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Abstract Background To explore whether the combination of white matter hyperintensities (WMHs) and amyloid-beta (Aβ) deposition is associated with worse cognitive performance on cognitive composites (CCs) domain scores in individuals with subjective cognitive decline (SCD). Methods Two hundred participants from the FACEHBI cohort underwent structural magnetic resonance imaging (MRI), 18F-florbetaben positron emission tomography (FBB-PET), and neuropsychological assessment. WMHs were addressed through the Fazekas scale, the Age-Related White Matter Changes (ARWMC) scale, and the FreeSurfer pipeline. Eight CCs domain scores were created using the principal component analysis (PCA). Age, sex, education, and apolipoprotein E (APOE) were used as adjusting variables. Results Adjusted multiple linear regression models showed that FreeSurfer (B − .245; 95% CI − .1.676, − .393, p = .016) and β burden (SUVR) (B − .180; 95% CI − 2.140, − .292; p = .070) were associated with face–name associative memory CCs domain score, although the latest one was not statistically significant after correction for multiple testing (p = .070). There was non-significant interaction of these two factors on this same CCs domain score (p = .54). However, its cumulative effects on face–name associative performance indicated that those individuals with either higher WMH load or higher Aβ burden showed the worst performance on the face–name associative memory CCs domain score. Conclusions Our results suggest that increased WMH load and increased Aβ are independently associated with poorer episodic memory performance in SCD individuals, indicating a cumulative effect of the combination of these two pathological conditions in promoting lower cognitive performance, an aspect that could help in terms of treatment and prevention.

Background : Alzheimer's disease (AD) dementia and mild cognitive impairment (MCI) are currently underdiagnosed in the community, and early detection of cognitive deficits is crucial for timely intervention. FACEmemory ® , the first completely self-administered online memory test with voice recognition, has been launched as an accessible tool to detect such deficits. This study aims to investigate the neuropsychological associations between FACEmemory subscores and cognitive composites derived from traditional paper-and-pencil neuropsychological tests and to develop an optimal algorithm using FACEmemory data and demographics to discriminate cognitively healthy (CH) individuals from those with MCI. Methods : A total of 669 participants (266 CH, 206 non-amnestic MCI [naMCI], and 197 amnestic MCI [aMCI]) were included. Multiple linear regression analyses were conducted using a cognitive composite as the dependent variable and FACEmemory subscores and demographic data (age, sex, and schooling) as independent variables. Machine learning models were compared to identify an optimal algorithm for distinguishing between CH and MCI (whole MCI, aMCI, and naMCI). Results : Multiple regression analyses showed associations between FACEmemory scores and the domains of memory (ρ = 0.67), executive functions (ρ = 0.63), visuospatial/visuoperceptual abilities (ρ = 0.55), language (ρ = 0.43), praxis (ρ = 0.52), and attention (ρ = 0.31). An optimal algorithm distinguished between CH and aMCI, achieving a FACEmemory cutoff score of 44.5, with sensitivity and specificity values of 0.81 and 0.72, respectively. Conclusions : FACEmemory is a promising online tool for identifying early cognitive impairment, particularly aMCI. It may contribute to addressing the underdiagnosis of MCI and dementia in the community and in promoting preventive strategies.

Background: Second-generation tau tracers for positron emission tomography (PET) show high affinity for paired helical filaments tau deposits characteristic of Alzheimer´s disease and low off-target binding. Differences in their chemical structure though may lead to variations in their regional tau uptake and off-target signal. In this work, we aimed to compare the in-vivo uptake of tau tracers [ 18 F]PI-2620 and [ 18 F]RO948 in the early stages of the AD continuum., Methods: Data from the TAU-PET FACEHBI clinical trial (EUDRA-CT 2021-000473-83) were analyzed. All participants were non-demented and underwent tau imaging with [ 18 F]PI-2620 and [ 18 F]RO948 PET within 3 months, amyloid imaging with [ 18 F]Florbetaben and brain magnetic resonance imaging. Tau PET standardized uptake values ratios (SUVR) were calculated in Braak and typical off-target regions using the inferior cerebellar cortex as a reference region., Results: The cohort consisted of 18 individuals with subjective cognitive decline (n = 13) and mild cognitive impairment (n = 5), with centiloid values ranging from 17 to 159. Both tau tracers showed similar tau pathology distribution but presented a distinct off-target signal pattern on visual read. SUVR measurements for [ 18 F]PI-2620 and [ 18 F]RO948 were highly correlated in all Braak regions (R 2 range [0.65-0.80]). Regarding off-target signal, [ 18 F]PI-2620 had higher SUVRs in vascular structures, and [ 18 F]RO948 had higher SUVRs in the skull/meninges., Conclusions: In a cohort of individuals at early stages of the AD continuum, tau PET tracers [ 18 F]PI-2620 and [ 18 F]RO948 showed similar in-vivo uptake in all Braak regions and distinct off-target signal. These preliminary results support the development of standardized quantification scales for tau deposition that are tracer-independent., Trial Registration: AEMPS EudraCT 2021-000473-83. Registered 30 December 2021., Competing Interests: Declarations. Ethics approval and consent to participate: The study was conducted in accordance with the Declaration of Helsinki. The TAU-PET FACEHBI protocol received the approval from the Spanish Drug Agency (AEMPS for its initials in Spanish) and was registered as phase II clinical trial (CT) (EudraCT: 2021-000473-83, approval date December 15th 2021) and by the Ethics Committee of Hospital Universitari de Bellvitge in Hospitalet de Llobregat, Spain. The FACEHBI-2 protocol (which includes study v5) was approved by the Ethics Committee of Hospital Clínic i Provincial in Barcelona, Spain. Informed consent was obtained from all participants involved in the study. Consent for publication: The authors affirm that human research participants provided informed consent for publication of the images in Fig. 2. Competing interests: MB has consulted for Araclon, Avid, Grifols, Lilly, Nutricia, Roche, Eisai and Servier. She received fees from lectures and funds for research from Araclon, Biogen, Grifols, Nutricia, Roche and Servier. She reports grants/research funding from Abbvie, Araclon, Biogen Research Limited, Bioiberica, Grifols, Lilly, S.A, Merck Sharp & Dohme, Kyowa Hakko Kirin, Laboratorios Servier, Nutricia SRL, Oryzon Genomics, Piramal Imaging Limited, Roche Pharma SA, and Schwabe Farma Iberica SLU, all outside the submitted work. She has not received personal compensations from these organizations. AR is member of scientific advisory board of Landsteiner Genmed and Grifols SA. AR has stocks of Landsteiner Genmed. MM has consulted for F. Hoffmann-La Roche Ltd and is a member of the Scientific Advisory Board of Biomarkers of Araclon. MT, EB, CG, GK are full-time employees, and owns stock or stock options, of F. Hoffmann-La Roche Ltd. NRV, SB, EPM, ES are full-time employees of Life Molecular Imaging GmbH. The rest of authors declare that they have no competing interests., (© 2024. The Author(s).)

