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Background: The present study aimed to explore the association between Apolipoprotein E (APOE) genotype, the main genetic risk factor for sporadic Alzheimer's Disease (AD), age, and cerebral β‐amyloid (Aβ) aggregation, the earliest pathological event in AD in a large, multicenter, European cohort, the AMYPAD study. Method: We included 876 participants from the AMYPAD cohort who had known APOE genotype and went through at least one Aβ PET imaging. We first looked at the association between Aβ deposition and age according to sex, APOE genotype, and cognitive status. We then used linear regression models to look at the association between Aβ aggregation and APOE genotype in different cerebral regions with age, sex, history of dementia, MMSE score, CDR score, depression, hypercholesterolemia, diabetes and center as covariates. Result: Our participants had a mean age of 67 years old with a mean MMSE score of 28.9/30 and counted 60% of women. We found a positive association between Aβ deposition and age with a gradually stronger association in heterozygous ԑ4 carriers (β (SD) = 1.94 (0.27)) and homozygous ԑ4 carriers (3.18 (0.52)) compared to non‐carriers (0.99 (0.12), p<0.001; Figure). We found similar results when restricting the analyses to cognitively unimpaired participants (heterozygous ԑ4: 1.65 (0.27), p<0.001; homozygous ԑ4: 3.01 (0.52), p<0.001), however Aβ aggregation was less associated to age in participants with mild cognitive impairment (heterozygous ԑ4: 1.33 (1.4), p = 0.33; homozygous ԑ4: 2.34 (1.9), p = 0.29). Moreover, we found an effect of sex on the association between Aβ aggregation and age in ԑ4 non‐carriers characterized by a stronger association in men (1.61 (0.22)) compared to women (0.63 (0.13)). Finally, we observed that the effect of APOE genotype on Aβ aggregation remained similar in the different cerebral regions, with less discernable differences between genotypes in the medial temporal and occipital regions. Conclusion: The number of APOE4 alleles has an impact on the association between age and Aβ aggregation, such that high amyloid was observed at younger ages in homozygous APOE4 carriers than in heterozygous APOE4 carriers and in non‐carriers. The effect of APOE4 on Aβ deposition was global rather than regional in our analysis. [ABSTRACT FROM AUTHOR]

The flavoenzyme glycolate oxidase oxidizes glycolic acid to glyoxylate and the latter, more slowly, to oxalate. It is a member of an FMN‐dependent enzyme family that oxidizes l‐2‐hydroxy acids to keto acids. There has been a controversy concerning the chemical mechanism of substrate oxidation by these enzymes. Do they proceed by hydride transfer, as observed for NAD‐dependent enzymes, or by initial formation of a carbanion that transfers the electrons to the flavin? The present work describes a comparison of the reactivity of glycolate, lactate and trifluorolactate with recombinant human glycolate oxidase, by means of rapid‐kinetics experiments in anaerobiosis. We show that trifluorolactate is a substrate for glycolate oxidase, whereas it is known as an inhibitor for NAD‐dependent enzymes, as is trifluoroethanol for NAD‐dependent alcohol dehydrogenases. Unexpectedly, it was observed that, once reduced, a flavin transfers an electron to an oxidized flavin, so that the end species is a flavin semiquinone, whatever the substrate. This phenomenon has not previously been described for a glycolate oxidase. Altogether, considering that another member of this flavoenzyme family (flavocytochrome b2, a lactate dehydrogenase) has also been shown to oxidize trifluorolactate (Lederer F et al. (2016) Biochim Biophys Acta 1864, 1215–21), this work provides another important piece of evidence which is hardly compatible with a hydride transfer mechanism for this flavoenzyme family. [ABSTRACT FROM AUTHOR]

