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INTRODUCTION: Cerebral blood flow (CBF) is reduced in cognitively impaired (CI) Alzheimer's disease (AD) patients. We checked the sensitivity of time‐encoded arterial spin labeling (te‐ASL) in measuring CBF alterations in individuals with positive AD biomarkers and associations with relevant biomarkers in cognitively unimpaired (CU) individuals. METHODS: We compared te‐ASL with single‐postlabel delay (PLD) ASL in measuring CBF in 59 adults across the AD continuum, classified as CU amyloid beta (Aβ) negative (−), CU Aβ positive (+), and CI Aβ+. We sought associations of CBF with biomarkers of AD, cerebrovascular disease, synaptic dysfunction, neurodegeneration, and cognition in CU participants. RESULTS: te‐ASL was more sensitive at detecting CBF reduction in the CU Aβ+ and CI Aβ+ groups. In CU participants, lower CBF was associated with altered biomarkers of Aβ, tau, synaptic dysfunction, and neurodegeneration. DISCUSSION: CBF reduction occurs early in the AD continuum. te‐ASL is more sensitive than single‐PLD ASL at detecting CBF changes in AD. Highlights: Lower CBF can be detected in CU subjects in the early AD continuum.te‐ASL is more sensitive than single‐PLD ASL at detecting CBF alterations in AD.CBF is linked to biomarkers of AD, synaptic dysfunction, and neurodegeneration. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Existing blood‐based biomarkers for Alzheimer's disease (AD) mainly focus on its pathological features. However, studies on blood‐based biomarkers associated with other biological processes for a comprehensive evaluation of AD status are limited. METHODS: We developed a blood‐based, multiplex biomarker assay for AD that measures the levels of 21 proteins involved in multiple biological pathways. We evaluated the assay's performance for classifying AD and indicating AD‐related endophenotypes in three independent cohorts from Chinese or European‐descent populations. RESULTS: The 21‐protein assay accurately classified AD (area under the receiver operating characteristic curve [AUC] = 0.9407 to 0.9867) and mild cognitive impairment (MCI; AUC = 0.8434 to 0.8945) while also indicating brain amyloid pathology. Moreover, the assay simultaneously evaluated the changes of five biological processes in individuals and revealed the ethnic‐specific dysregulations of biological processes upon AD progression. DISCUSSION: This study demonstrated the utility of a blood‐based, multi‐pathway biomarker assay for early screening and staging of AD, providing insights for patient stratification and precision medicine. Highlights: The authors developed a blood‐based biomarker assay for Alzheimer's disease.The 21‐protein assay classifies AD/MCI and indicates brain amyloid pathology.The 21‐protein assay can simultaneously assess activities of five biological processes.Ethnic‐specific dysregulations of biological processes in AD were revealed. [ABSTRACT FROM AUTHOR]

INTRODUCTION: This study examined the relationship between blood‐brain‐barrier permeability (BBBp), measured by cerebrospinal fluid/serum albumin ratio (QAlb), and cognitive decline progression in a clinical cohort. METHODS: This prospective observational study included 334 participants from the BIODEGMAR cohort. Cognitive decline progression was defined as an increase in Global Deterioration Scale and/or Clinical Dementia Rating scores. Associations between BBBp, demographics, and clinical factors were explored. RESULTS: Male sex, diabetes mellitus, and cerebrovascular burden were associated with increased log‐QAlb. Vascular cognitive impairment patients had the highest log‐QAlb levels. Among the 273 participants with valid follow‐up data, 154 (56.4%) showed cognitive decline progression. An 8% increase in the hazard of clinical worsening was observed for each 10% increase in log‐QAlb. DISCUSSION: These results suggest that increased BBBp in individuals with cognitive decline may contribute to clinical worsening, pointing to potential targeted therapies. QAlb could be a useful biomarker for identifying patients with a worse prognosis. [ABSTRACT FROM AUTHOR]