Background: Optical coherence tomography (OCT) enables high-resolution imaging of ocular structures in health and disease. Choroid thickness (CT) is a key vascular retinal parameter that can be assessed by OCT and might be relevant in the evaluation of the vascular component of cognitive decline. We aimed to investigate CT changes in a large cohort of individuals cognitive unimpaired (CU), with mild cognitive impairment due to Alzheimer's (MCI-AD), mild cognitive impairment due to cerebrovascular disease (MCI-Va), Alzheimer's disease dementia (ADD), and vascular dementia (VaD)., Methods: Clinical, demographical, ophthalmological and OCT data from the Neuro-ophthalmological Research at Fundació ACE (NORFACE) project were analyzed. CT was assessed in the macula across nine Early Treatment Diabetic Retinopathy Study (ETDRS) quadrants, average thickness, total volume, and subfoveal choroidal thickness. Differences of CT among the five diagnostic groups were assessed in a multivariate regression model, adjusting for demographic and cardiovascular risk factors and OCT image quality. A comparison between manual and automatic CT measurements in a subset of participants was also performed., Results: The study cohort comprised 1,280 participants: 301 CU, 196 MCI-AD, 112 MCI-Va, 578 ADD, and 93 VaD. CT was significantly increased in individuals with cognitive impairment compared to those CU, particularly in the VaD and MCI-Va groups and in the peripheral ETDRS regions. No significant differences were found in inner superior, center and subfoveal choroidal thickness. The interaction of sex and diagnosis had no effect in differentiating CT. Mini-Mental State Examination (MMSE) scores were not correlated to CT. Manual and automated CT measurements showed good reliability., Discussion: Our findings indicated that peripheral choroidal thickening, especially in patients with cerebrovascular disease, may serve as a potential choroidal biomarker for cognitive decline and suggest different pathogenic pathways in AD and VaD. Further research is required to explore CT as a reliable ocular biomarker for cognitive impairment., Competing Interests: Declarations Ethics approval and consent to participate This study and its informed consent were approved by the Ethics Committee of the Hospital Clínic i Provincial de Barcelona in accordance with Spanish biomedical laws (Law 14/2007, of July 3, on biomedical research; Royal Decree 1716/2011, of November 18) and followed the recommendations of the declaration of Helsinki. All participants signed an informed consent form (in the case of individuals with moderate stages of dementia, informed consent was signed by their legal representative or family member). Consent for publication Not applicable. Competing interests MB has consulted for Araclon, Avid, Grifols, Lilly, Nutricia, Roche, Eisai and Servier. She received fees from lectures and funds for research from Araclon, Biogen, Grifols, Nutricia, Roche and Servier. She reports grants/research funding from Abbvie, Araclon, Biogen Research Limited, Bioiberica, Grifols, Lilly, S.A, Merck Sharp & Dohme, Kyowa Hakko Kirin, Laboratorios Servier, Nutricia SRL, Oryzon Genomics, Piramal Imaging Limited, Roche Pharma SA, and Schwabe Farma Iberica SLU, all outside the submitted work. She has not received personal compensations from these organizations. AR is member of scientific advisory board of Landsteiner Genmed and Grifols SA. AR has stocks of Landsteiner Genmed. MM has consulted for F. Hoffmann-La Roche Ltd. The rest of authors declare that they have no competing interests., (© 2024. The Author(s).)

Background: The identification of patients with an elevated risk of developing Alzheimer's disease (AD) dementia and eligible for the disease-modifying treatments (DMTs) in the earliest stages is one of the greatest challenges in the clinical practice. Plasma biomarkers has the potential to predict these issues, but further research is still needed to translate them to clinical practice. Here we evaluated the clinical applicability of plasma pTau181 as a predictive marker of AD pathology in a large real-world cohort of a memory clinic., Methods: Three independent cohorts (modelling [n = 991, 59.7% female], testing [n = 642, 56.2% female] and validation [n = 441, 55.1% female]) of real-world patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), AD dementia, and other dementias were included. Paired cerebrospinal fluid (CSF) and plasma samples were used to measure AT(N) CSF biomarkers and plasma pTau181., Findings: CSF and plasma pTau181 showed correlation in all phenotypes except in SCD and other dementias. Age significantly influenced the biomarker's performance. The general Aβ(+) vs Aβ(-) ROC curve showed an AUC = 0.77 [0.74-0.80], whereas the specific ROC curve of MCI due to AD vs non-AD MCI showed an AUC = 0.89 [0.85-0.93]. A cut-off value of 1.30 pg/ml of plasma pTau181 exhibited a sensitivity of 93.57% [88.72-96.52], specificity of 72.38% [62.51-79.01], VPP of 77.85% [70.61-83.54], and 8.30% false negatives in the subjects with MCI of the testing cohort. The HR of cox regression showed that patients with MCI up to this cut-off value exhibited a HR = 1.84 [1.05-3.22] higher risk to convert to AD dementia than patients with MCI below the cut-off value., Interpretation: Plasma pTau181 has the potential to be used in the memory clinics as a screening biomarker of AD pathology in subjects with MCI, presenting a valuable prognostic utility in predicting the MCI conversion to AD dementia. In the context of a real-world population, a confirmatory test employing gold-standard procedures is still advisable., Funding: This study has been mainly funded by Ace Alzheimer Center Barcelona, Instituto de Salud Carlos III (ISCIII), Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Spanish Ministry of Science and Innovation, Fundación ADEY, Fundación Echevarne and Grífols S.A., Competing Interests: Declaration of interests Alberto Lleó received personal fees for service on the advisory boards from Biogen, Eisai, Fujirebio-Europe, Lilly, Novartis, NovoNordisk, Nutricia, Otsuka Pharmaceutical, and Zambón, and received speaker honoraria from Lilly, Biogen, KRKA and Zambon. Juan Fortea received personal fees for service on the advisory boards, adjudication committees or speaker honoraria from AC Immune, Lilly, Lundbeck, Roche, Fujirebio and Biogen, outside the submitted work. D.A., A.L. and J.F. report holding a patent for markers of synaptopathy in neurodegenerative disease (licensed to Adx, EPI8382175.0). Marta Marquié received personal fees for service on the advisory boards from Araclon Biotech–Grifols, S.A. Marta Marquié received grants or contracts from Instituto de Salud Carlos III (ISCIII) Accion Estrategica en Salud, integrated in the Spanish National RCDCI Plan and financed by ISCIII-Subdireccion General de Evaluacion and the Fondo Europeo de Desarrollo Regional (FEDER—Una manera de hacer Europa) grant PI19/00335. Daniel Alcolea received personal fees for service on the advisory boards from Fujirebio-Europe, Roche Diagnostics, Nutricia, Krka Farmacéutica S.L., Zambon S.A.U., Grifols, S.A., Lilly, and Esteve Pharmaceuticals S.A., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Optical coherence tomography angiography (OCT-A) is a novel tool that allows the detection of retinal vascular changes. We investigated the association of macular vessel density (VD) in the superficial plexus assessed by OCT-A with measures of cerebrovascular pathology and atrophy quantified by brain magnetic resonance imaging (MRI) in non-demented individuals., Methods: Clinical, demographical, OCT-A, and brain MRI data from non-demented research participants were included. We analyzed the association of regional macular VD with brain vascular burden using the Fazekas scale assessed in a logistic regression analysis, and the volume of white matter hyperintensities (WMH) assessed in a multiple linear regression analysis. We also explored the associations of macular VD with hippocampal volume, ventricle volume and Alzheimer disease cortical signature (ADCS) thickness assessed in multiple linear regression analyses. All analyses were adjusted for age, sex, syndromic diagnosis and cardiovascular variables., Results: The study cohort comprised 188 participants: 89 with subjective cognitive decline and 99 with mild cognitive impairment. No significant association of regional macular VD with the Fazekas categories (all, p > 0.111) and WMH volume (all, p > 0.051) were detected. VD in the nasal quadrant was associated to hippocampal volume (p = 0.007), but no other associations of macular VD with brain atrophy measures were detected (all, p > 0.05)., Discussion: Retinal vascular measures were not a proxy of cerebrovascular damage in non-demented individuals, while VD in the nasal quadrant was associated with hippocampal atrophy independently of the amyloid status., (© 2024. The Author(s).)

