Pub Date : 2026-01-30DOI: 10.1016/j.tjpad.2026.100498
Nadeemullah Khan, Somnath De, Suhasini Boddu, Navya Pravala
Neurodegeneration on demand represents a groundbreaking approach to modeling Alzheimer's disease (AD) in animals, enabling precise study of its molecular and behavioral hallmarks. Novel techniques, including optogenetic activation of amyloidogenic pathways, viral vector-mediated delivery of mutated human genes (e.g., APP, MAPT), and synthetic tau fibril analogs, induce AD-like pathology, including amyloid-beta plaques, tau hyperphosphorylation, neuroinflammation, and synaptic loss in diverse species, ranging from transgenic rodents to cephalopods and cannies. Emerging platforms, such as bioengineered neural organoids grafted into immunocompromised hosts, allowed for the controlled onset of AD-like features, providing unique insights into disease progression. Advanced tools like real-time neuroimaging and single-cell multi-omics help elucidate the temporal and cellular dynamics of neurodegeneration. These models provided unparalleled opportunities to dissect AD's complex mechanisms, including protein misfolding, glial dysregulation, and cognitive decline. However, challenges remained, including interspecies molecular disparities, incomplete replication of human AD complexity, and ethical concerns surrounding cognitive impairment in sentient models. This review explores these innovative strategies, their contributions to understanding AD's pathogenesis, and their potential to accelerate the development of transformative therapies, while also addressing limitations and future directions for refining these pioneering models.
{"title":"Experimental and translational models of Alzheimer's disease: From neurodegeneration to novel therapeutic insights.","authors":"Nadeemullah Khan, Somnath De, Suhasini Boddu, Navya Pravala","doi":"10.1016/j.tjpad.2026.100498","DOIUrl":"10.1016/j.tjpad.2026.100498","url":null,"abstract":"<p><p>Neurodegeneration on demand represents a groundbreaking approach to modeling Alzheimer's disease (AD) in animals, enabling precise study of its molecular and behavioral hallmarks. Novel techniques, including optogenetic activation of amyloidogenic pathways, viral vector-mediated delivery of mutated human genes (e.g., APP, MAPT), and synthetic tau fibril analogs, induce AD-like pathology, including amyloid-beta plaques, tau hyperphosphorylation, neuroinflammation, and synaptic loss in diverse species, ranging from transgenic rodents to cephalopods and cannies. Emerging platforms, such as bioengineered neural organoids grafted into immunocompromised hosts, allowed for the controlled onset of AD-like features, providing unique insights into disease progression. Advanced tools like real-time neuroimaging and single-cell multi-omics help elucidate the temporal and cellular dynamics of neurodegeneration. These models provided unparalleled opportunities to dissect AD's complex mechanisms, including protein misfolding, glial dysregulation, and cognitive decline. However, challenges remained, including interspecies molecular disparities, incomplete replication of human AD complexity, and ethical concerns surrounding cognitive impairment in sentient models. This review explores these innovative strategies, their contributions to understanding AD's pathogenesis, and their potential to accelerate the development of transformative therapies, while also addressing limitations and future directions for refining these pioneering models.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":"13 4","pages":"100498"},"PeriodicalIF":7.8,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12874412/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097478","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}
Pub Date : 2026-01-30DOI: 10.1016/j.tjpad.2026.100497
Jonathan Vogelgsang, Clara Beck, Regan Patrick, Ipsit Vahia, Sara Weisenbach
Introduction: Neuropsychiatric symptoms may represent early Alzheimer's disease (AD) manifestations, but their relationship with amyloid pathology in cognitively unimpaired individuals remains unclear.
Methods: We analyzed 4,492 cognitively unimpaired adults (aged 65-85) from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Study. Participants completed amyloid-PET imaging and assessments of anxiety, depression, memory complaints, and AD concerns.
Results: 1,231 participants (27.4%) were amyloid-positive. While anxiety and depression scores remained within normal ranges, amyloid-positive participants reported higher memory complaints (p = 0.008) and AD concerns (p < 0.001) before status disclosure. Regression analyses showed amyloid burden associated with anxiety (β = 0.04, standardized, p = 0.003) but not depression (p = 0.68). Mediation analyses revealed anxiety was directly associated with amyloid, while depression was mediated through subjective cognitive concerns.
Discussion: Preclinical amyloid pathology directly associates with subclinical anxiety but only indirectly with depression through subjective stress, suggesting distinct neuropsychiatric pathways in early AD that could inform detection strategies.
{"title":"Preclinical amyloid pathology is associated with anxiety but not depression in cognitively normal older adults: Evidence for differential neuropsychiatric pathways.","authors":"Jonathan Vogelgsang, Clara Beck, Regan Patrick, Ipsit Vahia, Sara Weisenbach","doi":"10.1016/j.tjpad.2026.100497","DOIUrl":"10.1016/j.tjpad.2026.100497","url":null,"abstract":"<p><strong>Introduction: </strong>Neuropsychiatric symptoms may represent early Alzheimer's disease (AD) manifestations, but their relationship with amyloid pathology in cognitively unimpaired individuals remains unclear.</p><p><strong>Methods: </strong>We analyzed 4,492 cognitively unimpaired adults (aged 65-85) from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Study. Participants completed amyloid-PET imaging and assessments of anxiety, depression, memory complaints, and AD concerns.</p><p><strong>Results: </strong>1,231 participants (27.4%) were amyloid-positive. While anxiety and depression scores remained within normal ranges, amyloid-positive participants reported higher memory complaints (p = 0.008) and AD concerns (p < 0.001) before status disclosure. Regression analyses showed amyloid burden associated with anxiety (β = 0.04, standardized, p = 0.003) but not depression (p = 0.68). Mediation analyses revealed anxiety was directly associated with amyloid, while depression was mediated through subjective cognitive concerns.</p><p><strong>Discussion: </strong>Preclinical amyloid pathology directly associates with subclinical anxiety but only indirectly with depression through subjective stress, suggesting distinct neuropsychiatric pathways in early AD that could inform detection strategies.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":"13 4","pages":"100497"},"PeriodicalIF":7.8,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12874419/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097476","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}
Pub Date : 2026-01-30DOI: 10.1016/j.tjpad.2026.100496
Peter Fusdahl, Miguel G Borda, Dag Aarsland
{"title":"Re-thinking funding success in Alzheimer's disease research: Why good science is not enough.","authors":"Peter Fusdahl, Miguel G Borda, Dag Aarsland","doi":"10.1016/j.tjpad.2026.100496","DOIUrl":"10.1016/j.tjpad.2026.100496","url":null,"abstract":"","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":"13 4","pages":"100496"},"PeriodicalIF":7.8,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12878676/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097440","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}
Pub Date : 2026-01-30DOI: 10.1016/j.tjpad.2026.100494
Fang-Fei Wei, Dubo Chen, Chaoxin Xu, Zhongping Yu, Zihao Chen, Chang Chen, Xin He, JingJing Zhao, Wenqing Li, Cuiping Zhao, Jiangui He, Yugang Dong, Jan A Staessen, Chen Liu
Background: Little is known about the association of high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) with changes in cognitive performance over time.