Introduction: Studies on the association of cancer and risk of dementia are inconclusive due to result heterogeneity and concerns of survivor bias and unmeasured confounding. Methods: This study uses data from the Memento cohort, a French multicenter cohort following persons with either mild or isolated cognitive complaints for a median of 5 years. Illness‐death models (IDMs) were used to estimate transition‐specific hazard ratios (HRs) and 95% confidence intervals (CIs) for incident cancer in relation to dementia from time since study entry. Results: The analytical sample (N = 2258) excluded 65 individuals without follow‐up information. At the end of follow‐up, 286 individuals were diagnosed with dementia, 166 with incident cancer, and 95 died. Incident cancer was associated with a reduced risk of dementia (HR = 0.58, 95% CI = 0.35‐0.97), with a corresponding E‐value of 2.84 (lower CI = 1.21). Discussion: This study supports a protective relationship between incident cancer and dementia, encouraging further investigations to understand potential underlying mechanisms. [ABSTRACT FROM AUTHOR]

Introduction: The clinical relevance of brain atrophy subtypes categorization in non‐demented persons without a priori knowledge regarding their amyloid status or clinical presentation is unknown. Methods: A total of 2083 outpatients with either subjective cognitive complaint or mild cognitive impairment at study entry were followed during 4 years (MEMENTO cohort). Atrophy subtypes were defined using baseline magnetic resonance imaging (MRI) and previously described algorithms. Results: Typical/diffuse atrophy was associated with faster cognitive decline and the highest risk of developing dementia and Alzheimer's disease (AD) over time, both in the whole analytic sample and in amyloid‐positive participants. Hippocampal‐sparing and limbic‐predominant atrophy were also associated with incident dementia, with faster cognitive decline in the limbic predominant atrophy group. Lewy body dementia was more frequent in the hippocampal‐sparing and minimal/no atrophy groups. Discussion: Atrophy subtypes categorization predicted different subsequent patterns of cognitive decline and rates of conversion to distinct etiologies of dementia in persons attending memory clinics. [ABSTRACT FROM AUTHOR]

Background: Understanding the role of amyloid imaging in the earliest stages of Alzheimer's Disease (AD) becomes increasingly relevant for secondary prevention. In this context, the AMYPAD Prognostic and Natural History Study (PNHS) is an open‐label, prospective, multi‐centre cohort study (http://amypad.eu/) to determine the value of quantitative amyloid PET imaging in determining AD dementia risk. The study aims at enrolling 2000 non‐demented individuals from several European cohorts, with a focus on those with emerging amyloid pathology. Method: As of January 31th 2020, 438 participants have consented into AMYPAD PNHS across 15 active sites. Of those, 347 are from EPAD LCS, 9 from ALFA+ and 82 from EMIF‐AD (Figure 1). To date, 329 subjects have been scanned with [18F]flutemetamol or [18F]florbetaben, and 108 PET scans have been analyzed with IXICO's LEAP pipeline. The primary variable is the Centiloid value (CL) using the whole cerebellum as reference region. Scans were categorized as negative (CL<12); gray‐zone (1250) for amyloid burden, and associations between CL values and age, CDR and RBANS were assessed. Result: Site activation is almost complete, with two remaining sites to be activated by February 2020. In addition to current recruitment sources, two additional cohorts (FACEHBI and FPACK) have started recruitment, and at least one more is expected in February. Current AMYPAD PNHS participants have a mean age of 67.08 ± 7.71 years and 59% of them are female. The distribution of CL values ranged from ‐12.75 to 141.79 (Figure 2), and showed a positive association with age (p<0.001) as expected, with similar behavior for the each radiotracer (Figure 3). Forty‐five scans (42%) were classified as negative, 40 (37%) gray‐zone, and 23 (21%) positive. Within EPAD LCS participants, increasing amyloid burden was related to lower global scores on RBANS (ANOVA, F=3.6, p<0.05), and CDR=0.5 was most frequently observed in the gray‐zone (9.5%) and positive (12.0%) groups compared to amyloid‐negative subjects (2.1%). Conclusion: The AMYPAD Prognostic and Natural History Study is currently ongoing and a total of 17 sites will be actively recruiting by February 2020. Preliminary quantitative results indicate that the trial is effectively recruiting the intended target population. [ABSTRACT FROM AUTHOR]