Extracts made from plants are complex mixtures of substances with varying compositions depending on the plant material and method of manufacture. This complexity makes it difficult for scientists and clinicians to interpret findings from pharmacological and clinical research. We performed a narrative review summarizing information on ginkgo biloba leaf extract, its composition, pharmacological data and clinical evidence supporting its administration for the treatment of Alzheimer's disease (AD). Medicinal products containing ginkgo biloba leaf extract which are manufactured in compliance with the requirements of the European Pharmacopoeia are approved as medicinal products for the treatment of dementia and related conditions by drug regulatory agencies in Europe, Asia and South America. As multicomponent mixtures, they may affect various targets in the pathogenesis of AD, the most common form of dementia. Pharmacodynamic studies demonstrate the effects of EGb 761 and individual constituents on various pathophysiological features of experimentally induced cognitive impairment and neurodegeneration that could contribute to its clinical efficacy. The safety and efficacy in the treatment of AD and cognitive decline has been studied in randomized, placebo-controlled clinical trials. Most of the studies that investigate the effects of ginkgo biloba extract (GbE) used the special extract EGb 761, which makes it the best-researched plant preparation worldwide. It is therefore the only herbal alternative to standard-of-care anti-dementia drugs. However, the mechanism of action has not been fully elucidated yet, and the clinical studies in AD show heterogeneity.

Background: Decline in language has emerged as a new potential biomarker for the early detection of Alzheimer's disease (AD). It remains unclear how sensitive language measures are across different tasks, language domains, and languages, and to what extent changes can be reliably detected in early stages such as subjective cognitive decline (SCD) and mild cognitive impairment (MCI)., Method: Using a scene construction task for speech elicitation in a new Spanish/Catalan speaking cohort ( N = 119), we automatically extracted features across seven domains, three acoustic (spectral, cepstral, and voice quality), one prosodic, and three from text (morpholexical, semantic, and syntactic). They were forwarded to a random forest classifier to evaluate the discriminability of participants with probable AD dementia, amnestic and nonamnestic MCI, SCD, and cognitively healthy controls. Repeated-measures analyses of variance and paired-samples Wilcoxon signed-ranks test were used to assess whether and how performance differs significantly across groups and linguistic domains., Results: The performance scores of the machine learning classifier were generally satisfactorily high, with the highest scores over .9. Model performance was significantly different for linguistic domains ( p < .001), and speech versus text ( p = .043), with speech features outperforming textual features, and voice quality performing best. High diagnostic classification accuracies were seen even within both cognitively healthy (controls vs. SCD) and MCI (amnestic and nonamnestic) groups., Conclusion: Speech-based machine learning is powerful in detecting cognitive decline and probable AD dementia across a range of different feature domains, though important differences exist between these domains as well., Supplemental Material: https://doi.org/10.23641/asha.23699733.

Although beta-amyloid (Aβ) and phosphorylated tau remain the preferred targets for disease-modifying treatments (DMT) against Alzheimer's disease (AD), part of the pathophysiological mechanisms of cognitive impairment are related to neuroinflammation and oxidative stress. In mild cognitive impairment (MCI), a prodromal stage of AD and other neurodegenerative conditions, the joint appearance of inflammation, oxidative stress, and metabolic alterations are the common pathways of neurotoxicity and neurodegeneration. The standardized extract of Ginkgo biloba EGb 761 interferes with the pathogenic mechanisms involved in both the development of cognitive impairment due to AD and that of vascular origin. The primary objective of this study is to compare changes in the levels of blood markers of inflammation and oxidative stress after treatment with EGb 761 in a cohort of 100 patients with MCI. In addition, we aim to assess changes in these blood markers during an additional 12-month extension phase in which patients in the control group will also receive EGb 761 and patients in the active group will extend their treatment duration. Secondary objectives include comparing changes in neuropsychiatric and cognitive test scores between the baseline (v0) and 12-month visits (v2). This study is a Phase IV, single-center, randomized, open-label, parallel-group clinical trial consisting of the 12-month follow-up of a cohort of participants with MCI [Global Deterioration Scale (GDS) = 3] and an extension with an additional 12-month follow-up. During the first 12 months, participants will be randomized into two arms: in one arm, patients will receive 1 daily tablet of EGb 761 240 mg orally (study group, n = 50), while in the other arm, patients will not receive EGb 761 and will undergo the same assessments as the treated group (control group, n = 50). After the first 12 months of the study, patients in the EGb 761-treated group will continue treatment, and patients in the control group will be offered one EGb 761 240 mg tablet per day orally. All participants will be monitored for an additional 12 months. A battery of blood markers of inflammation and oxidative stress will be quantified at v0, v1, v2, v3, and v4. The Olink Proteomics panel of inflammation markers ( https://www.olink.com/products/inflammation/ ) will be used to evaluate 92 proteins associated with inflammatory diseases and related biological processes. The second panel measures 92 proteins involved in neurological processes. At v0, v2, and v4, neuropsychological and neurological evaluations will be conducted in addition to vital signs and anthropometric studies using a body composition monitor with bioimpedance technology (Tanita). Sixty percent of the 100 MCI patients recruited were women. The mean age was 73.1 years, and the mean time between symptom onset and MCI diagnosis was 2.9 years. The mean Mini-Mental State Examination (MMSE) score was 26.7. Depressive and anxiety disorders, as well as vascular risk factors, were the most frequent comorbidities among the cohort. The study is still ongoing, and results for the first year of treatment (v0, v1, v2) are expected by 2023. Individuals with MCI have an elevated risk of developing dementia. EGb 761 is used worldwide for the symptomatic treatment of cognitive disorders due to its neuroprotective effects. In experimental models and clinical observational studies, EGb 761 has shown strong antioxidant and anti-inflammatory activity. As a result, this study has been proposed to evaluate the antioxidant and anti-inflammatory effects on plasma markers and their potential clinical correlation with the progression of cognitive decline in patients with MCI.Trial registration: Registro Español de estudios clínicos (REec) number 2020-003776-41, ClinicalTrials.gov Identifier: NCT05594355., (© 2023. The Author(s).)