Objectives: To investigate the association of cardiac biomarkers with cognitive changes over time.
Participants: The study population consisted of 2540 stroke-free participants (56.1 % women; 21.2 % Black; mean age, 74.5 years) enrolled in the Atherosclerosis Risk in Communities study.
Measurements: Associations of the changes in the Mini Mental State Examination (MMSE) scores with the log-transformed cardiac biomarkers were modelled using multivariable linear and restricted cubic spline regression.
Results: Over 6.6 years (median), the MMSE score decreased by 0.57 (95 % CI, 0.46-0.67) and the frequency of an MMSE score <24 increased from 5.339 % to 9.69 % (P < 0.001). In multivariable-adjusted models, the cardiac biomarkers measured at baseline were linearly related to absolute MMSE changes with association sizes amounting to 0.47 (0.27-0.66) and 0.58 (0.19-0.97) for NT-proBNP and hs-cTnT, respectively. Classification-by-cardiac biomarker interactions were significant for race, age group and diabetes in relation to NT-proBNP (P ≤ 0.031) and for race, age group and hypertension in relation to hs-cTnT (P ≤ 0.041). For both biomarkers, associations were stronger in Blacks than Whites and in older than younger individuals; for NT-proBNP in diabetic than non-diabetic participants; and for hs-cTnT in normotensive than hypertensive individuals.
Conclusion: NT-proBNP and hs-cTnT were associated with MMSE changes. Although association studies cannot prove causality, the clinical implication might be that targeting the heart within the framework of a multifactorial approach might be strategy in reducing cognitive decline.
{"title":"Association of cardiac biomarkers with longitudinal cognitive changes in the general population.","authors":"Fang-Fei Wei, Dubo Chen, Chaoxin Xu, Zhongping Yu, Zihao Chen, Chang Chen, Xin He, JingJing Zhao, Wenqing Li, Cuiping Zhao, Jiangui He, Yugang Dong, Jan A Staessen, Chen Liu","doi":"10.1016/j.tjpad.2026.100494","DOIUrl":"10.1016/j.tjpad.2026.100494","url":null,"abstract":"<p><strong>Background: </strong>Little is known about the association of high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) with changes in cognitive performance over time.</p><p><strong>Objectives: </strong>To investigate the association of cardiac biomarkers with cognitive changes over time.</p><p><strong>Participants: </strong>The study population consisted of 2540 stroke-free participants (56.1 % women; 21.2 % Black; mean age, 74.5 years) enrolled in the Atherosclerosis Risk in Communities study.</p><p><strong>Measurements: </strong>Associations of the changes in the Mini Mental State Examination (MMSE) scores with the log-transformed cardiac biomarkers were modelled using multivariable linear and restricted cubic spline regression.</p><p><strong>Results: </strong>Over 6.6 years (median), the MMSE score decreased by 0.57 (95 % CI, 0.46-0.67) and the frequency of an MMSE score <24 increased from 5.339 % to 9.69 % (P < 0.001). In multivariable-adjusted models, the cardiac biomarkers measured at baseline were linearly related to absolute MMSE changes with association sizes amounting to 0.47 (0.27-0.66) and 0.58 (0.19-0.97) for NT-proBNP and hs-cTnT, respectively. Classification-by-cardiac biomarker interactions were significant for race, age group and diabetes in relation to NT-proBNP (P ≤ 0.031) and for race, age group and hypertension in relation to hs-cTnT (P ≤ 0.041). For both biomarkers, associations were stronger in Blacks than Whites and in older than younger individuals; for NT-proBNP in diabetic than non-diabetic participants; and for hs-cTnT in normotensive than hypertensive individuals.</p><p><strong>Conclusion: </strong>NT-proBNP and hs-cTnT were associated with MMSE changes. Although association studies cannot prove causality, the clinical implication might be that targeting the heart within the framework of a multifactorial approach might be strategy in reducing cognitive decline.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":"13 4","pages":"100494"},"PeriodicalIF":7.8,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12874405/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097452","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}
Pub Date : 2026-01-24DOI: 10.1016/j.tjpad.2026.100486
Jesús García-Castro, Lawren VandeVrede, Michael C Donohue, Lídia Vaqué-Alcázar, Sara Rubio-Guerra, Judit Selma-González, Hilary W Heuer, Alejandra O Morcillo-Nieto, María Franquesa, Oriol Dols-Icardo, Alexandre Bejanin, Olivia Belbin, Juan Fortea, Daniel Alcolea, Maria Carmona-Iragui, Carla Abdelnour, Isabel Barroeta, Miguel Santos-Santos, María Belen Sánchez Saudinós, Isabel Sala, Alberto Lleó, Maria Luisa Gorno-Tempini, Maria Luisa Mandelli, Rema Raman, Anne-Marie A Wills, Eden Barragan, Irene Litvan, Brad Boeve, Brad Dickerson, Murray Grossman, Edward D Huey, David J Irwin, Alex Pantelyat, Carmela Tartaglia, Julio C Rojas, Adam L Boxer, Ignacio Illán-Gala
Background: Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are 4-repeat tauopathies (4RT) presenting with overlapping syndromes. Imperfect clinicopathological associations increase sample-size demands in clinical trials. We test whether MRI can enrich trials for PSP/CBD and provide sensitive MRI-based outcome measures.
