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Abstract 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.

Abstract 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 0.07). 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.

Abstract 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.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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. [ABSTRACT FROM AUTHOR]