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Resumen: Introducción: El análisis de biomarcadores bioquímicos de enfermedad de Alzheimer (EA) en líquido cefalorraquídeo (LCR) se recomienda como parte del diagnóstico en los centros en los que está disponible. Ante la ausencia de valores universales validados, se recomienda la determinación de puntos de corte (PdC) específicos para cada centro y su población. El objetivo principal del proyecto CORCOBIA fue determinar los PdC de biomarcadores de EA en LCR para varios centros (Parc de Salut Mar de Barcelona y Hospital General de Granollers) que trabajan con el mismo laboratorio de referencia (Laboratori de Referència de Catalunya). Métodos: Estudio prospectivo que incluyó sujetos cognitivamente sanos (n = 42), con deterioro cognitivo ligero amnésico (n = 35) y con demencia tipo Alzheimer (n = 48), a los que se realizó valoración clínica y neuropsicológica, neuroimagen, genotipado APOE y punción lumbar para analizar los péptidos beta-amiloides (Aβ42, Aβ40) y las proteínas tau total (tTau) y tau fosforilada (pTau181) mediante el autoanalizador Lumipulse® G600II (Fujirebio). Se calcularon los valores de sensibilidad y especificidad, los valores predictivos y el área bajo la curva (ABC), determinando el PdC según el índice de Youden comparando los grupos de sujetos cognitivamente sanos y con demencia tipo Alzheimer. Resultados: Los PdC y ABC fueron los siguientes: Aβ42 750 pg/ml (ABC 0,809); Aβ42/Aβ40 0,062 (ABC 0,78); pTau181 69,85 pg/ml (ABC 0,81); tTau 522,0 pg/ml (ABC 0,79); Aβ42/tTau 1,76 (ABC 0,86); Aβ42/pTau181 10,25 (ABC 0,86). Conclusiones: La determinación de PdC para biomarcadores de EA en LCR para los centros participantes permite una mejor precisión diagnóstica, siendo la ratio Aβ42/pTau181 en LCR el parámetro con mayor ABC y mejor balance entre sensibilidad y especificidad. Abstract: Introduction: The analysis of the core biomarkers of Alzheimer's disease (AD) in the cerebrospinal fluid (CSF) is recommended in the clinical units where it is available. Because of the absence of universal validated values, the determination of specific cut-off points (COP) for each center and its population is recommended. The main objective of the CORCOBIA study was to determine the COP of core AD CSF biomarkers for several centers (Parc de Salut Mar, Barcelona, and Hospital General de Granollers), which work with the same reference laboratory (Laboratori de Referència de Catalunya). Methods: Prospective study including cognitively healthy subjects (n = 42), subjects with amnestic mild cognitive impairment (n = 35) and patients with dementia due to AD (n = 48), in whom clinical and neuropsychological assessment, neuroimaging, APOE genotyping and lumbar puncture to analyze amyloid beta peptides (Aβ42, Aβ40), total tau (tTau) and phosphorylated Tau (pTau181) using the Lumipulse® G600II (Fujirebio) was performed. The values of sensitivity, specificity, predictive values and area under the curve (AUC) were calculated, determining the COP according to the Youden index by comparing the groups of cognitively healthy subjects and AD. Results: The resulting COP and their AUC were the following: Aβ42 750 pg/ml (AUC 0.809); Aβ42/Aβ40 0.062 pg/ml (AUC 0.78); pTau181 69.85 pg/ml (AUC 0.81); tTau 522.0 pg/ml (AUC 0.79); Aβ42/tTau 1.76 pg/ml (AUC 0.86); Aβ42/pTau181 10.25 pg/ml (AUC 0.86). Conclusions: The determination of COP of core AD CSF biomarkers for the participating centers allows a better diagnostic accuracy. The ratio CSF Aβ42/pTau181 shows the highest AUC and better balance between sensitivity and specificity.

Abstract Staging amyloid-beta (Aβ) pathophysiology according to the intensity of neurodegeneration could identify individuals at risk for cognitive decline in Alzheimer’s disease (AD). In blood, phosphorylated tau (p-tau) associates with Aβ pathophysiology but an AD-type neurodegeneration biomarker has been lacking. In this multicenter study (n = 1076), we show that brain-derived tau (BD-tau) in blood increases according to concomitant Aβ (“A”) and neurodegeneration (“N”) abnormalities (determined using cerebrospinal fluid biomarkers); We used blood-based A/N biomarkers to profile the participants in this study; individuals with blood-based p-tau+/BD-tau+ profiles had the fastest cognitive decline and atrophy rates, irrespective of the baseline cognitive status. Furthermore, BD-tau showed no or much weaker correlations with age, renal function, other comorbidities/risk factors and self-identified race/ethnicity, compared with other blood biomarkers. Here we show that blood-based BD-tau is a biomarker for identifying Aβ-positive individuals at risk of short-term cognitive decline and atrophy, with implications for clinical trials and implementation of anti-Aβ therapies.