Methods: Longitudinal cohort analysis including participants from the 4 Repeat Tauopathy Neuroimaging Initiative (4RTNI) and phase 2/3 Davunetide trial (DAV). An MRI model trained on autopsy-confirmed cases predicted PSP (MRI-PSP) or CBD (MRI-CBD); corticobasal syndrome (CBS) with positive Alzheimer's biomarkers was reclassified. Clinical scales and MRI-derived thickness/volume were analyzed with linear mixed-effects models. We derived data-driven MRI-signatures (optimal regional combinations) to minimize required trial sample sizes.
Results: 206 participants from 4RTNI (n = 106 with Richardson's syndrome [RS], CBS, or nonfluent/agrammatic primary progressive aphasia [nfvPPA]) and DAV (n = 100 with RS). In 4RTNI, 49 participants were predicted MRI-PSP and 43 MRI-CBD. 76% of MRI-PSP had RS, 24% had CBS/nfvPPA; 66% of MRI-CBD had CBS. PSP and CBD signatures shared midbrain/pontine atrophy but differed in cortical involvement. PSP signature correlated strongly with 12-month change on the PSP Rating Scale (β = -0.59, p < 0.001). MRI-based signatures reduced the estimated sample sizes required to detect 30% reduction in progression over 12-months by 50% for MRI-PSP and 87% for MRI-CBD, compared with clinical outcomes. In DAV, feasibility was replicated.
Conclusion: MRI-derived models can identify PSP or CBD with high accuracy, and MRI-based signatures track progression more sensitively than established clinical outcomes. Incorporating these tools into therapeutic trial design could reduce sample sizes and enable more inclusive disease-modifying trials for 4RT.
{"title":"Potential role of MRI to optimize clinical trial design for progressive supranuclear palsy and corticobasal degeneration.","authors":"Jesús García-Castro, Lawren VandeVrede, Michael C Donohue, Lídia Vaqué-Alcázar, Sara Rubio-Guerra, Judit Selma-González, Hilary W Heuer, Alejandra O Morcillo-Nieto, María Franquesa, Oriol Dols-Icardo, Alexandre Bejanin, Olivia Belbin, Juan Fortea, Daniel Alcolea, Maria Carmona-Iragui, Carla Abdelnour, Isabel Barroeta, Miguel Santos-Santos, María Belen Sánchez Saudinós, Isabel Sala, Alberto Lleó, Maria Luisa Gorno-Tempini, Maria Luisa Mandelli, Rema Raman, Anne-Marie A Wills, Eden Barragan, Irene Litvan, Brad Boeve, Brad Dickerson, Murray Grossman, Edward D Huey, David J Irwin, Alex Pantelyat, Carmela Tartaglia, Julio C Rojas, Adam L Boxer, Ignacio Illán-Gala","doi":"10.1016/j.tjpad.2026.100486","DOIUrl":"10.1016/j.tjpad.2026.100486","url":null,"abstract":"<p><strong>Background: </strong>Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are 4-repeat tauopathies (4RT) presenting with overlapping syndromes. Imperfect clinicopathological associations increase sample-size demands in clinical trials. We test whether MRI can enrich trials for PSP/CBD and provide sensitive MRI-based outcome measures.</p><p><strong>Methods: </strong>Longitudinal cohort analysis including participants from the 4 Repeat Tauopathy Neuroimaging Initiative (4RTNI) and phase 2/3 Davunetide trial (DAV). An MRI model trained on autopsy-confirmed cases predicted PSP (MRI-PSP) or CBD (MRI-CBD); corticobasal syndrome (CBS) with positive Alzheimer's biomarkers was reclassified. Clinical scales and MRI-derived thickness/volume were analyzed with linear mixed-effects models. We derived data-driven MRI-signatures (optimal regional combinations) to minimize required trial sample sizes.</p><p><strong>Results: </strong>206 participants from 4RTNI (n = 106 with Richardson's syndrome [RS], CBS, or nonfluent/agrammatic primary progressive aphasia [nfvPPA]) and DAV (n = 100 with RS). In 4RTNI, 49 participants were predicted MRI-PSP and 43 MRI-CBD. 76% of MRI-PSP had RS, 24% had CBS/nfvPPA; 66% of MRI-CBD had CBS. PSP and CBD signatures shared midbrain/pontine atrophy but differed in cortical involvement. PSP signature correlated strongly with 12-month change on the PSP Rating Scale (β = -0.59, p < 0.001). MRI-based signatures reduced the estimated sample sizes required to detect 30% reduction in progression over 12-months by 50% for MRI-PSP and 87% for MRI-CBD, compared with clinical outcomes. In DAV, feasibility was replicated.</p><p><strong>Conclusion: </strong>MRI-derived models can identify PSP or CBD with high accuracy, and MRI-based signatures track progression more sensitively than established clinical outcomes. Incorporating these tools into therapeutic trial design could reduce sample sizes and enable more inclusive disease-modifying trials for 4RT.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":"13 3","pages":"100486"},"PeriodicalIF":7.8,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12860716/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146047057","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}
Pub Date : 2026-01-24DOI: 10.1016/j.tjpad.2026.100489
Lisa B E Shields, Hust Hannah, Gregory E Cooper, Theresa Kluthe, Rachel N Hart, Andrew P Thaliath, Brandon C Dennis, Stephanie W Freeman, Jessica F Cain, Whoy Y Shang, Kendall M Wasz, Adam T Orr, Christopher B Shields, Shirish S Barve, Kenneth G Pugh
