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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Optical Coherence Tomography angiography (OCT‐A) is a novel tool that allows the detection of retinal vascular changes. The comparison of OCT‐A measures with brain vascular burden is essential to validate the former as a surrogate of cerebrovascular damage and biomarker of cognitive decline. We aimed to investigate the association of macular vessel density (VD) in the superficial plexus assessed by OCT‐A with measures of cerebrovascular pathology quantified by brain magnetic resonance imaging (MRI) in a cohort of non‐demented individuals. Method: Clinical, demographical, APOE ε4 status, amyloid status, OCT‐A and brain MRI data from non‐demented participants of the FACEHBI and BIOFACE studies were included. We analyzed the association of macular VD in four quadrants (superior, nasal, inferior and temporal) with brain vascular burden using the Fazekas scale scores (dichotomized in two categories, 0‐1 vs 2‐3), assessed in a logistic regression analysis, and the volume of white matter hyperintensities (WMH) quantified by Freesurfer assessed in a multiple regression analysis. We additionally explored the associations of macular VD with hippocampal volume, ventricles volume and Alzheimer Disease cortical signature (ADCS) thickness assessed in a multiple regression analysis. All analyses were adjusted for age and dyslipidemia. Result: The study cohort comprised 188 participants: 89 with subjective cognitive decline (SCD) and 99 with mild cognitive impairment (MCI). Logistic regression analysis showed no significant differences of regional macular VD between the two Fazekas groups (all, p>0.05). Multiple regression analysis showed no significant association of regional macular VD with the volume of WMH (all, p>0.05). Macular VD in the nasal and inferior quadrants were positively associated with hippocampal volume (p = 0.009 and p = 0.021, respectively), but no association was detected with ventricles volume or ADCS thickness (both p>0.05). Conclusion: Our study showed that retinal vascular measures (regional macular VD in the superficial vascular plexus) assessed by OCT‐A were not associated with brain vascular damage quantified by the Fazekas scale and the WMH burden n in a cohort of non‐demented research participants with SCD and MCI. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Mild cognitive impairment (MCI) due to Alzheimer's disease (AD) diagnosis is based on cerebrospinal fluid (CSF) or neuroimaging biomarkers. Currently, non-invasive and inexpensive blood-based biomarkers are being investigated, such as neuronal-derived plasma exosomes (NPEs). Neuroinflammation and early vascular changes have been described in AD pathogenesis and can be traced in plasma and NPEs. However, they have not been studied in early onset MCI (EOMCI).Objective: To describe the rationale, design, and baseline characteristics of the participants from the BIOFACE cohort, a two-year observational study on EOMCI conducted at Fundació ACE. The study goal is to characterize the different phenotypes from a clinical, neuropsychological, and biomarker point of view and to investigate the CSF and plasma proteomics as well as the role of NPEs as early biomarkers of AD.Methods: Participants underwent extended neurological and neuropsychological batteries, multimodal biomarkers including brain MRI, blood, saliva, CSF, anthropometric, and neuro-ophthalmological examinations.Results: Ninety-seven patients with EOMCI were recruited. 59.8%were women. Mean age at symptom onset was 57 years; mean MMSE was 28. First degree and presenile family history of dementia was present in 60.8%and 15.5%, respectively. Depressive and anxiety disorders along with vascular risk factors were the most frequent comorbidities. 29%of participants were APOE ɛ4 carriers, and 67%showed a CSF normal ATN profile.Conclusion: BIOFACE is a two-year study of clinical, cognition, and biomarkers that will shed light on the physiopathology and the potential utility of plasma and NPEs as non-invasive early diagnostic and prognostic biomarkers in people younger than 65 years. [ABSTRACT FROM AUTHOR]

Background: Comprehensive clinicopathological studies of neuropsychiatric symptoms (NPS) in dementia are lacking.Objective: To describe the pathological correlations of NPS in a sample of institutionalized people with dementia.Methods: We studied 59 people who were consecutively admitted to a nursing home and donated their brain. Correlations between pathological variables and NPS upon admission (n = 59) and at one-year follow-up assessment (n = 46) were explored and confirmed using bivariate and multivariate statistical methods.Results: Mean (SD) age at admission was 83.2 (6.4) years and mean (SD) age at demise was 85.4 (6.6); 73% of the subjects were female and 98% presented advanced dementia. The most frequent etiological diagnosis was Alzheimer's disease (AD; 74.6% clinical diagnosis, 67.8% pathological diagnosis). The pathological diagnosis of AD was associated with aggression (β est 0.31), depression (β est 0.31), anxiety (β est 0.38), and irritability (β est 0.28). Tau stage correlated with aggressive symptoms (β est 0.32) and anxiety (βest 0.33). Coexistence of AD and Lewy body pathology was associated with depression (β est 0.32), while argyrophilic grains were associated with eating symptoms (β est 0.29). Predictive models were achieved for apathy, including cognitive performance, basal ganglia ischemic lesions, and sex as predictors (R2 0.38) and for sleep disorders, including pathological diagnosis of AD and age at demise (R2 0.18) (all p-values <0.05, unadjusted).Conclusion: AD was the main pathological substrate of NPS in our sample of very elderly people with advanced dementia. However, correlations were mild, supporting a model of focal/asymmetric rather than diffuse brain damage, along with relevance of environmental and other personal factors, in the genesis of those symptoms. [ABSTRACT FROM AUTHOR]