Background: The Catalan Early Onset Neurodegenerative Dementia Network is a multicenter project launched in 2020 with the aim of understanding the epidemiology and clinical care of people with early‐onset neurodegenerative dementia and their caregivers. Methods: Neurologists and geriatricians visiting patients with cognitive impairment in Catalonia were invited to prospectively collect demographical and clinical data from patients with age at onset (AAO) less than 65 years visited during the year 2021. Result: We registered information of 1221 subjects from 14 centers. Mean age was 56,2 years (SD 8.7), 64% were woman. Mean age at symptom onset was 53,9 years (SD 9.1). The most frequent cognitive symptoms at onset were memory impairment (72,9%) and dysexecutive difficulties (21,8%). Mean Mini Mental State Examination (MMSE) score was 26,7 (range 7‐30). Initial clinical diagnose was a non‐neurodegenerative disorder in 81,4% of cases and a neurodegenerative disorder in 17,81%. Genetic counseling accounted for 0,8% of visits. The suspected non‐neurodegenerative and neurodegenerative patients were studied with a neuropsychological test (85,5% vs 86,7%, respectively), magnetic resonance imaging (MRI) (39,9% vs 55,6%), computerized tomography (CT) scan (33,2% vs 34,4%), fluorodeoxyglucose positron emission tomography (FDG‐PET) (6,8% vs 39,0%), amyloid‐PET (3,9% vs 34,4%) and lumbar puncture (7,1%, vs 44,8%). 16,6% of participants had a final diagnose of a neurodegenerative cognitive disorder (10,9% Alzheimer's disease, 2,3% frontotemporal lobular degeneration, 2,1% MCI of suspected neurodegenerative etiology, 0,58% other neurodegenerative dementias); 83,4% were diagnosed with a non‐degenerative disorder (28,4% subjective cognitive decline (SCD), 25,0% mild cognitive impairment of non‐neurodegenerative etiology, 19,8% cognitive impairment after Covid‐19, 10,2% other dementias). Diagnostic delay was higher for neurodegenerative disorders (17 months: median 12 months (interquartile range (IQR) 19) between AAO and first visit +5 months (IQR 8) between first visit and diagnose) than non‐degenerative disorders (12 months: 9 months (IQR 19,6) + 3 months (IQR 7) respectively). Conclusion: Of 1221 patients under 65 years old visited in cognitive disorders units, only 16,6% had a final diagnose of neurodegenerative cognitive disorder. More than a quarter of subjects were diagnosed as SCD and a fifth as cognitive impairment after Covid‐19. In 2021, diagnosis delay was higher in neurodegenerative disorders (median 17 months). [ABSTRACT FROM AUTHOR]

INTRODUCTION: Amyloid‐β (Aβ) and tau can be quantified in blood. However, biological factors can influence the levels of brain‐derived proteins in the blood. The blood‐brain barrier (BBB) regulates protein transport between cerebrospinal fluid (CSF) and blood. BBB altered permeability might affect the relationship between brain and blood biomarkers. METHODS: We assessed 224 participants in research (TRIAD, n = 96) and clinical (BIODEGMAR, n = 128) cohorts with plasma and CSF/positron emission tomography Aβ, p‐tau, and albumin measures. RESULTS: Plasma Aβ42/40 better identified CSF Aβ42/40 and Aβ‐PET positivity in individuals with high BBB permeability. An interaction between plasma Aβ42/40 and BBB permeability on CSF Aβ42/40 was observed. Voxel‐wise models estimated that the association of positron emission tomography (PET), with plasma Aβ was most affected by BBB permeability in AD‐related brain regions. BBB permeability did not significantly impact the relationship between brain and plasma p‐tau levels. DISCUSSION: These findings suggest that BBB integrity may influence the performance of plasma Aβ, but not p‐tau, biomarkers in research and clinical settings. HIGHLIGHTS: BBB permeability affects the association between brain and plasma Aβ levels.BBB integrity does not affect the association between brain and plasma p‐tau levels.Plasma Aβ was most affected by BBB permeability in AD‐related brain regions.BBB permeability increases with age but not according to cognitive status. [ABSTRACT FROM AUTHOR]

Introduction: Direct comparisons of the main blood phosphorylated tau immunoassays in memory clinic populations are needed to understand possible differences. Methods: In the BIODEGMAR study, 197 participants presenting with cognitive complaints were classified into an Alzheimer's disease (AD) or a non‐AD cerebrospinal fluid (CSF) profile group, according to their amyloid beta 42/ phosphorylated tau (Aβ42/p‐tau) ratio. We performed a head‐to‐head comparison of nine plasma and nine CSF tau immunoassays and determined their accuracy to discriminate abnormal CSF Aβ42/p‐tau ratio. Results: All studied plasma tau biomarkers were significantly higher in the AD CSF profile group compared to the non‐AD CSF profile group and significantly discriminated abnormal CSF Aβ42/p‐tau ratio. For plasma p‐tau biomarkers, the higher discrimination accuracy was shown by Janssen p‐tau217 (r = 0.76; area under the curve [AUC] = 0.96), ADx p‐tau181 (r = 0.73; AUC = 0.94), and Lilly p‐tau217 (r = 0.73; AUC = 0.94). Discussion: Several plasma p‐tau biomarkers can be used in a specialized memory clinic as a stand‐alone biomarker to detect biologically‐defined AD. Highlights: Patients with an Alzheimer's disease cerebrospinal fluid (AD CSF) profile have higher plasma phosphorylated tau (p‐tau) levels than the non‐AD CSF profile group.All plasma p‐tau biomarkers significantly discriminate patients with an AD CSF profile from the non‐AD CSF profile group.Janssen p‐tau217, ADx p‐tau181, and Lilly p‐tau217 in plasma show the highest accuracy to detect biologically defined AD.Janssen p‐tau217, ADx p‐tau181, Lilly p‐tau217, Lilly p‐tau181, and UGot p‐tau231 in plasma show performances that are comparable to their CSF counterparts. [ABSTRACT FROM AUTHOR]