<p><strong>Background and objectives: </strong>The anti-amyloid monoclonal antibody lecanemab (Leqembi®) treats patients with mild cognitive impairment (MCI) or mild dementia due to Alzheimer's disease (AD). We sought to evaluate the incidence of amyloid-related imaging abnormalities) ARIA and other adverse events associated with lecanemab.</p><p><strong>Design, setting, and participants: </strong>This retrospective and observational study features 187 patients who received at least one lecanemab infusion at our multidisciplinary Norton Neuroscience Institute Memory Center over a two-year duration (August 25, 2023-August 24, 2025).</p><p><strong>Results: </strong>A total of 109 (58.3 %) patients were diagnosed with MCI, and 78 (41.7 %) had mild dementia prior to starting lecanemab. The mean age at the initial infusion was 73 years (Range: 49-90 years). Most (127 [67.9 %]) patients were female, and the majority (181 [96.8 %]) were Caucasian. Of the 175 patients who underwent at least one surveillance brain MRI following lecanemab initiation, 39 (22.3 %) had evidence of ARIA (both ARIA-H and ARIA-E: 13 [33.3 %]; solitary ARIA-H: 17 [43.6 %]; and solitary ARIA-E: 9 [23.1 %]). Of these 39 patients, 20 (51.3 %) were ε4 heterozygous, 12 (30.8 %) were ε4 homozygous, and 7 (17.9 %) were ε4 non-carriers. Patients who were ε4 homozygous more frequently had evidence of any ARIA (p-value = 0.002), ARIA-E (p = 0.041), and ARIA-H (p = 0.004). Of the 25 patients who underwent at least one surveillance brain MRI and were ε4 homozygous, 12 (48.0 %) had ARIA detected. Five (12.8 %) patients with ARIA were symptomatic, requiring lecanemab suspension. Three of these symptomatic patients were ε4 homozygous, and two were ε4 heterozygous. The ARIA was most frequently detected on the surveillance brain MRI performed before the 5<sup>th</sup> infusion (29 [74.4 %] patients). All 39 cases of ARIA occurred before the 14<sup>th</sup> lecanemab infusion. Patients with more baseline microbleeds more frequently developed any ARIA (ARIA-H and ARIA-E) (p = 0.041) and solitary ARIA-H (p = 0.022). The presence of baseline microbleeds was associated with a higher frequency of solitary ARIA-H, though was only marginally statistically significant (p = 0.051). Sixty (32.1 %) patients experienced infusion-related adverse effects, with 54 (90.0 %) occurring after the first lecanemab infusion. Mild and transient headaches were most common, affecting 26 (48.1 %) of these patients after the first infusion. After initiating a pre-infusion oral cocktail of acetaminophen 650 mg, loratadine 10 mg, and famotidine 20 mg, the number of patients who experienced an infusion-related adverse event decreased from 45.2 % to 28.3 %. Thirty-two (17.1 %) patients discontinued lecanemab, primarily due to cognitive decline associated with progressive AD (10 [31.2 %]) and ARIA progression (9 [28.1 %]). Of the 73 patients who had MMSE scores performed at baseline and after 1 year post-lecanemab, 13 (17.8 %) h
{"title":"Lecanemab over a two-year duration: Key insights from a regional specialty medical center.","authors":"Lisa B E Shields, Hust Hannah, Gregory E Cooper, Theresa Kluthe, Rachel N Hart, Andrew P Thaliath, Brandon C Dennis, Stephanie W Freeman, Jessica F Cain, Whoy Y Shang, Kendall M Wasz, Adam T Orr, Christopher B Shields, Shirish S Barve, Kenneth G Pugh","doi":"10.1016/j.tjpad.2026.100489","DOIUrl":"10.1016/j.tjpad.2026.100489","url":null,"abstract":"<p><strong>Background and objectives: </strong>The anti-amyloid monoclonal antibody lecanemab (Leqembi®) treats patients with mild cognitive impairment (MCI) or mild dementia due to Alzheimer's disease (AD). We sought to evaluate the incidence of amyloid-related imaging abnormalities) ARIA and other adverse events associated with lecanemab.</p><p><strong>Design, setting, and participants: </strong>This retrospective and observational study features 187 patients who received at least one lecanemab infusion at our multidisciplinary Norton Neuroscience Institute Memory Center over a two-year duration (August 25, 2023-August 24, 2025).</p><p><strong>Results: </strong>A total of 109 (58.3 %) patients were diagnosed with MCI, and 78 (41.7 %) had mild dementia prior to starting lecanemab. The mean age at the initial infusion was 73 years (Range: 49-90 years). Most (127 [67.9 %]) patients were female, and the majority (181 [96.8 %]) were Caucasian. Of the 175 patients who underwent at least one surveillance brain MRI following lecanemab initiation, 39 (22.3 %) had evidence of ARIA (both ARIA-H and ARIA-E: 13 [33.3 %]; solitary ARIA-H: 17 [43.6 %]; and solitary ARIA-E: 9 [23.1 %]). Of these 39 patients, 20 (51.3 %) were ε4 heterozygous, 12 (30.8 %) were ε4 homozygous, and 7 (17.9 %) were ε4 non-carriers. Patients who were ε4 homozygous more frequently had evidence of any ARIA (p-value = 0.002), ARIA-E (p = 0.041), and ARIA-H (p = 0.004). Of the 25 patients who underwent at least one surveillance brain MRI and were ε4 homozygous, 12 (48.0 %) had ARIA detected. Five (12.8 %) patients with ARIA were symptomatic, requiring lecanemab suspension. Three of these symptomatic patients were ε4 homozygous, and two were ε4 heterozygous. The ARIA was most frequently detected on the surveillance brain MRI performed before the 5<sup>th</sup> infusion (29 [74.4 %] patients). All 39 cases of ARIA occurred before the 14<sup>th</sup> lecanemab infusion. Patients with more baseline microbleeds more frequently developed any ARIA (ARIA-H and ARIA-E) (p = 0.041) and solitary ARIA-H (p = 0.022). The presence of baseline microbleeds was associated with a higher frequency of solitary ARIA-H, though was only marginally statistically significant (p = 0.051). Sixty (32.1 %) patients experienced infusion-related adverse effects, with 54 (90.0 %) occurring after the first lecanemab infusion. Mild and transient headaches were most common, affecting 26 (48.1 %) of these patients after the first infusion. After initiating a pre-infusion oral cocktail of acetaminophen 650 mg, loratadine 10 mg, and famotidine 20 mg, the number of patients who experienced an infusion-related adverse event decreased from 45.2 % to 28.3 %. Thirty-two (17.1 %) patients discontinued lecanemab, primarily due to cognitive decline associated with progressive AD (10 [31.2 %]) and ARIA progression (9 [28.1 %]). Of the 73 patients who had MMSE scores performed at baseline and after 1 year post-lecanemab, 13 (17.8 %) h","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":"13 3","pages":"100489"},"PeriodicalIF":7.8,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12860706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146047046","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}