Background: The COVID-19 pandemic has brought great disruption to health systems worldwide. This affected ongoing clinical research, particularly among those most vulnerable to the pandemic, like dementia patients. Fundació ACE is a research center and memory clinic based in Barcelona, Spain, one of the hardest-hit countries.Objective: To describe the ad-hoc strategic plan developed to cope with this crisis and to share its outcomes.Methods: We describe participants' clinical and demographic features. Additionally, we explain our strategic plan aimed at minimizing the impact on clinical trial research activities, which included SARS-CoV-2 RT-PCR and IgG serological tests to all participants and personnel. The outcomes of the plan are described in terms of observed safety events and drop-outs during the study period.Results: A total of 130 patients were participating in 16 active clinical trials in Fundació ACE when the lockdown was established. During the confinement, we performed 1018 calls to the participants, which led to identify adverse events in 26 and COVID-19 symptoms in 6. A total of 83 patients (64%) could restart on-site visits as early as May 11, 2020. All SARS-CoV-2 RT-PCR diagnostic tests performed before on-site visits were negative and only three IgG serological tests were positive. Throughout the study period, we only observed one drop-out, due to an adverse event unrelated to COVID-19.Discussion: The plan implemented by Fundació ACE was able to preserve safety and integrity of ongoing clinical trials. We must use the lessons learned from the pandemic and design crisis-proof protocols for clinical trials. [ABSTRACT FROM AUTHOR]

Background: Clinical diagnosis of Alzheimer's disease (AD) increasingly incorporate CSF biomarkers. However due to the intrinsic variability of the immunodetection techniques used to measure these biomarkers, it is recommended to establish in‐house cutoffs defining the positivity/negativity of CSF biomarkers. Method: We quantified CSF Aβ1‐42, t‐Tau, p181Tau and Aβ1‐40 with standard INNOTEST® ELISA and Lumipulse G® chemiluminescence enzyme‐immunoassay (CLEIA) performed on automated Lumipulse G600II. Determination of cutoffs included patients clinically diagnosed with Alzheimer Disease (AD, n=37) and amyloid‐negative Subjective Cognitive Decline subjects (SCD, n=45), cognitively stable during 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) were analyzed. Kappa agreement of single biomarkers and Aβ1‐42/Aβ1‐40 was performed in an independent group of mild cognitive impairment (MCI) and dementia patients (n=68). Result: Cutoffs 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 were good but lower for Aβ1‐42/Aβ1‐40. Conclusion: We established internal cutoffs to discriminate AD patients from amyloid‐negative SCD individuals. Results obtained by both methods are not interchangeable but showed good agreement. We propose automated CLEIA as a good alternative to manual ELISA together with Aβ1‐42/Aβ1‐40 to classify amyloidosis. [ABSTRACT FROM AUTHOR]

Transient focal neurological episodes (TFNEs) are a recently recognized clinical presentation of cerebral amyloid angiopathy (CAA). Our aim was to describe the clinical and radiological features of a series of patients with AS. We included 11 patients presenting with recurrent transient focal neurological symptoms and radiological features related to CAA. Mean age was 76,6 and 5 patients were women. All patients reported transient, stereotyped, and recurrent episodes (6 patients had >10 episodes). Gradual spread of the symptoms was recorded in 9 patients. Initially, 3 patients were misdiagnosed as having recurrent transient ischemic attack (TIA), 6 as having seizures, and 2 as having both. Two patients were prescribed antiplatelet therapy. A cerebral MRI with T2* gradient-recalled echo sequence revealed cortical superficial siderosis (cSS) in 5 patients, cortical microbleeds in 1 patient, and both features in 5 cases. After a median follow-up of 36 months, intracranial hemorrhage (ICH) was recorded in 4 patients. All 4 had cSS in the previous cerebral MRI, and 1 was on antiplatelet therapy. CAA-related TFNEs are an underdiagnosed entity, often mimicking TIA, seizures, or migraine aura. This misdiagnosis can lead to the prescription of antiplatelet or anticoagulant therapy, which increases the risk of ICH. Our results suggest that cSS might be a radiological marker that is closely related to an increased risk of bleeding. A T2* gradient-recalled echo MRI should be performed in elderly patients with transient focal neurological symptoms suggestive of CAA. • Cerebral amyloid angiopathy (CAA) may manifest clinically as transient focal neurological episodes (TFNEs). • CAA-related TFNE may be confused with other conditions such as TIA, seizures or migraine auras. • This misdiagnosis can lead to the prescription of antiplatelet or anticoagulant therapy, which increases the risk of ICH. • cSS might be a radiological marker that is closely related to an increased risk of bleeding. [ABSTRACT FROM AUTHOR]