Background: Optical coherence tomography angiography (OCT-A) is a novel method in the dementia field that allows the detection of retinal vascular changes. The comparison of OCT-A measures with established Alzheimer's disease (AD)-related biomarkers is essential to validate the former as a marker of cerebrovascular impairment in the AD continuum. We aimed to investigate the association of macular vessel density (VD) in the superficial plexus quantified by OCT-A with the AT(N) classification based on cerebrospinal fluid (CSF) Aβ1-42, p181-tau and t-tau measurements in individuals with mild cognitive impairment (MCI)., Materials and Methods: Clinical, demographic, ophthalmological, OCT-A and CSF core biomarkers for AD data from the Neuro-ophthalmology Research at Fundació ACE (NORFACE) project were analyzed. Differences in macular VD in four quadrants (superior, nasal, inferior, and temporal) among three AT(N) groups [Normal, Alzheimer and Suspected non-Alzheimer pathology (SNAP)] were assessed in a multivariate regression model, adjusted for age, APOE ε4 status, hypertension, diabetes mellitus, dyslipidemia, heart disease, chronic obstructive pulmonary disease and smoking habit, using the Normal AT(N) group as the reference category., Results: The study cohort comprised 144 MCI participants: 66 Normal AT(N), 45 Alzheimer AT(N) and 33 SNAP AT(N). Regression analysis showed no significant association of the AT(N) groups with any of the regional macular VD measures (all, p > 0.16). The interaction between sex and AT(N) groups had no effect on differentiating VD. Lastly, CSF Aβ1-42, p181-tau and t-tau measures were not correlated to VD (all r < 0.13; p > 0.13)., Discussion: Our study showed that macular VD measures were not associated with the AT(N) classification based on CSF biomarkers in patients with MCI, and did not differ between AD and other underlying causes of cognitive decline in our cohort., Competing Interests: MB has consulted for Araclon, Avid, Grifols, Lilly, Nutricia, Roche, Eisai and Servier. She received fees from lectures and funds for research from Araclon, Biogen, Grifols, Nutricia, Roche and Servier. She reports grants/research funding from Abbvie, Araclon, Biogen Research Limited, Bioiberica, Grifols, Lilly, SA, Merck Sharp & Dohme, Kyowa Hakko Kirin, Laboratorios Servier, Nutricia SRL, Oryzon Genomics, Piramal Imaging Limited, Roche Pharma SA, and Schwabe Farma Iberica SLU, all outside the submitted work. She has not received personal compensation from these organizations. AR was member of the scientific advisory board of Landsteiner Genmed and Grifols SA. AR holds stocks in Landsteiner Genmed. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Marquié, García-Sánchez, Alarcón-Martín, Martínez, Castilla-Martí, Castilla-Martí, Orellana, Montrreal, de Rojas, García-González, Puerta, Olivé, Cano, Hernández, Rosende-Roca, Vargas, Tartari, Esteban-De Antonio, Bojaryn, Ricciardi, Ariton, Pytel, Alegret, Ortega, Espinosa, Pérez-Cordón, Sanabria, Muñoz, Lleonart, Aguilera, Tárraga, Valero, Ruiz and Boada.)

Few studies have addressed the impact of the association between Alzheimer's disease (AD) biomarkers and NPSs in the conversion to dementia in patients with mild cognitive impairment (MCI), and no studies have been conducted on the interaction effect of these two risk factors. AT(N) profiles were created using AD-core biomarkers quantified in cerebrospinal fluid (CSF) (normal, brain amyloidosis, suspected non-Alzheimer pathology (SNAP) and prodromal AD). NPSs were assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q). A total of 500 individuals with MCI were followed-up yearly in a memory unit. Cox regression analysis was used to determine risk of conversion, considering additive and multiplicative interactions between AT(N) profile and NPSs on the conversion to dementia. A total of 224 participants (44.8%) converted to dementia during the 2-year follow-up study. Pathologic AT(N) groups (brain amyloidosis, prodromal AD and SNAP) and the presence of depression and apathy were associated with a higher risk of conversion to dementia. The additive combination of the AT(N) profile with depression exacerbates the risk of conversion to dementia. A synergic effect of prodromal AD profile with depressive symptoms is evidenced, identifying the most exposed individuals to conversion among MCI patients.

Background: Accessible and cost-effective diagnostic tools are urgently needed to accurately quantify blood biomarkers to support early diagnosis of Alzheimer's disease (AD). In this study, we investigated the ability of plasma amyloid-beta (Aβ)42/Aβ40 ratio measured by an antibody-free mass-spectrometric (MS) method, ABtest-MS, to detect early pathological changes of AD., Methods: This cohort study included data from the baseline and 2-year follow-up visits from the Fundació ACE Healthy Brain Initiative (FACEHBI) study. Plasma Aβ42/Aβ40 was measured with ABtest-MS and compared to 18 F-Florbetaben PET as the reference standard (cutoff for early amyloid deposition of 13.5 centiloids). Cross-validation was performed in an independent DPUK-Korean cohort. Additionally, associations of plasma Aβ42/Aβ40 with episodic memory performance and brain atrophy were assessed., Results: The FACEHBI cohort at baseline included 200 healthy individuals with subjective cognitive decline (SCD), of which 36 (18%) were Aβ-PET positive. Plasma Aβ42/Aβ40 levels were significantly lower in Aβ-PET positive individuals (median [interquartile range, IQR], 0.215 [0.203-0.236]) versus Aβ-PET negative subjects (median [IQR], 0.261 [0.244-0.279]) (P < .001). Plasma Aβ42/Aβ40 was significantly correlated with Aβ-PET levels (rho = -0.390; P < .001) and identified Aβ-PET status with an area under the receiver operating characteristic curve (AUC) of 0.87 (95% confidence interval [CI], 0.80-0.93). A cutoff for the Aβ42/Aβ40 ratio of 0.241 (maximum Youden index) yielded a sensitivity of 86.1% and a specificity of 80.5%. These findings were cross-validated in an independent DPUK-Korean cohort (AUC 0.86 [95% CI 0.77-0.95]). Lower plasma Aβ42/Aβ40 ratio was associated with worse episodic memory performance and increased brain atrophy. Plasma Aβ42/Aβ40 at baseline predicted clinical conversion to mild cognitive impairment and longitudinal changes in amyloid deposition and brain atrophy at 2-year follow-up., Conclusions: This study suggests that plasma Aβ42/Aβ40, as determined by this MS-based assay, has potential value as an accurate and cost-effective tool to identify individuals in the earliest stages of AD, supporting its implementation in clinical trials, preventative strategies and clinical practice., (© 2023. The Author(s).)

Optical coherence tomography angiography (OCT-A) allows the detection of retinal vessel density (VD) loss, which is a reflection of brain vascular pathology. We aimed to investigate differences in macular VD in the superficial plexus in a large cohort of individuals cognitively unimpaired (CU), with mild cognitive impairment due to Alzheimer´s disease (MCI-AD), MCI due to cerebrovascular pathology (MCI-Va), probable Alzheimer´s disease dementia (ADD) and Vascular Dementia (VaD). Clinical, demographical, ophthalmological and OCT-A data from the Neuro-ophthalmology Research at Fundació ACE (NORFACE) project were analyzed. Differences of macular VD in four quadrants (superior, nasal, inferior and temporal) among the five diagnostic groups were assessed in a multivariate regression model, adjusted by age, sex, education, hypertension, diabetes mellitus, heart disease and stroke. The study cohort comprised 672 participants: 128 CU, 120 MCI-AD, 111 MCI-Va, 257 ADD and 56 VaD. Regression analysis showed a significantly higher VD in the temporal quadrant in MCI-AD compared to CU participants (49.05 ± 4.91 vs 47.27 ± 4.17, p = 0.02, d = 0.40), and a significantly lower VD in the inferior quadrant in MCI-Va compared to CU participants (48.70 ± 6.57 vs 51.27 ± 6.39, p = 0.02, d = 0.40). Individuals with heart disease presented significantly lower VD in the inferior quadrant than those without (p = 0.01). The interaction of sex and diagnosis had no effect in differentiating VD. Mini-Mental State Examination (MMSE) scores were not correlated to VD (all r < 0.16; p > 0.07). In conclusion, our study showed that the MCI-AD and MCI-Va groups had significant differences in macular VD in opposite directions in the temporal and inferior quadrants, respectively, compared to CU participants, suggesting that macular VD might be able to differentiate two pathogenic pathways (AD- and cerebrovascular-related) in early stages of cognitive decline., (© 2022. The Author(s).)