Pub Date : 2026-01-22DOI: 10.1016/j.tjpad.2026.100484
Yong Shen, Xiaochun Chen, Jiong Shi
{"title":"CTAD China advanced workshop and course in AD clinical trials - Shanghai, September 6-7, 2025.","authors":"Yong Shen, Xiaochun Chen, Jiong Shi","doi":"10.1016/j.tjpad.2026.100484","DOIUrl":"10.1016/j.tjpad.2026.100484","url":null,"abstract":"","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":"13 3","pages":"100484"},"PeriodicalIF":7.8,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12858721/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146041701","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}
Pub Date : 2026-01-21DOI: 10.1016/j.tjpad.2026.100480
Claude M Wischik, Richard Stefanacci, Peter Bentham, Serge Gauthier, Henrik Zetterberg, Gordon K Wilcock, Lutz Froelich, Alistair Burns, Emer MacSweeney, Clive Ballard, Jin-Tai Yu, Tay Siew Choon, Vahe Asvatourian, Natalia Muehlemann, Jan Priel, Karin Kook, Tenecia Sullivan, Diane Downie, Sonya Miller, Carol Pringle, John M D Storey, Tom Baddeley, Charles R Harrington, Lewis K Penny, Mohammad Arastoo, Roger Staff, Anca-Larisa Sandu, Helen Shiells, Serena Lo, Nafeesa Nazlee, Emily Evans, Claire Hull, Bjoern O Schelter
<p><strong>Background: </strong>Hydromethylthionine mesylate (HMTM) targets tau pathology and has tau-independent symptomatic activity.</p><p><strong>Objectives: </strong>To evaluate the safety and efficacy of HMTM in participants with mild cognitive impairment (MCI) and mild to moderate dementia due to Alzheimer's disease (AD).</p><p><strong>Setting: </strong>82 centres in Canada, European Union, United Kingdom and United States of America.</p><p><strong>Participants: </strong>A total of 598 amyloid β-PET positive participants were included; 44% (263) met clinical criteria for MCI due to Alzheimer's disease and 56% (335) were diagnosed with mild to moderate dementia due to AD.</p><p><strong>Intervention: </strong>HMTM 16 mg/day and 8 mg/day were compared with methylthioninium chloride (MTC) 4 mg twice weekly, intended as an inactive urinary colourant to preserve blinding with respect to possible urinary discolouration caused by HMTM.</p><p><strong>Measurements: </strong>HMTM and MTC were compared on cognitive and functional endpoints for the first 52 weeks followed by all receiving HMTM 16 mg/day to 104 weeks in a modified delayed-start trial design. Biomarker outcomes included change in plasma levels of neurofilament light chain (NfL), pTau217 and MRI measures of grey matter atrophy.</p><p><strong>Results: </strong>It was not possible to demonstrate significant differences on the co-primary clinical endpoints (ADAS-cog<sub>11</sub> and ADCS-ADL<sub>23</sub>) at 52 weeks due to symptomatic activity in the control arm. In participants with MCI, statistically significant differences in cognitive decline (ADAS-cog<sub>13</sub>) emerged at 78 weeks (p = 0·0291) and 104 weeks (p = 0·0308) between early- and delayed-start HMTM 16 mg/day in analyses specified prior to the 24-month database lock. Statistically significant cognitive improvement over baseline score was sustained for 78 weeks in the early start MCI group, with no significant cognitive or functional decline to 104 weeks. There was a significant reduction in progression of neurodegeneration measured by NfL change (p = 0·0291) at 52 weeks in the whole population, consistent with significant reductions in progression of grey matter atrophy at 52 and 104 weeks, and a reduction in progression of tau pathology (pTau217, p = 0·0165) in MCI. Headache (1·5%) and diarrhoea (1·2%) were the most frequent adverse effects.</p><p><strong>Conclusions: </strong>Although HMTM 16 mg/day arrested progression of neurodegeneration and reduced grey matter atrophy at 52 weeks, symptomatic activity in the control arm precluded separation of treatment arms at 52 weeks on primary clinical endpoints. In participants with MCI, significant clinical separation was seen only at 78 and 104 weeks. This effect has been confirmed in a further study. HMTM was well tolerated and has the potential to offer an accessible oral treatment option with a benign safety profile which could be delivered with minimal patient/physician bur
{"title":"Clinical, imaging and blood biomarker outcomes in a Phase 3 clinical trial of tau aggregation inhibitor hydromethylthionine mesylate in mild cognitive impairment and mild to moderate dementia due to Alzheimer's disease.","authors":"Claude M Wischik, Richard Stefanacci, Peter Bentham, Serge Gauthier, Henrik Zetterberg, Gordon K Wilcock, Lutz Froelich, Alistair Burns, Emer MacSweeney, Clive Ballard, Jin-Tai Yu, Tay Siew Choon, Vahe Asvatourian, Natalia Muehlemann, Jan Priel, Karin Kook, Tenecia Sullivan, Diane Downie, Sonya Miller, Carol Pringle, John M D Storey, Tom Baddeley, Charles R Harrington, Lewis K Penny, Mohammad Arastoo, Roger Staff, Anca-Larisa Sandu, Helen Shiells, Serena Lo, Nafeesa Nazlee, Emily Evans, Claire Hull, Bjoern O Schelter","doi":"10.1016/j.tjpad.2026.100480","DOIUrl":"10.1016/j.tjpad.2026.100480","url":null,"abstract":"<p><strong>Background: </strong>Hydromethylthionine mesylate (HMTM) targets tau pathology and has tau-independent symptomatic activity.