The concept of polypharmacology involves the interaction of drug molecules with multiple molecular targets. It provides a unique opportunity for the repurposing of already‐approved drugs to target key factors involved in human diseases. Herein, we used an in silico target prediction algorithm to investigate the mechanism of action of mebendazole, an antihelminthic drug, currently repurposed in the treatment of brain tumors. First, we confirmed that mebendazole decreased the viability of glioblastoma cells in vitro (IC50 values ranging from 288 nm to 2.1 µm). Our in silico approach unveiled 21 putative molecular targets for mebendazole, including 12 proteins significantly upregulated at the gene level in glioblastoma as compared to normal brain tissue (fold change > 1.5; P < 0.0001). Validation experiments were performed on three major kinases involved in cancer biology: ABL1, MAPK1/ERK2, and MAPK14/p38α. Mebendazole could inhibit the activity of these kinases in vitro in a dose‐dependent manner, with a high potency against MAPK14 (IC50 = 104 ± 46 nm). Its direct binding to MAPK14 was further validated in vitro, and inhibition of MAPK14 kinase activity was confirmed in live glioblastoma cells. Consistent with biophysical data, molecular modeling suggested that mebendazole was able to bind to the catalytic site of MAPK14. Finally, gene silencing demonstrated that MAPK14 is involved in glioblastoma tumor spheroid growth and response to mebendazole treatment. This study thus highlighted the role of MAPK14 in the anticancer mechanism of action of mebendazole and provides further rationale for the pharmacological targeting of MAPK14 in brain tumors. It also opens new avenues for the development of novel MAPK14/p38α inhibitors to treat human diseases. [ABSTRACT FROM AUTHOR]

Background: In early 2020, COVID‐19 outbreak struck France leading to a national lockdown between March 17th and May 11th. While standard in‐person medical consultation was complicated, telemedicine dramatically expanded. In order to evaluate the impact of this unpreceded situation on clinical practice and use of psychoactive drug in dementia care, we conducted a nationwide clinical prospective and retrospective study. Method: During the lockdown period, telemedicine patients' demographic and clinical data were retrospectively collected from 7 French memory clinics (telemedicine cohort). Clinical diagnoses, treatment changes, cognitive modifications since last consultations and living conditions during the lockdown were systematically retrieved. In Rouen site, we also included patients only reached by a secretary to propose a postponed visit after lockdown (no‐telemedicine cohort) and patients seen in 2019 during the same period of the year (Rouen‐2019). The primary outcome was any change in psychoactive drug and a specific analysis on sedative treatment increase was the secondary outcome, defined as any increase in the prescriptions of antipsychotics or benzodiazepines. Result: The telemedicine cohort included 874 patients (73 from Rouen), while no‐telemedicine control cohort and Rouen‐2019 cohorts included respectively 86 and 234 patients (table 1). In the telemedicine cohort, treatments were modified for 10.7% of the patients with more treatment modification among the patients living with a relative (+5.8% (CI95% [0.2%; 11.4%] p=0.04) and among the patients with Alzheimer's disease (+12.2% (CI95% [7.1%; 17.3%] p<0.001). When comparing therapeutic strategies in 2020 and 2019 for Rouen site, 24.6% of the patients had their treatment modified in 2020 and 12.4% in 2019. That difference was however not statically significant with an adjusted percentage difference of ‐4% (CI95% [‐10.8%; 3.4%] p=0.27, including the telemedicine and no‐telemedicine cohorts for 2020. Conclusion: Telemedicine seems to have had only minor negative impacts on clinical practice in memory clinics. [ABSTRACT FROM AUTHOR]