Background: MRI multi‐echo sequences can be used to compute quantitative R2 maps (1/T2). This pilot study aimed to determine whether R2 maps might offer relevant information on GM changes in AD continuum. Method: The sample consisted of 60 subjects: 20 healthy controls (HC), 20 cognitively unimpaired individuals with CSF Aβ42/40<0.071 (preAD) and 20 subjects with clinical diagnosis of Alzheimer disease (AD) validated by biomarkers (Ab42/p‐Tau181 ratio <10.25; Lumipulse‐Fujirebio). The MRI protocol included 3D T1W (voxel size: 1.2×1.2×1.2mm3, TR = 9.8ms, TE = 3ms, TI = 900ms) and multi‐echo (GRASE, voxel size: 2×2.2×2 mm3, TR = 2000ms, 32 echoes, TE: successive multiples of 9.3ms). R2 maps were obtained through linear regression of the logarithm of multi‐echo images. GM and R2 maps were spatially normalized to the MNI and smoothed (8mm FWHM). Voxel‐wise one‐way 3‐group ANOVA and post‐hoc paired t‐tests were performed on modulated GM (GMv) and R2 maps using age and sex as confounders and applying a common GM mask (SPM12, statistical threshold: p<0.001 uncorrected; k>100 voxels (∼0.33cm3) in all analyses). Result: Table 1 displays the descriptive statistics of the sample. Figure 1 shows the results from post‐hoc two‐sample t‐tests between HC and AD for GMv and R2 maps. GMv decrements were mostly located in temporal and parietal regions, as expected. Differences in R2 maps covered those regions but also others such anterior cingulate. No differences were found between HC and preAD neither in R2 maps nor in GMv. Conclusion: Results might indicate that changes in R2 are not only reflecting atrophy but other undetermined tissular changes. Further research is warranted to further determine the mechanisms underlying R2 maps changes and the potential usefulness of R2 maps in AD characterization and diagnosis. [ABSTRACT FROM AUTHOR]

Background: Pseudo continuous arterial spin labelling (pcASL) is an MRI technique to quantify cerebral blood flow (CBF). Time encoded ASL (te‐ASL) is a multiple time‐point pcASL variant that by acquiring several post‐label delays (PLD) to have more accurate CBF estimation allowing to measure arterial‐transit time (ATT). The aim of this study was to assess the performance of te‐ASL in detecting CBF and ATT changes in the Alzheimer's disease (AD) continuum. Method: The sample consisted of 59 subjects: 25 healthy controls (HC), 17 cognitively unimpaired individuals with positive cerebrospinal fluid (CSF) biomarkers (Ab42<1.098pg/mL; p‐Tau181>19pg/mL; Elecsys® ‐Roche Diagnostics) (preAD) and 17 patients with clinical diagnosis of AD (Ab42/p‐Tau181 ratio <10.25; Lumipulse‐Fujirebio). The MRI protocol comprised of anatomical T1, and ASL sequences (M0 and te‐ASL). CBF and ATT maps were calculated in the oxford_asl toolbox in FSL. CBF and ATT maps were spatially normalized to the MNI, smoothed (12mm FWHM) and intensity normalized to the cerebellar gray matter. To detect patterns of lower CBF, voxel‐wise one way 3‐group ANOVA and post‐hoc paired t‐tests were performed using age and sex as confounders (SPM12; statistical threshold: p<0.001 uncorrected; k>100 voxels (∼0.33cm3) in all analyses). We compared results with those obtained using a single PLD by computing CBF from the last PLD (perfusion block, nominal PLD time of 2000ms) of the te‐ASL schema. Result: Table 1 displays the descriptive statistics of the sample. Figure 1 shows that, with te‐ASL, AD patients displayed lower CBF (yellow) in extensive bilateral pareto‐temporal, cingulate and occipital areas. Preclinical AD participants showed an overlapping pattern (green), albeit reduced in extension. When using pcASL, the detected pattern of lower CBF in the AD group was less extended and did not overlap with that of the PreAD groups. No ATT differences were found associated to AD. Conclusion: te‐ASL was more sensitive to detect CBF differences across the AD continuum than single PLD ASL. The pattern of lower CBF in the AD group covered expected areas, and that in the preclinical AD group partially overlapped. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular risk factors (CVRF) have been associated with an increased risk of cognitive decline and dementia. Increase of blood‐brain barrier permeability (BBBp) measured by CSF/serum albumin ratio (Qalb) have been associated with CVRF. The aim of this study was to analyze the possible role of Qalb as a predictor of conversion to dementia in patients with mild cognitive impairment (MCI). Method: A total of 144 individuals with MCI were recruited from the BIODEGMAR cohort at Hospital del Mar (Barcelona) from 2017 to 2021. Study protocol included neuropsychological assessment, blood sampling, lumbar puncture and brain MRI. Follow‐up visits were performed yearly (12 +‐2 months) until January 2023. The endpoint of the study was a diagnosis of dementia (Global Deterioration Scale –GDS‐ > 3 and/or Clinical Dementia Rating ‐CDR‐ score > 0.5). BBBp was measured by CSF/serum albumin ratio (Qalb). Azheimer's Disease (AD) was biologically‐defined according to CSF Aβ42/p‐tau ratio (AD+/‐). A composite vascular score (CVS) was calculated by assigning one point for the presence of each of the following CVRF (hypertension, hyperlipidemia and diabetes mellitus) plus another point if Fazekas scale higher than 1 or presence of brain infarcts on MRI. We performed a multivariate Cox regression analysis including the following variables: age, sex, AD and CVS. Result: Sixty‐two cases (39.2%) developed dementia in a median follow‐up of 25.89 +/‐ 13.98 months. Univariate analysis showed that Qalb (p < 0.01), AD+ (p < 0.01) and CVS (p = 0.016) were associated with dementia. The regression model results showed an independent relationship between conversion to dementia and Qalb, HR = 1.333 (95% CI 1.185‐1.499) and AD+, HR = 4.118 (2.202‐7.699). Conclusion: An increase in BBBp was independently associated with a higher risk of conversion to dementia in MCI patients. This result points to a potential role of Qalb as a useful biomarker of clinical prognosis of MCI patients. [ABSTRACT FROM AUTHOR]