</p><p><strong>Objectives: </strong>To evaluate the safety and efficacy of HMTM in participants with mild cognitive impairment (MCI) and mild to moderate dementia due to Alzheimer's disease (AD).</p><p><strong>Setting: </strong>82 centres in Canada, European Union, United Kingdom and United States of America.</p><p><strong>Participants: </strong>A total of 598 amyloid β-PET positive participants were included; 44% (263) met clinical criteria for MCI due to Alzheimer's disease and 56% (335) were diagnosed with mild to moderate dementia due to AD.</p><p><strong>Intervention: </strong>HMTM 16 mg/day and 8 mg/day were compared with methylthioninium chloride (MTC) 4 mg twice weekly, intended as an inactive urinary colourant to preserve blinding with respect to possible urinary discolouration caused by HMTM.</p><p><strong>Measurements: </strong>HMTM and MTC were compared on cognitive and functional endpoints for the first 52 weeks followed by all receiving HMTM 16 mg/day to 104 weeks in a modified delayed-start trial design. Biomarker outcomes included change in plasma levels of neurofilament light chain (NfL), pTau217 and MRI measures of grey matter atrophy.</p><p><strong>Results: </strong>It was not possible to demonstrate significant differences on the co-primary clinical endpoints (ADAS-cog<sub>11</sub> and ADCS-ADL<sub>23</sub>) at 52 weeks due to symptomatic activity in the control arm. In participants with MCI, statistically significant differences in cognitive decline (ADAS-cog<sub>13</sub>) emerged at 78 weeks (p = 0·0291) and 104 weeks (p = 0·0308) between early- and delayed-start HMTM 16 mg/day in analyses specified prior to the 24-month database lock. Statistically significant cognitive improvement over baseline score was sustained for 78 weeks in the early start MCI group, with no significant cognitive or functional decline to 104 weeks. There was a significant reduction in progression of neurodegeneration measured by NfL change (p = 0·0291) at 52 weeks in the whole population, consistent with significant reductions in progression of grey matter atrophy at 52 and 104 weeks, and a reduction in progression of tau pathology (pTau217, p = 0·0165) in MCI. Headache (1·5%) and diarrhoea (1·2%) were the most frequent adverse effects.</p><p><strong>Conclusions: </strong>Although HMTM 16 mg/day arrested progression of neurodegeneration and reduced grey matter atrophy at 52 weeks, symptomatic activity in the control arm precluded separation of treatment arms at 52 weeks on primary clinical endpoints. In participants with MCI, significant clinical separation was seen only at 78 and 104 weeks. This effect has been confirmed in a further study. HMTM was well tolerated and has the potential to offer an accessible oral treatment option with a benign safety profile which could be delivered with minimal patient/physician bur","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":"13 3","pages":"100480"},"PeriodicalIF":7.8,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12861207/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030955","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}
Pub Date : 2026-01-20DOI: 10.1016/j.tjpad.2026.100483
Kristofer Harris, Madison Shyer, Dulin Wang, Elizabeth He, Matias Cattani, Catherine Zhang, Christine M Farrell, Xiaoqian Jiang, Yejin Kim, Paul E Schulz
<p><strong>Background: </strong>A subset of Alzheimer's disease patients progresses much more rapidly than average. These rapid progressors exhibit accelerated cognitive and functional decline. Potential differences in Alzheimer's biomarkers for rapid progressors and their responses to disease-modifying treatments remain poorly understood, with previous clinical trials and studies producing limited biomarker data and inconsistent results.</p><p><strong>Objectives: </strong>Examine differences in rapid progressor versus non-rapid progressor outcomes in two AD treatment trials (bapineuzumab and semagacestat) and investigate cognitive and biomarker progression in the placebo groups.</p><p><strong>Design: </strong>Retrospective cohort study.</p><p><strong>Setting: </strong>Four randomized, double-blind, phase 3 clinical trials from the Center for Global Clinical Research Data (Semagacestat) and the Yale University Open Data Access Project (Bapineuzumab).</p><p><strong>Participants: </strong>4,902 patients (2,355 in bapineuzumab trials, 2,647 in semagacestat trials). Rapid progressors were operationally defined as the 10% of patients with the largest changes in cognitive scores from baseline to trial end.</p><p><strong>Intervention: </strong>Bapineuzumab (monoclonal antibody) and Semagacestat (γ-secretase inhibitor).</p><p><strong>Measurements: </strong>Cognitive assessments (CDR-SB, MMSE, ADAS-Cog, ADCS-ADL) and biological markers (CSF and plasma levels, MRI, FDG PET Scan, and Amyloid PET Scan) at baseline and endpoint.</p><p><strong>Results: </strong>Rapid progressors showed distinct baseline characteristics in both the bapineuzumab and semagacestat trials: younger age (61.27 vs 63.14 years, p=0.008; and, 72.64 v. 73.64 years, p=0.046), a higher proportion of APOE4 carriers (87.6% vs 41.4%, p<0.001; and, 85.2% vs 49.3%, p = 0.022), and greater cognitive impairment across all measures (p<0.001). Both progression groups demonstrated improvement in specific biomarkers with treatment, though with different patterns. With bapineuzumab according to Conditional Average Treatment Effect analysis, rapid progressors showed biomarker improvement in amyloid CSF, p-Tau CSF, and amyloid PET scan, while non-rapid progressors demonstrated biomarker improvements in p-Tau CSF, amyloid PET, and MRI. With semagacestat, rapid progressors showed improvements in amyloid CSF and plasma while non-rapid progressors showed improvements in amyloid CSF, FDG PET, and MRI.</p><p><strong>Conclusions: </strong>This study provides crucial insights for clinical practice and trial design. The distinct response patterns between progression groups suggest that early identification and balancing of RPs between groups could improve clinical trial efficiency. The findings support the development of personalized treatment approaches for rapid progressors, who have aggressive disease progression. These results may significantly modify clinical trial design and patient care in Alzheimer's dis