Background: Clinical diagnosis of Alzheimer's disease (AD) increasingly incorporates CSF biomarkers. However, due to the intrinsic variability of the immunodetection techniques used to measure these biomarkers, establishing in-house cutoffs defining the positivity/negativity of CSF biomarkers is recommended. However, the cutoffs currently published are usually reported by using cross-sectional datasets, not providing evidence about its intrinsic prognostic value when applied to real-world memory clinic cases., Methods: We quantified CSF Aβ1-42, Aβ1-40, t-Tau, and p181Tau with standard INNOTEST ® ELISA and Lumipulse G ® chemiluminescence enzyme immunoassay (CLEIA) performed on the automated Lumipulse G600II. Determination of cutoffs included patients clinically diagnosed with probable Alzheimer's disease (AD, n = 37) and subjective cognitive decline subjects (SCD, n = 45), cognitively stable for 3 years and with no evidence of brain amyloidosis in 18F-Florbetaben-labeled positron emission tomography (FBB-PET). To compare both methods, a subset of samples for Aβ1-42 (n = 519), t-Tau (n = 399), p181Tau (n = 77), and Aβ1-40 (n = 44) was analyzed. Kappa agreement of single biomarkers and Aβ1-42/Aβ1-40 was evaluated in an independent group of mild cognitive impairment (MCI) and dementia patients (n = 68). Next, established cutoffs were applied to a large real-world cohort of MCI subjects with follow-up data available (n = 647)., Results: Cutoff values of Aβ1-42 and t-Tau were higher for CLEIA than for ELISA and similar for p181Tau. Spearman coefficients ranged between 0.81 for Aβ1-40 and 0.96 for p181TAU. Passing-Bablok analysis showed a systematic and proportional difference for all biomarkers but only systematic for Aβ1-40. Bland-Altman analysis showed an average difference between methods in favor of CLEIA. Kappa agreement for single biomarkers was good but lower for the Aβ1-42/Aβ1-40 ratio. Using the calculated cutoffs, we were able to stratify MCI subjects into four AT(N) categories. Kaplan-Meier analyses of AT(N) categories demonstrated gradual and differential dementia conversion rates ( p = 9.815 -27 ). Multivariate Cox proportional hazard models corroborated these findings, demonstrating that the proposed AT(N) classifier has prognostic value. AT(N) categories are only modestly influenced by other known factors associated with disease progression., Conclusions: We established CLEIA and ELISA internal cutoffs to discriminate AD patients from amyloid-negative SCD individuals. The results obtained by both methods are not interchangeable but show good agreement. CLEIA is a good and faster alternative to manual ELISA for providing AT(N) classification of our patients. AT(N) categories have an impact on disease progression. AT(N) classifiers increase the certainty of the MCI prognosis, which can be instrumental in managing real-world MCI subjects.

Background: FACEmemory® is the first computerized, self-administered verbal episodic memory test with voice recognition. It can be conducted under minimal supervision and contains an automatic scoring system to avoid administrator errors. Moreover, it is suitable for discriminating between cognitively healthy and amnestic mild cognitive impairment (MCI) individuals, and it is associated with Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers. This study aimed to determine whether FACEmemory scoring is related to performance on classical memory tests and to AD biomarkers of brain magnetic resonance imaging (MRI) and CSF in patients with early-onset MCI (EOMCI)., Methods: Ninety-four patients with EOMCI from the BIOFACE study completed FACEmemory, classical memory tests (the Spanish version of the Word Free and Cued Selective Reminding Test -FCSRT-, the Word List from the Wechsler Memory Scale, third edition, and the Spanish version of the Rey-Osterrieth Complex Figure Test), and a brain MRI. Eighty-two individuals also underwent a lumbar puncture., Results: FACEmemory scoring was moderately correlated with FCSRT scoring. With regard to neuroimaging MRI results, worse execution on FACEmemory was associated with lower cortical volume in the right prefrontal and inferior parietal areas, along with the left temporal and associative occipital areas. Moreover, the total FACEmemory score correlated with CSF AD biomarkers (Aβ1-42/Aβ1-40 ratio, p181-tau, and Aβ1-42/p181-tau ratio). When performance on FACEmemory was compared among the ATN classification groups, significant differences between the AD group and normal and SNAP groups were found., Conclusions: FACEmemory is a promising tool for detecting memory deficits sensitive to early-onset AD, but it also allows the detection of memory-impaired cases due to other etiologies. Our findings suggest that FACEmemory scoring can detect the AD endophenotype and that it is also associated with AD-related changes in MRI and CSF in patients with EOMCI. The computerized FACEmemory tool might be an opportunity to facilitate early detection of MCI in younger people than 65, who have a growing interest in new technologies., (© 2022. The Author(s).)

Background: Neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) can be disruptive for patients and their families., Objective: We aimed to classify patients based on NPS and to explore the relationship of these classes with sex and with caregiver burden., Methods: The study cohort comprised individuals with AD dementia diagnosed at Ace Alzheimer Center in Barcelona, Spain, between 2011-2020. NPS were ascertained by using the Neuropsychiatric Inventory-Questionnaire. Latent class analysis was used to identify clusters of individuals sharing a similar NPS profile. We evaluated the caregiver burden using the Zarit Burden Interview. Multivariable regression models were used to obtain adjusted estimates of the association between sex, NPS classes, and caregiver burden., Results: A total of 1,065 patients with AD dementia and their primary caregivers were included. We classified patients into five different classes according to their NPS profile: "Affective", "High-behavioral-disturbance", "Negative-affect", "Affective/deliriant", and "Apathy". We found that age, sex, and type of AD diagnosis differed greatly across classes. We found that patients from the "High-behavioral-disturbance" (OR = 2.56, 95% CI: 1.00-6.56), "Negative-affect" (OR = 2.72, 95% CI: 1.26-3.64), and "Affective/deliriant" (OR = 2.14, 95% CI: 1.26-3.64) classes were over two times more likely to have a female caregiver than those in "Apathy" class. These three classes were also the ones associated to the greatest caregiver burden in the adjusted analyses, which seems to explain the increased burden observed among female caregivers., Conclusion: Caregiver burden is highly dependent on the patient's NPS profiles. Female caregivers provide care to patients that pose a greater burden, which makes them more susceptible to become overwhelmed.

Introduction: Mild cognitive impairment is often associated with affective and other neuropsychiatric symptoms (NPS). This co-occurrence might have a relevant impact on disease progression, from MCI to dementia. Objective: The aim of this study was to explore the trajectories of cognitive decline in an MCI sample from a memory clinic, taking into consideration a perspective of isolated cognitive functions and based on NPS clusters, accounting for the different comorbid symptoms collected at their baseline visit. Methods: A total of 2,137 MCI patients were monitored over a 2.4-year period. Four clusters of NPS (i.e., Irritability, Apathy, Anxiety/Depression and Asymptomatic) were used to run linear mixed models to explore the interaction of cluster with time on cognitive trajectories using a comprehensive neuropsychological battery (NBACE) administered at baseline and at the three subsequent follow-ups. Results: A significant interaction between cluster and time in cognitive decline was found when verbal learning and cued-recall were explored ( p = 0.002 for both memory functions). For verbal learning, the Irritability cluster had the largest effect size (0.69), whereas the Asymptomatic cluster showed the smallest effect size (0.22). For cued-recall, the Irritability cluster had the largest effect size among groups (0.64), and Anxiety/Depression had the smallest effect size (0.21). Conclusions: In MCI patients, the Irritability and Apathy NPS clusters shared similar patterns of worsening in memory functioning, which could point to these NPS as risk factors of a faster cognitive decline, acting as early prognostic markers and helping in the diagnostic process., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Roberto, Portella, Marquié, Alegret, Hernández, Mauleón, Rosende-Roca, Abdelnour, Esteban de Antonio, Tartari, Vargas, López-Cuevas, Bojaryn, Espinosa, Ortega, Pérez-Cordón, Sanabria, Orellana, de Rojas, Moreno-Grau, Montrreal, Alarcón-Martín, Ruíz, Tárraga, Boada and Valero.)