Background: Understanding the role of amyloid imaging in the earliest stages of Alzheimer’s Disease (AD) becomes increasingly relevant for secondary prevention. In this context, the AMYPAD Prognostic and Natural History Study (PNHS) is an open‐label, prospective, multi‐centre cohort study (http://amypad.eu/) to determine the value of quantitative amyloid PET imaging in determining AD dementia risk. The study recruits from several European cohorts and aims at enrolling 2000 non‐demented individuals with a particular focus on those with emerging amyloid pathology. Method: As of January 25th, 2020, AMYPAD PNHS had 17 actively recruiting sites across Europe, and 782 non‐demented participants (>95% cognitively unimpaired) had consented to participate in the study. Of those, 448 are from EPAD LCS, 129 from EMIF‐AD Twin 60++, 111 from FACEHBI, 70 from ALFA+, 17 from FPACK, and 7 from the UCL‐2010‐412 cohort. Of the consented subjects, 334 already had an amyloid PET scan before this study. Within AMYPAD PNHS, 588 subjects have hitherto been scanned with either [18F]flutemetamol or [18F]florbetaben. Of note, 53.6% of the total number of scans have been acquired with a dual‐time window dynamic protocol. The primary outcome measure is the Centiloid value (CL) using the whole cerebellum as reference region, to enable quantitative comparability between the two tracers in the study. Also, images have been visually assessed by local raters. Of the 588 acquired scans, 296 have been quantified with IXICO’s LEAP pipeline and passed Quality Control, thus rendering valid CL values. Subjects were categorized as amyloid‐negative (CL≤12); as in a “gray‐zone” (1250) and a Gaussian Mixture Model was used to assess the population’s Centiloid distribution. Result: Based on visual assessment, 28% of the fully 296 quantified scans were visually rated as positive and 72% as negative. Quantitatively, 50% of them were categorized as negative, 33% in the gray‐zone, and 17% were positive (Figure 1). Centiloid values ranged from ‐30.3 to 154.2 (Mean±SD: 22.5±32.0 CL) (Figure 2). Conclusion: Preliminary quantitative results indicate that PNHS is being successful in recruiting a cohort mostly composed of cognitively unimpaired individuals who are enriched for early amyloid abnormalities, which is the intended target population. [ABSTRACT FROM AUTHOR]

Introduction: Although some studies have previously addressed the clinical impact of amyloid positron emission tomography (PET), none has specifically addressed its selective and hierarchical implementation in relation to cerebrospinal fluid analysis in a naturalistic setting. Methods: This multicenter study was performed at French tertiary memory clinics in patients presenting with most complex clinical situations (i.e., early‐onset, atypical clinical profiles, suspected mixed etiological conditions, unexpected rate of progression), for whom cerebrospinal fluid analysis was indicated but either not feasible or considered as noncontributory (ClinicalTrials.gov: NCT02681172). Results: Two hundred five patients were enrolled with evaluable florbetaben PET scans; 64.4% of scans were amyloid positive. PET results led to changed diagnosis and improved confidence in 66.8% and 81.5% of patients, respectively, and altered management in 80.0% of cases. Discussion: High‐level improvement of diagnostic certainty and management is provided by selective and hierarchical implementation of florbetaben PET into current standard practices for the most complex dementia cases. Highlights: Impact of amyloid positron emission tomography (PET) on diagnosis and management in a naturalistic setting.Patients with complex clinical situations in absence of conclusive cerebrospinal fluid results.Highly selected patient population and hierarchical positioning of Alzheimer's disease biomarkers.Use of amyloid PET without interfering with the clinical standard practices.Immediate benefit of amyloid PET in the most complex situations in current practice. [ABSTRACT FROM AUTHOR]