背景：一部分阿尔茨海默病患者的病情进展比平均水平快得多。这些快速进展者表现出加速的认知和功能衰退。阿尔茨海默病快速进展者生物标志物的潜在差异及其对疾病改善治疗的反应仍然知之甚少，先前的临床试验和研究产生有限的生物标志物数据和不一致的结果。目的：研究两项阿尔茨海默病治疗试验（巴哌珠单抗和semagacestat）快速进展和非快速进展结果的差异，并调查安慰剂组的认知和生物标志物进展。设计：回顾性队列研究。环境：来自全球临床研究数据中心（Semagacestat）和耶鲁大学开放数据获取项目（Bapineuzumab）的四项随机、双盲、3期临床试验。参与者：4,902例患者（2,355例巴哌珠单抗试验，2,647例semagacestat试验）。快速进展者被手术定义为从基线到试验结束认知评分变化最大的10%的患者。干预：巴单抗（单克隆抗体）和Semagacestat （γ-分泌酶抑制剂）。测量：基线和终点的认知评估（CDR-SB、MMSE、ADAS-Cog、ADCS-ADL）和生物标志物（CSF和血浆水平、MRI、FDG PET扫描和淀粉样蛋白PET扫描）。结果：快速进展者在巴哌珠单抗和semagacestat试验中均显示出明显的基线特征：年龄更小（61.27 vs 63.14岁，p=0.008; 72.64 vs 73.64岁，p=0.046）， APOE4携带者比例更高（87.6% vs 41.4%）。进展组之间不同的反应模式表明，早期识别和平衡组间rp可以提高临床试验效率。该研究结果支持针对具有侵袭性疾病进展的快速进展患者开发个性化治疗方法。这些结果可能会显著改变阿尔茨海默病的临床试验设计和患者护理。
{"title":"The influence of bapineuzumab and semagacestat on rapid progressors: A retrospective cohort study.","authors":"Kristofer Harris, Madison Shyer, Dulin Wang, Elizabeth He, Matias Cattani, Catherine Zhang, Christine M Farrell, Xiaoqian Jiang, Yejin Kim, Paul E Schulz","doi":"10.1016/j.tjpad.2026.100483","DOIUrl":"10.1016/j.tjpad.2026.100483","url":null,"abstract":"<p><strong>Background: </strong>A subset of Alzheimer's disease patients progresses much more rapidly than average. These rapid progressors exhibit accelerated cognitive and functional decline. Potential differences in Alzheimer's biomarkers for rapid progressors and their responses to disease-modifying treatments remain poorly understood, with previous clinical trials and studies producing limited biomarker data and inconsistent results.</p><p><strong>Objectives: </strong>Examine differences in rapid progressor versus non-rapid progressor outcomes in two AD treatment trials (bapineuzumab and semagacestat) and investigate cognitive and biomarker progression in the placebo groups.</p><p><strong>Design: </strong>Retrospective cohort study.</p><p><strong>Setting: </strong>Four randomized, double-blind, phase 3 clinical trials from the Center for Global Clinical Research Data (Semagacestat) and the Yale University Open Data Access Project (Bapineuzumab).</p><p><strong>Participants: </strong>4,902 patients (2,355 in bapineuzumab trials, 2,647 in semagacestat trials). Rapid progressors were operationally defined as the 10% of patients with the largest changes in cognitive scores from baseline to trial end.</p><p><strong>Intervention: </strong>Bapineuzumab (monoclonal antibody) and Semagacestat (γ-secretase inhibitor).</p><p><strong>Measurements: </strong>Cognitive assessments (CDR-SB, MMSE, ADAS-Cog, ADCS-ADL) and biological markers (CSF and plasma levels, MRI, FDG PET Scan, and Amyloid PET Scan) at baseline and endpoint.</p><p><strong>Results: </strong>Rapid progressors showed distinct baseline characteristics in both the bapineuzumab and semagacestat trials: younger age (61.27 vs 63.14 years, p=0.008; and, 72.64 v. 73.64 years, p=0.046), a higher proportion of APOE4 carriers (87.6% vs 41.4%, p<0.001; and, 85.2% vs 49.3%, p = 0.022), and greater cognitive impairment across all measures (p<0.001). Both progression groups demonstrated improvement in specific biomarkers with treatment, though with different patterns. With bapineuzumab according to Conditional Average Treatment Effect analysis, rapid progressors showed biomarker improvement in amyloid CSF, p-Tau CSF, and amyloid PET scan, while non-rapid progressors demonstrated biomarker improvements in p-Tau CSF, amyloid PET, and MRI. With semagacestat, rapid progressors showed improvements in amyloid CSF and plasma while non-rapid progressors showed improvements in amyloid CSF, FDG PET, and MRI.</p><p><strong>Conclusions: </strong>This study provides crucial insights for clinical practice and trial design. The distinct response patterns between progression groups suggest that early identification and balancing of RPs between groups could improve clinical trial efficiency. The findings support the development of personalized treatment approaches for rapid progressors, who have aggressive disease progression. These results may significantly modify clinical trial design and patient care in Alzheimer's dis","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":"13 3","pages":"100483"},"PeriodicalIF":7.8,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12859249/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146019620","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}
Pub Date : 2026-01-19DOI: 10.1016/j.tjpad.2026.100479
Ashwati Vipin, James Xiao Yuan Chen, Mervin Tee, Saima Hilal, Yi Jin Leow, Simon Konstandin, Klaus Eickel, Matthias Günther, Jan Petr, Henk Jmm Mutsaerts, Nagaendran Kandiah
Background: Utilizing non-invasive neuroimaging for characterization of blood brain barrier (BBB) changes and perfusion deficits underlying small vessel disease pathobiology including white matter hyperintensities (WMH) remains largely unexplored.