Abstract Background Cerebrospinal fluid (CSF) p-tau235 is a novel biomarker highly specific of Alzheimer’s disease (AD). However, CSF p-tau235 has only been studied in well-characterized research cohorts, which do not fully reflect the patient landscape found in clinical settings. Therefore, in this multicentre study, we investigated the performance of CSF p-tau235 to detect symptomatic AD in clinical settings and compared it with CSF p-tau181, p-tau217 and p-tau231. Methods CSF p-tau235 was measured using an in-house single molecule array (Simoa) assay in two independent memory clinic cohorts: Paris cohort (Lariboisière Fernand-Widal University Hospital Paris, France; n=212) and BIODEGMAR cohort (Hospital del Mar, Barcelona, Spain; n=175). Patients were classified by the syndromic diagnosis (cognitively unimpaired [CU], mild cognitive impairment [MCI] or dementia) and their biological diagnosis (amyloid-beta [Aβ]+ or Aβ $$-$$ - ). Both cohorts included detailed cognitive assessments and CSF biomarker measurements (clinically validated core AD biomarkers [Lumipulse CSF Aβ1–42/40 ratio, p-tau181 and t-tau] and in-house developed Simoa CSF p-tau181, p-tau217 and p-tau231). Results High CSF p-tau235 levels were strongly associated with CSF amyloidosis regardless of the clinical diagnosis, being significantly increased in MCI Aβ+ and dementia Aβ+ when compared with all other Aβ− groups (Paris cohort: P ˂0.0001 for all; BIODEGMAR cohort: P ˂0.05 for all). CSF p-tau235 was pronouncedly increased in the A+T+ profile group compared with A−T− and A+T− groups (P ˂0.0001 for all). Moreover, CSF p-tau235 demonstrated high diagnostic accuracies identifying CSF amyloidosis in symptomatic cases (AUCs=0.86 to 0.96) and discriminating AT groups (AUCs=0.79 to 0.98). Overall, CSF p-tau235 showed similar performances to CSF p-tau181 and CSF p-tau231 when discriminating CSF amyloidosis in various scenarios, but lower than CSF p-tau217. Finally, CSF p-tau235 associated with global cognition and memory domain in both cohorts. Conclusions CSF p-tau235 was increased with the presence of CSF amyloidosis in two independent memory clinic cohorts. CSF p-tau235 accurately identified AD in both MCI and dementia patients. Overall, the diagnostic performance of CSF p-tau235 was comparable to that of other CSF p-tau measurements, indicating its suitability to support a biomarker-based AD diagnosis in clinical settings.

Recent advances in blood-based biomarkers of Alzheimer’s Disease (AD) show great promise for clinical applications, offering a less invasive alternative to current cerebrospinal fluid (CSF) measures. However, the relationships between these biomarkers and specific cognitive functions, as well as their utility in predicting longitudinal cognitive decline, are not yet fully understood. This descriptive review surveys the literature from 2018 to 2023, focusing on the associations of amyloid-β (Aβ), Total Tau (t-Tau), Phosphorylated Tau (p-Tau), Neurofilament Light (NfL), and Glial Fibrillary Acidic Protein (GFAP) with cognitive measures. The reviewed studies are heterogeneous, varying in design and population (cognitively unimpaired, cognitively impaired, or mixed populations), and show results that are sometimes conflicting. Generally, cognition positively correlates with Aβ levels, especially when evaluated through the Aβ42/Aβ40 ratio. In contrast, t-Tau, p-Tau, Nfl, and GFAP levels typically show a negative correlation with cognitive performance. While p-Tau measures generally exhibit stronger associations with cognitive functions compared to other biomarkers, no single blood marker has emerged as being predominantly linked to a specific cognitive domain. These findings contribute to our understanding of the complex relationship between blood biomarkers and cognitive performance and underscore their potential utility in clinical assessments of cognition.