Introduction: Progress in understanding and management of vascular cognitive impairment (VCI) has been hampered by lack of consensus on diagnosis, reflecting the use of multiple different assessment protocols. A large multinational group of clinicians and researchers participated in a two‐phase Vascular Impairment of Cognition Classification Consensus Study (VICCCS) to agree on principles (VICCCS‐1) and protocols (VICCCS‐2) for diagnosis of VCI. We present VICCCS‐2. Methods: We used VICCCS‐1 principles and published diagnostic guidelines as points of reference for an online Delphi survey aimed at achieving consensus on clinical diagnosis of VCI. Results: Six survey rounds comprising 65–79 participants agreed guidelines for diagnosis of VICCCS‐revised mild and major forms of VCI and endorsed the National Institute of Neurological Disorders–Canadian Stroke Network neuropsychological assessment protocols and recommendations for imaging. Discussion: The VICCCS‐2 suggests standardized use of the National Institute of Neurological Disorders–Canadian Stroke Network recommendations on neuropsychological and imaging assessment for diagnosis of VCI so as to promote research collaboration. [ABSTRACT FROM AUTHOR]

Introduction Numerous diagnostic criteria have tried to tackle the variability in clinical manifestations and problematic diagnosis of vascular cognitive impairment (VCI) but none have been universally accepted. These criteria have not been readily comparable, impacting on clinical diagnosis rates and in turn prevalence estimates, research, and treatment. Methods The Vascular Impairment of Cognition Classification Consensus Study (VICCCS) involved participants (81% academic researchers) from 27 countries in an online Delphi consensus study. Participants reviewed previously proposed concepts to develop new guidelines. Results VICCCS had a mean of 122 (98–153) respondents across the study and a 67% threshold to represent consensus. VICCCS redefined VCI including classification of mild and major forms of VCI and subtypes. It proposes new standardized VCI-associated terminology and future research priorities to address gaps in current knowledge. Discussion VICCCS proposes a consensus-based updated conceptualization of VCI intended to facilitate standardization in research. [ABSTRACT FROM AUTHOR]

Silene sect. Siphonomorpha (Caryophyllaceae) has historically either been split into three different and homogeneous entities (sect. Italicae, sect. Paradoxae, sect. Siphonomorpha s.str.) or considered as a single group (sect. Siphonomorpha s.l.). In this study, we investigate the delimitation of sect. Siphonomorpha s.l. and the three subgroups, in order to sort out previous taxonomic concepts. We first performed an analysis of nuclear ribosomal internal transcribed spacer (ITS) sequences with wide taxonomic sampling to place sect. Siphonomorpha within the genus. Then, using nuclear and chloroplast sequences in a multi-species coalescent context, we constructed two species trees with independent specimen sampling. One was based on ITS, the nuclear RPA2 gene, and the plastid rps16 gene, the other used ITS and the plastid trnH-psbA and trnS-trnG regions. The results are congruent among the three analyses and show that sect. Siphonomorpha s.l. is not supported as being monophyletic and that an extended concept of this section would include species also belonging to sections Saxifragoideae, Coronatae, Tataricae, Chloranthae, Barbeyanae, Nanosilene, Otites, Koreanae, Brachypodae, Graminiformes, Dianthoidea, Longitubulosae and Holopetalae. However, the three entities "Italicae", "Paradoxae" and "Siphonomorpha s.str." are monophyletic with minor alterations and deserve taxonomic recognition as sect ions. Several ambiguous species are now resolved, among them the position of S. gigantea which is shown to be a highly supported clade, sister of sect. Italicae, that could therefore be named sect. Giganteae. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is among the most significant health care burdens. Disappointing results from clinical trials in late-stage AD persons combined with hopeful results from trials in persons with early-stage suggest that research in the preclinical stage of AD is necessary to define an optimal therapeutic success window. We review the justification for conducting trials in the preclinical stage and highlight novel ethical challenges that arise and are related to determining appropriate risk-benefit ratios and disclosing individuals' biomarker status. We propose that to conduct clinical trials with these participants, we need to improve public understanding of AD using unified vocabulary, resolve the acceptable risk-benefit ratio in asymptomatic participants, and disclose or not biomarker status with attention to study type (observational studies vs clinical trials). Overcoming these challenges will justify clinical trials in preclinical AD at the societal level and aid to the development of societal and legal support for trial participants. [ABSTRACT FROM AUTHOR]