Objectives: We examined the underlying haemodynamics of WMH by assessing complex relationships between cerebral blood flow, BBB permeability and WMH burden.
Design, setting, participants: Cross-sectional data from study participants belonging to the community-based Biomarker and Cognition Cohort Study, Singapore was obtained.
Measurements: Brain structural and novel non-invasive multi-echo Arterial Spin Labeling data was obtained from 128 participants to derive cerebral blood flow (CBF), arterial transit time (ATT) and BBB time of exchange (Tex).
Results: Neurovascular measures from BBB imaging comprising lower CBF (β=-0.005; p = 0.0139), longer ATT (β=0.644; p = 0.0132) and shorter BBB Tex (β=-0.002; p = 0.0023) were independently associated with higher WMH and higher age-at-visit. Model fit statistics indicated good fit for the structural equation model with a comparative fit index of 0.975 and Standardized Root Mean Square Residual of 0.074. Structural equation modelling revealed CBF (β=0.533; p < 0.001) and ATT (β=-0.254; p = 0.001) as predictors of BBB permeability. Subsequently higher BBB permeability predicted higher WMH burden (β=-0.387; p < 0.001). Additionally, vascular risk factors comprising higher blood pressure and haemoglobinA1C related to lower CBF and shorter BBB Tex.
Conclusions: Our study highlights that CBF and ATT contribute to BBB permeability, which in turn impacts WMH burden. Vascular risk factors also impact neurovascular measures. These findings add to the growing evidence on the potential role of BBB and perfusion deficits underlying small vessel disease burden.
背景：利用非侵入性神经影像学表征血脑屏障（BBB）变化和灌注缺陷，包括白质高信号（WMH）在内的小血管疾病病理生物学仍未得到广泛研究。目的：我们通过评估脑血流、血脑屏障通透性和脑mh负荷之间的复杂关系来研究脑mh的潜在血流动力学。设计，环境，参与者：来自新加坡社区生物标志物和认知队列研究的研究参与者的横断面数据。测量方法：从128名参与者中获得脑结构和新型无创多回声动脉自旋标记数据，以获得脑血流量（CBF）、动脉传递时间（ATT）和血脑屏障交换时间（Tex）。结果：血脑屏障成像的神经血管测量包括较低的CBF (β=-0.005; p = 0.0139)，较长的ATT （β=0.644; p = 0.0132）和较短的血脑屏障Tex （β=-0.002; p = 0.0023）与较高的WMH和较高的就诊年龄独立相关。模型拟合统计表明，结构方程模型拟合良好，比较拟合指数为0.975，标准化均方根残差为0.074。结构方程模型显示CBF （β=0.533, p < 0.001）和ATT （β=-0.254, p = 0.001）是血脑屏障通透性的预测因子。血脑屏障通透性越高，WMH负荷越高（β=-0.387; p < 0.001）。此外，包括高血压和血红蛋白a1c在内的血管危险因素与较低的CBF和较短的血脑屏障Tex有关。结论：我们的研究强调脑血流和ATT有助于血脑屏障的通透性，从而影响WMH负担。血管危险因素也影响神经血管测量。这些发现增加了越来越多的证据，证明血脑屏障和灌注缺陷在小血管疾病负担中的潜在作用。
{"title":"Cerebral haemodynamics and white matter hyperintensities: findings using non-invasive brain imaging.","authors":"Ashwati Vipin, James Xiao Yuan Chen, Mervin Tee, Saima Hilal, Yi Jin Leow, Simon Konstandin, Klaus Eickel, Matthias Günther, Jan Petr, Henk Jmm Mutsaerts, Nagaendran Kandiah","doi":"10.1016/j.tjpad.2026.100479","DOIUrl":"10.1016/j.tjpad.2026.100479","url":null,"abstract":"<p><strong>Background: </strong>Utilizing non-invasive neuroimaging for characterization of blood brain barrier (BBB) changes and perfusion deficits underlying small vessel disease pathobiology including white matter hyperintensities (WMH) remains largely unexplored.</p><p><strong>Objectives: </strong>We examined the underlying haemodynamics of WMH by assessing complex relationships between cerebral blood flow, BBB permeability and WMH burden.</p><p><strong>Design, setting, participants: </strong>Cross-sectional data from study participants belonging to the community-based Biomarker and Cognition Cohort Study, Singapore was obtained.</p><p><strong>Measurements: </strong>Brain structural and novel non-invasive multi-echo Arterial Spin Labeling data was obtained from 128 participants to derive cerebral blood flow (CBF), arterial transit time (ATT) and BBB time of exchange (T<sub>ex</sub>).</p><p><strong>Results: </strong>Neurovascular measures from BBB imaging comprising lower CBF (β=-0.005; p = 0.0139), longer ATT (β=0.644; p = 0.0132) and shorter BBB T<sub>ex</sub> (β=-0.002; p = 0.0023) were independently associated with higher WMH and higher age-at-visit. Model fit statistics indicated good fit for the structural equation model with a comparative fit index of 0.975 and Standardized Root Mean Square Residual of 0.074. Structural equation modelling revealed CBF (β=0.533; p < 0.001) and ATT (β=-0.254; p = 0.001) as predictors of BBB permeability. Subsequently higher BBB permeability predicted higher WMH burden (β=-0.387; p < 0.001). Additionally, vascular risk factors comprising higher blood pressure and haemoglobinA1C related to lower CBF and shorter BBB T<sub>ex</sub>.</p><p><strong>Conclusions: </strong>Our study highlights that CBF and ATT contribute to BBB permeability, which in turn impacts WMH burden. Vascular risk factors also impact neurovascular measures. These findings add to the growing evidence on the potential role of BBB and perfusion deficits underlying small vessel disease burden.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":"13 3","pages":"100479"},"PeriodicalIF":7.8,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12856470/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146012215","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号