Background: To explore whether the combination of white matter hyperintensities (WMHs) and amyloid-beta (Aβ) deposition is associated with worse cognitive performance on cognitive composites (CCs) domain scores in individuals with subjective cognitive decline (SCD)., Methods: Two hundred participants from the FACEHBI cohort underwent structural magnetic resonance imaging (MRI), 18 F-florbetaben positron emission tomography (FBB-PET), and neuropsychological assessment. WMHs were addressed through the Fazekas scale, the Age-Related White Matter Changes (ARWMC) scale, and the FreeSurfer pipeline. Eight CCs domain scores were created using the principal component analysis (PCA). Age, sex, education, and apolipoprotein E (APOE) were used as adjusting variables., Results: Adjusted multiple linear regression models showed that FreeSurfer (B - .245; 95% CI - .1.676, - .393, p = .016) and β burden (SUVR) (B - .180; 95% CI - 2.140, - .292; p = .070) were associated with face-name associative memory CCs domain score, although the latest one was not statistically significant after correction for multiple testing (p = .070). There was non-significant interaction of these two factors on this same CCs domain score (p = .54). However, its cumulative effects on face-name associative performance indicated that those individuals with either higher WMH load or higher Aβ burden showed the worst performance on the face-name associative memory CCs domain score., Conclusions: Our results suggest that increased WMH load and increased Aβ are independently associated with poorer episodic memory performance in SCD individuals, indicating a cumulative effect of the combination of these two pathological conditions in promoting lower cognitive performance, an aspect that could help in terms of treatment and prevention., (© 2021. The Author(s).)

Background: Alzheimer disease (AD) is a progressive neurodegenerative disorder affecting the elderly with a prevalence of 7.1% in women and 3.3% in men. Sex-related patterns have been reported in prognosis, biomarker status, and risk factors. Despite this, the interaction of sex has received limited attention, with AD trials persistently recruiting lower numbers of women than the population distribution and a lack of information on the sex-disaggregated effects of anti-dementia therapies. This is the first study aiming to identify the role of sex in the selection for screening in AD clinical trials., Methods: This cross-sectional study provides a comprehensive analysis of screening eligibility according to a set of pre-selection criteria currently applied at Fundació ACE memory clinic for a more efficient trial screening process. A cohort of 6667 women and 2926 men diagnosed with AD dementia (55%) or mild cognitive impairment (45%) was analyzed. We also assessed the frequencies of men and women effectively screened for trial enrolment over a period of 10 years. Additionally, data from AddNeuroMed study was used to explore trends in eligibility based on the education criteria., Results: Women showed a significantly lower chance of being eligible for screening than men (OR = 1.26; p < 0.01). This imbalance was confirmed by a lower frequency of women screened for enrolment compared to the study population (63.0% vs. 69.5%). Education was revealed as the key criterion contributing to this unbalance, with men showing over twice the chance of being screened compared with women (OR = 2.25, p < 0.01). Education-based differences were greater in earlier born patients, but the gap narrowed and achieved balance with increasing year of birth. This observation was replicated using data from other European populations included in AddNeuroMed study. Comorbidity was the most limiting criterion with sex differences in frequencies and significant discrimination against the selection of men (OR = 0.86, p < 0.01)., Conclusions: The large number of low-educated elderly women with AD demands for a sex-focused approach in clinical research. New assessment tools insensitive to education level should be developed to enable a proportional representation of women. Although this gender education gap is mostly inexistent in developed countries, economic or cultural factors may lead to different scenarios in other regions. Overlooking the impact of sex may lead to a handicap in AD research with a direct adverse impact on women's health.

Background and Purpose: Recently, some emerging cerebrospinal fluid (CSF) markers have been proposed as diagnostic tools for Alzheimer disease (AD) that can have an effect on disease progression. We analyze the accuracy of these CSF markers for diagnosis of AD in reference to brain amyloid positron emission tomography (PET). We also investigated whether they help in differentiating AD from other dementias and examined their influence in tracing the progression to dementia., Methods: Amyloid-β (Aβ) 1-42, total tau (t-tau), phosphorylated tau, Aβ 40 , Aβ 38 , beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1), neurogranin (ng), phosphorylated neurofilament heavy-chain, and α-synuclein (α-syn) CSF levels were analyzed in 319 subjects, among whom 57 also underwent an amyloid PET scan. We also analyzed longitudinal clinical data from 239 subjects., Results: Emerging CSF markers, especially ng/BACE-1 ratio (area under the curve = 0.77) and their combinations with core AD CSF markers (all AUCs >0.85), showed high accuracy to discriminate amyloid PET positivity. Subjects with AD had higher CSF BACE-1, ng, and α-syn levels than those with non-AD dementia. CSF t-tau/α-syn ratio was higher in subjects with dementia with Lewy bodies than in those with frontotemporal dementia. Most emerging/core AD ratios predicted a faster conversion from mild cognitive impairment (MCI) stage to AD and appeared to be helpful when core AD CSF markers were discordant. In addition, the rate of cognitive decline was associated with all CSF core AD markers, several emerging/core AD two-marker ratios, and CSF ng levels., Conclusions: These results suggest that emerging biomarkers in conjunction with core AD markers improve diagnosis of AD, are associated with the conversion from MCI into AD, and predict a faster progression of dementia., (© 2020 European Academy of Neurology.)

Background: A low amount and extent of Aβ deposition at early stages of Alzheimer's disease (AD) may limit the use of previously developed pathology-proven composite SUVR cutoffs. This study aims to characterize the population with earliest abnormal Aβ accumulation using 18 F-florbetaben PET. Quantitative thresholds for the early (SUVR early ) and established (SUVR estab ) Aβ deposition were developed, and the topography of early Aβ deposition was assessed. Subsequently, Aβ accumulation over time, progression from mild cognitive impairment (MCI) to AD dementia, and tau deposition were assessed in subjects with early and established Aβ deposition., Methods: The study population consisted of 686 subjects (n = 287 (cognitively normal healthy controls), n = 166 (subjects with subjective cognitive decline (SCD)), n = 129 (subjects with MCI), and n = 101 (subjects with AD dementia)). Three categories in the Aβ-deposition continuum were defined based on the developed SUVR cutoffs: Aβ-negative subjects, subjects with early Aβ deposition ("gray zone"), and subjects with established Aβ pathology., Results: SUVR using the whole cerebellum as the reference region and centiloid (CL) cutoffs for early and established amyloid pathology were 1.10 (13.5 CL) and 1.24 (35.7 CL), respectively. Cingulate cortices and precuneus, frontal, and inferior lateral temporal cortices were the regions showing the initial pathological tracer retention. Subjects in the "gray zone" or with established Aβ pathology accumulated more amyloid over time than Aβ-negative subjects. After a 4-year clinical follow-up, none of the Aβ-negative or the gray zone subjects progressed to AD dementia while 91% of the MCI subjects with established Aβ pathology progressed. Tau deposition was infrequent in those subjects without established Aβ pathology., Conclusions: This study supports the utility of using two cutoffs for amyloid PET abnormality defining a "gray zone": a lower cutoff of 13.5 CL indicating emerging Aβ pathology and a higher cutoff of 35.7 CL where amyloid burden levels correspond to established neuropathology findings. These cutoffs define a subset of subjects characterized by pre-AD dementia levels of amyloid burden that precede other biomarkers such as tau deposition or clinical symptoms and accelerated amyloid accumulation. The determination of different amyloid loads, particularly low amyloid levels, is useful in determining who will eventually progress to dementia. Quantitation of amyloid provides a sensitive measure in these low-load cases and may help to identify a group of subjects most likely to benefit from intervention., Trial Registration: Data used in this manuscript belong to clinical trials registered in ClinicalTrials.gov ( NCT00928304 , NCT00750282 , NCT01138111 , NCT02854033 ) and EudraCT (2014-000798-38).