Introduction The purpose of this study was to study the effect of donepezil on the rate of hippocampal atrophy in prodromal Alzheimer's disease (AD). Methods A double-blind, randomized, placebo-controlled parallel group design using donepezil (10 mg/day) in subjects with suspected prodromal AD. Subjects underwent two brain magnetic resonance imaging scans (baseline and final visit). The primary efficacy outcome was the annualized percentage change (APC) of total hippocampal volume (left + right) measured by an automated segmentation method. Results Two-hundred and sixteen only subjects were randomized across 28 French expert clinical sites. In the per protocol population (placebo = 92 and donepezil = 82), the donepezil group exhibited a significant reduced rate of hippocampal atrophy (APC = −1.89%) compared with the placebo group (APC = −3.47%), P < .001. There was no significant difference in neuropsychological performance between treatment groups. Discussion A 45% reduction of rate of hippocampal atrophy was observed in prodromal AD following 1 year of treatment with donepezil compared with placebo. [ABSTRACT FROM AUTHOR]

Background A large proportion of dementia cases are still undiagnosed. Although early dementia care has been hypothesized to benefit both patients and families, evidence-based benefits are lacking. Thus, investigating the benefits for newly demented persons according to their recourse to care in the “real life” appears critical. Methods We examined the relation between initial care recourse care and demented individuals' survival in a large cohort of incident dementia cases screened in a prospective population-based cohort, the Three-City Study. We assessed recourse to care for cognitive complaint at the early beginning of dementia when incident cases were screened. We classified patients in three categories: no care recourse, general practitioner consultation or specialist consultation. We used proportional hazard regression models to test the association between recourse to care and mortality, adjusting on socio-demographical and clinical characteristics. Results Two hundred and fifty-three incident dementia participants were screened at the 2 year or 4 year follow-up. One third of the incident demented individuals had not consulted a physician for cognitive problems. Eighty-six (34.0%) individuals had reported a cognitive problem only to their general practitioner (GP) and 80 (31.6%) had consulted a specialist. Mean duration of follow-up after incident dementia was 5.1 years, during which 146 participants died. After adjustment on potential confounders, participants who had consulted a specialist early in the disease course presented a poorer survival than those who did not consult any physician (hazard ratio = 1.64, 95% confidence interval 1.03–2.62). There was a trend but no significant differential survival profile between participants who complained to their GP and those without any care recourse. Conclusion Neither recourse to a specialist nor recourse to GP improve survival of new dementia cases. Those who had consulted a specialist early in the disease course even reported a worse life expectancy than those who did not. [ABSTRACT FROM AUTHOR]

An imaged-based profiling and analysis system was developed to predict clinically effective synergistic drug combinations that could accelerate the identification of effective multi-drug therapies for the treatment of triple-negative breast cancer and other challenging malignancies. The identification of effective drug combinations for the treatment of triple-negative breast cancer (TNBC) was achieved by integrating high-content screening, computational analysis, and experimental biology. The approach was based on altered cellular phenotypes induced by 55 FDA-approved drugs and biologically active compounds, acquired using fluorescence microscopy and retained in multivariate compound profiles. Dissimilarities between compound profiles guided the identification of 5 combinations, which were assessed for qualitative interaction on TNBC cell growth. The combination of the microtubule-targeting drug vinblastine with KSP/Eg5 motor protein inhibitors monastrol or ispinesib showed potent synergism in 3 independent TNBC cell lines, which was not substantiated in normal fibroblasts. The synergistic interaction was mediated by an increase in mitotic arrest with cells demonstrating typical ispinesib-induced monopolar mitotic spindles, which translated into enhanced apoptosis induction. The antitumour activity of the combination vinblastine/ispinesib was confirmed in an orthotopic mouse model of TNBC. Compared to single drug treatment, combination treatment significantly reduced tumour growth without causing increased toxicity. Image-based profiling and analysis led to the rapid discovery of a drug combination effective against TNBC in vitro and in vivo , and has the potential to lead to the development of new therapeutic options in other hard-to-treat cancers. [ABSTRACT FROM AUTHOR]

