passing-Bablok regression and Bland-Altman plots for pairwise comparison of p-tau181 or p-tau217 assays. Subsequently, we evaluated the diagnostic accuracy of all the assays for discrimination between AD-dem and Control groups.</p><p><strong>Results: </strong>We found a strong, positive correlation between all the measurements. Fixed and/or proportional bias was observed for each of compared p-tau181 assay pairs or p-tau217 assay pairs. While both plasma p-tau181 and p-tau217 levels were significantly increased in AD-dem vs. Control groups as measured by all assays, higher median concentration AD-dem/Control fold change and AUC values were observed for p-tau217 (assays range: fold change 3.72-6.74, AUC 0.916-0.956) compared with p-tau181 (assays range 1.81-2.94, AUC 0.829-0.909), independently of the platform used. No significant differences were observed between diagnostic performance of p-tau181 assays or p-tau217 assays targeting tau N-terminus or mid-region.</p><p><strong>Conclusions: </strong>Although all plasma p-tau measurements enabled discrimination between clinical groups, p-tau217 assays showed the highest robustness, independently of the pan-tau detector antibody targeting N-terminal or mid-region, and independently of the platform used. Considering the observed method disagreement in measured absolute concentrations, we stress the need for development of certified reference material, harmonizing measurements across different platforms.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"266"},"PeriodicalIF":7.9,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Greater baseline cortical atrophy in the dorsal attention network predicts faster clinical decline in Posterior Cortical Atrophy.","authors":"Yuta Katsumi, Ryan Eckbo, Marianne Chapleau, Bonnie Wong, Scott M McGinnis, Alexandra Touroutoglou, Bradford C Dickerson, Deepti Putcha","doi":"10.1186/s13195-024-01636-z","DOIUrl":"https://doi.org/10.1186/s13195-024-01636-z","url":null,"abstract":"<p><strong>Background: </strong>Posterior Cortical Atrophy (PCA) is a clinical syndrome characterized by progressive visuospatial and visuoperceptual impairment. As the neurodegenerative disease progresses, patients lose independent functioning due to the worsening of initial symptoms and development of symptoms in other cognitive domains. The timeline of clinical progression is variable across patients, and the field currently lacks robust methods for prognostication. Here, evaluated the utility of MRI-based cortical atrophy as a predictor of longitudinal clinical decline in a sample of PCA patients.</p><p><strong>Methods: </strong>PCA patients were recruited through the Massachusetts General Hospital Frontotemporal Disorders Unit PCA Program. All patients had cortical thickness estimates from baseline MRI scans, which were used to predict longitudinal change in clinical impairment assessed by the CDR Sum-of-Boxes (CDR-SB) score. Multivariable linear regression was used to estimate the magnitude of cortical atrophy in PCA patients relative to a group of amyloid-negative cognitively unimpaired participants. Linear mixed-effects models were used to test hypotheses about the utility of baseline cortical atrophy for predicting longitudinal clinical decline.</p><p><strong>Results: </strong>Data acquired from 34 PCA patients (mean age = 65.41 ± 7.90, 71% females) and 24 controls (mean age = 67.34 ± 4.93, 50% females) were analyzed. 62% of the PCA patients were classified as having mild cognitive impairment (CDR 0.5) at baseline, with the rest having mild dementia (CDR 1). Each patient had at least one clinical follow-up, with the mean duration of 2.78 ± 1.62 years. Relative to controls, PCA patients showed prominent baseline atrophy in the posterior cortical regions, with the largest effect size observed in the visual network of the cerebral cortex. Cortical atrophy localized to the dorsal attention network, which supports higher-order visuospatial function, selectively predicted the rate of subsequent clinical decline.</p><p><strong>Conclusions: </strong>These results demonstrate the utility of a snapshot measure of cortical atrophy of the dorsal attention network for predicting the rate of subsequent clinical decline in PCA. If replicated, this topographically-specific MRI-based biomarker could be useful as a clinical prognostication tool that facilitates personalized care planning.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"262"},"PeriodicalIF":7.9,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}