Neuropsychiatric symptoms (NPS) have been recently addressed as risk factors of conversion to Alzheimer's disease (AD) and other dementia types in patients diagnosed with Mild Cognitive Impairment (MCI). Our aim was to determine profiles based on the prominent NPS in MCI patients and to explore the predictive value of these profiles on conversion to specific types of dementia. A total of 2137 MCI patients monitored in a memory clinic were included in the study. Four NPS profiles emerged (classes), which were defined by preeminent symptoms: Irritability, Apathy, Anxiety/Depression and Asymptomatic. Irritability and Apathy were predictors of conversion to dementia (HR = 1.43 and 1.56, respectively). Anxiety/depression class showed no risk effect of conversion when compared to Asymptomatic class. Irritability class appeared as the most discriminant neuropsychiatric condition to identify non-AD converters (i.e., frontotemporal dementia, vascular dementia, Parkinson's disease and dementia with Lewy Bodies). The findings revealed that consistent subgroups of MCI patients could be identified among comorbid basal NPS. The preeminent NPS showed to behave differentially on conversion to dementia, beyond AD. Therefore, NPS should be used as early diagnosis facilitators, and should also guide clinicians to detect patients with different illness trajectories in the progression of MCI.

Introduction: Essential tremor (ET) is one of the most common movement disorders. Despite its high prevalence and heritability, its genetic etiology remains elusive with only a few susceptibility genes identified and poorly replicated. Our aim was to find novel candidate genes involved in ET predisposition through whole exome sequencing., Methods: We studied eight multigenerational families (N = 40 individuals) with an autosomal-dominant inheritance using a comprehensive strategy combining whole exome sequencing followed by case-control association testing of prioritized variants in a separate cohort comprising 521 ET cases and 596 controls. We further performed gene-based burden analyses in an additional dataset comprising 789 ET patients and 770 healthy individuals to investigate whether there was an enrichment of rare deleterious variants within our candidate genes., Results: Fifteen variants co-segregated with disease status in at least one of the families, among which rs749875462 in CCDC183, rs535864157 in MMP10 and rs114285050 in GPR151 showed a nominal association with ET. However, we found no significant enrichment of rare variants within these genes in cases compared with controls. Interestingly, MMP10 protein is involved in the inflammatory response to neuronal damage and has been previously associated with other neurological disorders., Conclusions: We prioritized a set of promising genes, especially MMP10, for further genetic and functional studies in ET. Our study suggests that rare deleterious coding variants that markedly increase susceptibility to ET are likely to be found in many genes. Future studies are needed to replicate and further infer biological mechanisms and potential disease causality for our identified genes., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Over the last decade, teleneuropsychology has increased substantially. There is a need for valid neuropsychological batteries to be administered home-to-home. Since 2006, the neuropsychological battery of Fundació ACE (NBACE) has been administered face-to-face in our clinical settings. Recently, we adapted the NBACE for teleneuropsychology use to be administered home-to-home (NBACEtn)., Objective: The aims of the present study are: 1) to determine the home-to-home NBACE equivalence compared to its original face-to-face version; and 2) to examine home-to-home NBACE discriminant capacity by differentiating among cognitively healthy, mild cognitive impairment, or mild dementia subjects and comparing it with the face-to-face version., Methods: Data from 338 individuals assessed home-to-home (NBACEtn) were contrasted with 7,990 participants assessed with its face-to-face version (NBACE). Exploratory and confirmatory factorial structure, and invariance analysis of the two versions of the battery were performed., Results: Exploratory and confirmatory factor analysis supported the four-factor model (attention, memory, executive, and visuospatial/constructional functions). Configural, metric, and scalar measurement invariance was found between home-to-home and face-to-face NBACE versions. Significant differences in most of the neuropsychological variables assessed were observed between the three clinical groups in both versions of administration. No differences were found between the technological devices used by participants (computer or tablet and mobile devices)., Conclusion: For the first time, invariance analysis findings were addressed by determining a teleneuropsychological battery's equivalence in comparison with its face-to-face version. This study amplifies the neuropsychological assessment's applicability using a home-to-home format, maintaining the original measure's structure, interpretability, and discriminant capacity.

To date, very few studies have been focused on the impact of the convergence of neuropsychiatric symptoms (NPS) and APOE ε4 on the conversion to dementia in patients with Mild Cognitive Impairment patients (MCI), and none has been based in a clinical setting. The objective of the study is to determine the predictive value of additive and multiplicative interactions of NPS and APOE ε4 status on the prediction of incident dementia among MCI patients monitored in a Memory Clinic. 1512 patients (aged 60 and older) with prevalent MCI were followed for a mean of 2 years. Neuropsychiatric symptoms were assessed at baseline using the Neuropsychiatric Inventory Questionnaire. Cox proportional hazards models were calculated. Additive interactions for depression, apathy, anxiety, agitation, appetite, or irritability and a positive ε4 carrier status were obtained, significantly increasing the hazard ratios of incident dementia (HR range 1.3-2.03). Synergistic interactions between NPS and APOE ε4 are identified among MCI patients when predicting incident dementia. The combination of the behavioral status and the genetic trait could be considered a useful strategy to identify the most vulnerable MCI patients to dementia conversion in a Memory Clinic.

To determine whether lower performance on executive function tests in subjective cognitive decline (SCD) individuals are associated with higher levels of brain amyloid beta (Aβ) deposition and regional volumetric reduction in areas of interest for Alzheimer's disease (AD). 195 individuals with SCD from the FACEHBI study were assessed with a neuropsychological battery that included the following nine executive function tests: Trail Making Test A and B (TMTA, TMTB), the Rule Shift Cards subtest of BADS, the Automatic Inhibition subtest of the Syndrom Kurz Test (AI-SKT), Digit Span Backwards and Similarities from WAIS-III, and the letter, semantic, and verb fluency tests. All subjects underwent an 18F-Florbetaben positron emission tomography (FBB-PET) scan to measure global standard uptake value ratio (SUVR), and a magnetic resonance imaging (MRI). A multiple regression analysis, adjusted for age, was carried out to explore the association between global SUVR and performance on executive tests. Then, on those tests significantly associated with amyloid burden, a voxel-based morphometry (VBM) analysis was carried out to explore their correlates with grey matter volume. Multiple regression analysis revealed a statistically significant association between Aβ deposition and performance on one of the executive tests (the AI-SKT). Moreover, VBM analysis showed worse AI-SKT scores were related to lower volume in bilateral hippocampus and left inferior frontal regions. In conclusion, in SCD individuals, worse automatic inhibition ability has been found related to higher cerebral Aβ deposition and lower volume in the hippocampus and frontal regions. Thus, our results may contribute to the early detection of AD in individuals with SCD.