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: State of emergency caused by COVID-19 pandemic and subsequent lockdown hit Spain on 14th March 2020 and lasted until 21st June 2020. Social isolation measures were applied. Medical attention was focused on COVID-19. Primary and social care were mainly performed by telephone. This exceptional situation may affect especially vulnerable patients such as people living with dementia. Our aim was to describe the influence of restrictive measures on patients living with mild cognitive decline and dementia evaluating SARS-CoV2 infection, changes in routines, cognitive decline stage, neuropsychiatric symptoms, delirium, falls, caregiver stress, and access to sanitary care.Materials and Methods: We gathered MCI and dementia patients with clinical follow-up before and after confinement from DegMar registry (Hospital del Mar). A telephone ad-hoc questionnaire was administered. Global status was assessed using CDR scale. Changes in neuropsychiatric symptoms were assessed by Neuropsychiatric Inventory (NPI) and retrospective interview for pre-confinement base characteristics.Results: We contacted a total of 60 patients, age 75.4 years ± 5,192. 53.3% were women. Alzheimer's Disease (41.7%) and Mild Cognitive Impairment (25%) were the most prevalent diagnosis. Remaining cases included different dementia disorders. A total of 10% of patients had been diagnosed with SARS-CoV-2. During confinement 70% of patients abandoned previous daily activities, 60% had cognitive worsening reported by relatives/caretakers, 15% presented delirium episodes, and 13% suffered increased incidence of falls. Caregivers reported an increased burden in 41% cases and burnout in 11% cases. 16% reported difficulties accessing medical care, 33% received medical phone assistance, 20% needed emergency care and 21% had changes in psychopharmacological therapies. Neuropsychiatric profile globally worsened (p < 0.000), also in particular items like agitation (p = 0.003), depression (p < 0.000), anxiety (p < 0.000) and changes in appetite (p = 0.004).Conclusion: SARS-CoV2-related lockdown resulted in an important effect over social and cognitive spheres and worsening of neuropsychiatric traits in patients living with mild cognitive decline and dementia. Although the uncertainty regarding the evolution of the pandemic makes strategy difficult, we need to reach patients and caregivers and develop adequate strategies to reinforce and adapt social and health care.

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]

Recent advances in blood-based biomarkers of Alzheimer's Disease (AD) show great promise for clinical applications, offering a less invasive alternative to current cerebrospinal fluid (CSF) measures. However, the relationships between these biomarkers and specific cognitive functions, as well as their utility in predicting longitudinal cognitive decline, are not yet fully understood. This descriptive review surveys the literature from 2018 to 2023, focusing on the associations of amyloid-β (Aβ), Total Tau (t-Tau), Phosphorylated Tau (p-Tau), Neurofilament Light (NfL), and Glial Fibrillary Acidic Protein (GFAP) with cognitive measures. The reviewed studies are heterogeneous, varying in design and population (cognitively unimpaired, cognitively impaired, or mixed populations), and show results that are sometimes conflicting. Generally, cognition positively correlates with Aβ levels, especially when evaluated through the Aβ42/Aβ40 ratio. In contrast, t-Tau, p-Tau, Nfl, and GFAP levels typically show a negative correlation with cognitive performance. While p-Tau measures generally exhibit stronger associations with cognitive functions compared to other biomarkers, no single blood marker has emerged as being predominantly linked to a specific cognitive domain. These findings contribute to our understanding of the complex relationship between blood biomarkers and cognitive performance and underscore their potential utility in clinical assessments of cognition. [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: 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]

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., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

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., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

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., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Hypertrophic pachymeningitis is an infrequent disorder that produces focal or diffuse thickening of the dura mater. It can be idiopathic or secondary to infectious, autoimmune or neoplastic processes. The recently described 'IgG4-related disease' could be the cause of many cases considered cryptogenic., Case Report: A 54-year-old woman, with a history of bronchial asthma, presented with headache, dizziness and hearing loss on her left ear. The brain MRI study with gadolinium showed enhancement and thickening of the dura mater, extending from lateral wall of left cavernous sinus and medial temporal lobe to cerebellopontine angle and ipsilateral tentorium. CSF had 10 leukocytes/µL (90% mononuclear), with 1 g/L protein and without glucose consumption. Pathology showed fibrosis and lymphoplasmacytic infiltrate, with 16 IgG4+ plasma cells per high power field. The rest of analytical and microbiological studies were normal or negative. The plasma IgG4 rate was within normal limits. After treatment with steroids there was clinical improvement accompanied by the virtual disappearance of the alterations detected in neuroimaging., Conclusions: Hypertrophic pachymeningitis as a manifestation of IgG4-related disease can be diagnosed based on MRI findings if plasma IgG4 is elevated. In doubtful cases we must resort to meningeal biopsy. Corticosteroid therapy is usually effective and it is the first line treatment.