Background: Several blood phosphorylated tau (P‐tau) species (P‐tau181, P‐tau217, and P‐tau231) have shown high accuracy to detect AD pathology, but a direct comparison of the main blood P‐tau assays in a real‐world memory clinic is needed. The main aim of this study is to perform a head‐to‐head comparison of 9 plasma Tau assays and determine their accuracy to discriminate between symptomatic AD from non‐AD. Method: This is an observational and cross‐sectional study in the BIODEGMAR cohort, which includes patients presenting with cognitive complaints at the Cognitive Decline and Movement Disorders Unit of Hospital del Mar (Barcelona, Spain). Patients were classified into an AD CSF profile group or a non‐AD CSF profile group according to their CSF Aβ42/P‐tau181 ratio (Lumipulse, Fujirebio), and the discrimination accuracy of 9 plasma Tau assays was tested. All plasma samples were treated identically and measurements were performed in a blinded fashion. Result: A total of 197 participants (109 women [55.3%]; mean [SD] age, 72.3 [5.83] years), were investigated. All plasma Tau biomarkers were significantly higher in the AD CSF profile group than in the non‐AD CSF profile group. For plasma Tau biomarkers, the largest effect sizes were found in plasma Janssen P‐tau217 (r = 0.76), Lilly P‐tau217 (r = 0.73), ADx P‐tau181 (r = 0.73), Lilly P‐tau181 (r = 0.68), and UGot P‐tau231 (r = 0.63). All plasma Tau biomarkers significantly discriminated between patients with an AD CSF profile group from those with a non‐AD CSF profile. The AUC of plasma Tau biomarkers were the following (from highest to lower): Janssen P‐tau217 (0.96; 95% CI, 0.93‐0.99), ADx P‐tau181 (0.94; 95% CI, 0.91‐0.97) and Lilly P‐tau217 (0.94; 95% CI, 0.90‐0.98), Lilly P‐tau181 (0.91; 95% CI, 0.87‐0.96), UGot P‐tau231 (0.88; 95% CI, 0.83‐0.93), Quanterix P‐tau181 (0.80; 95% CI, 0.73‐0.87), UGot P‐tau181 (0.80; 95% CI, 0.73‐0.87), Lilly Total‐tau (0.73; 95% CI, 0.65‐0.81), and ADx P‐tau231 (0.66; 95% CI, 0.58‐0.74). Conclusion: The findings indicate that there are several plasma P‐tau biomarkers that can be used in a memory clinic setting as a stand‐alone biomarker to detect AD pathology in a diverse group of patients presenting with cognitive complaints. [ABSTRACT FROM AUTHOR]