Background: Optical coherence tomography (OCT) of the retina is a fast and easily accessible tool for the quantification of retinal structural measurements. Multiple studies show that patients with Alzheimer's disease (AD) exhibit thinning in several retinal layers compared to age-matched controls. Subjective cognitive decline (SCD) has been proposed as a risk factor for progression to AD. There is little data about retinal changes in preclinical AD and their correlation with amyloid-β (Aβ) uptake., Aims: We investigated the association of retinal thickness quantified by OCT with Aβ accumulation and conversion to mild cognitive impairment (MCI) over 24 months in individuals with SCD., Methods: One hundred twenty-nine individuals with SCD enrolled in Fundació ACE Healthy Brain Initiative underwent comprehensive neuropsychological testing, OCT scan of the retina and florbetaben (FBB) positron emission tomography (PET) at baseline (v0) and after 24 months (v2). We assessed the association of sixteen retinal thickness measurements at baseline with FBB-PET status (+/-) and global standardize uptake value ratio (SUVR) as a continuous measure at v0 and v2 and their predictive value on clinical status change (conversion to mild cognitive impairment (MCI)) at v2., Results: Mean age of the sample was 64.72 ± 7.27 years; 62.8% were females. Fifteen participants were classified as FBB-PET+ at baseline and 22 at v2. Every 1 μm of increased thickness in the inner nasal macular region conferred 8% and 6% higher probability of presenting a FBB-PET+ status at v0 (OR = 1.08, 95% CI = 1.02-1.14, p = 0.007) and v2 (OR = 1.06, 95% CI = 1.02-1.11, p = 0.004), respectively. Inner nasal macular thickness also positively correlated with global SUVR (at v0: β = 0.23, p = 0.004; at v2: β = 0.26, p = 0.001). No retinal measurements were associated to conversion to MCI over 24 months., Conclusions: Subtle retinal thickness changes in the macular region are already present in SCD and correlate with Aβ uptake.

Background: Fundació ACE is a non-profit organization providing care based on a holistic model to persons with cognitive disorders and their families for 25 years in Barcelona, Spain. Delivering care to this vulnerable population amidst the COVID-19 pandemic has represented a major challenge to our institution., Objective: To share our experience in adapting our model of care to the new situation to ensure continuity of care., Methods: We detail the sequence of events and the actions taken within Fundació ACE to swiftly adapt our face-to-face model of care to one based on telemedicine consultations. We characterize individuals under follow-up by the Memory Unit from 2017 to 2019 and compare the number of weekly visits in 2020 performed before and after the lockdown was imposed., Results: The total number of individuals being actively followed by Fundació ACE Memory Unit grew from 6,928 in 2017 to 8,147 in 2019. Among those newly diagnosed in 2019, most patients had mild cognitive impairment or mild dementia (42% and 25%, respectively). Weekly visits dropped by 60% following the suspension of face-to-face activity. However, by April 24 we were able to perform 78% of the visits we averaged in the weeks before confinement began., Discussion: We have shown that Fundació ACE model of care has been able to successfully adapt to a health and social critical situation as COVID-19 pandemic. Overall, we were able to guarantee the continuity of care while preserving the safety of patients, families, and professionals. We also seized the opportunity to improve our model of care.

Background: The Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases., Objectives: To perform the largest PD genome-wide association study restricted to a single country., Methods: We performed a GWAS for both risk of PD and age at onset in 7,849 Spanish individuals. Further analyses included population-specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression, and methylation data to gain insight into disease-associated loci, heritability estimates, genetic correlations, and burden analyses., Results: We identified a novel population-specific genome-wide association study signal at PARK2 associated with age at onset, which was likely dependent on the c.155delA mutation. We replicated four genome-wide independent signals associated with PD risk, including SNCA, LRRK2, KANSL1/MAPT, and HLA-DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non-Spanish origin. Seventeen PD-related genes showed functional consequence by two-sample Mendelian randomization in expression and methylation data sets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls., Conclusions: Our data demonstrate the utility of the Spanish risk haplotype substructure for future fine-mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points to PARK2 as a major hallmark of PD etiology in Spain. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Background: Cerebrospinal fluid (CSF) biomarker studies have shown variable accuracy for diagnosis of Alzheimer's disease (AD); therefore, internal validation is recommended., Objective: To investigate the correlation between CSF biomarkers and cerebral 18-Florbetapir positron emission tomography (Amyloid-PET) and calculate their sensitivity and specificity to obtain the optimal clinical cut-off points to diagnose the etiology of cognitive impairment., Methods: We performed Amyloid-PET scans and CSF biomarker levels analyses in 68 subjects (50 with mild cognitive impairment, 11 with AD dementia, and 7 with non-AD dementia). Visual examination of Amyloid-PET scans was performed. CSF analyses were performed using standard sandwich ELISA., Results: Amyloid-PET was positive in 36 subjects, negative in 26, and inconclusive in 6. Optimal clinical cut-off points for CSF markers were the following: amyloid-β 1-42 (Aβ42) = 629 pg/ml, total tau (t-tau) = 532 pg/ml, phosphorylated tau (p-tau) = 88 pg/ml, and t-tau/Aβ42 ratio = 0.58. T-tau/Aβ42 ratio showed the best sensitivity and specificity (92 and 84%, respectively). T-tau and p-tau CSF levels (r2 = 0.867) followed by the t-tau and t-tau/Aβ42 CSF ratio (r2 = 0.666) showed the strongest inter-marker correlation. Interestingly, subjects with inconclusive Amyloid-PET showed intermediate values for all CSF markers between negative and positive Amyloid-PET groups., Conclusions: CSF t-tau/Aβ42 ratio appears to be the most accurate AD CSF marker. The presence of intermediate values for CSF markers among the subjects with inconclusive Amyloid-PET suggests the presence of other dementias associated with AD pathology or intermediate phenotypes.

Background and Purpose: Epidemiologic studies of incidence and prevalence in Parkinson's Disease (PD) show highly variable results. Despite the large number of studies performed worldwide during the last decades, little is known about its prevalence in South America and no incidence studies have been performed. The goal of this study is to assess the incidence and prevalence of PD in a health maintenance organization from Buenos Aires City, the capital city of Argentina., Methods: The population were all members of the 'Plan de Salud, Hospital Italiano de Buenos Aires', a large prepaid health medical organization in Buenos Aires. From 1 January 2003 to 31 December 2008 patients diagnosed with PD according to Brain Bank of London diagnostic criteria were identified retrospectively. Incidence density was calculated with 95% confidence interval., Results: Hundred and forty thousand people were followed for a total of 754,082 person-years. A total of 239 incident cases of PD were identified. Crude incidence density was 31.2/100,000 person-years. Prevalence was 394/100,000 in the population older than 40 years. Male to female ratio was 1.31., Conclusions: This is the first study in South America that estimates the incidence of PD. Our results are consistent with other studies from other regions using similar methodologies., (© 2012 The Author(s). European Journal of Neurology © 2012 EFNS.)