Background: Little is known about the prodromal phase of Dementia with Lewy bodies (DLB). In a large prospective cohort of patients attending memory clinics presenting either subjective cognitive impairment (SCI) and mild neurocognitive impairment (MCI) patients, we undertook an ancillary study aiming at detecting early DLB in a longitudinal framework. Method: We conducted a french nationwide prospective cohort of patients with cognitive complaints and a minimum follow‐up of 4 years. Participants in the Memento cohort study were recruited for either isolated subjective cognitive impairment (SCI) or mild neurocognitive impairment (MCI). Among them, patients from 12 memory resource and research centers, representing eight hundred ninety‐two patients were included in the Lewy sub‐study. Probable Pro‐DLB diagnosis was done using a two‐criteria cut‐off score among the four core clinical features of Dementia with Lewy bodies. This Pro‐DLB group was compared to two other groups: one without any core symptoms (NS group), and the one with one core symptom (1S group). A comprehensive cognitive battery, brain 3D volumetric MRI, CSF, FDG PET and amyloid PET were done. Result: The pro‐DLB group comprised 148 patients (16.6%). Compared to the other two groups, the neuropsychological profile of the pro‐DLB group showed, regarding cognition, more multidomain (59.8%) MCI with slower processing speed, semantic and neurovisual impairment, and regarding behavior, a higher proportion of patients with depression, anxiety, and apathy. Pro‐DLB patients also presented more autonomic symptoms, including lower libido, constipation, rhinorrhea, sicca syndrome, and photophobia. The Pro‐DLB group had isolated lower P‐Tau and no difference in terms of amyloid PET and FDG PET. Brain MRI analysis showed widening of sulci including fronto‐insular, occipital and olfactory sulci (FDR corrected). Evolution to dementia was not different between the three groups after 4 years of follow‐up. Conclusion: Patients with pro‐DLB represented 16.6% of SCI and MCI patients, a finding consistent with the proportion observed at the stage of dementia. In addition to the core symptoms, pro‐DLB patients presented cognitive, behavioral and autonomic symptoms. Biomarkers confirmed the non‐Alzheimer profile. The occipital, fronto‐insular, and olfactory bulb involvement on brain MRI was consistent with the symptoms and known neuropathology. [ABSTRACT FROM AUTHOR]

Background: Given the burden related to dementia, identifying prevention targets against cognitive aging and Alzheimer's disease (AD) and related disorders is of high interest. While factors of resilience, i.e. education, physical or cognitive activity, or social network, are thought to mitigate the effect of cerebral damage on cognition, mechanisms involved are not well understood. This work thus aims to investigate the pathways involved in the association between resilience and cognition. Method: Data were collected as part of the Memento study, a French nationwide cohort including patients from 28 memory clinics with either isolated cognitive complaints or mild cognitive impairment. Factors contributing to resilience, such as education level, salary, physical activity, leisure activities, or social network, as well as MRI markers of brain health were collected at baseline. AD cerebrospinal fluid (CSF) biomarkers were assessed in a subsample (n=410). Based on resilience factors, we established a global resilience score using a latent variable from a structural equation model. Structural equation models were also used to evaluate cross‐sectional pathways between resilience, brain ageing biomarkers in relation to cognition, taking into account potential confounders (Figure). Estimates from latent variables were standardized and results reported are for one SD of resilience. Result: Participants' mean age was 70.9 years old, 62% were women, 28% were APOE‐ε4 carriers, and 59% had a CDR score of 0.5. Resilience score obtained for each participants, ranged from ‐2.28 to 2.73. AD CSF biomarkers were all significantly associated with worse cognition. Higher resilience was significantly associated with higher cognitive performances (total βres_cog=0.569, p<.0001). In addition to a direct effect on cognition (direct βres_cog=0.519, p<.0001), this association was partly mediated by an indirect effect of resilience on cognition (indirect βres_cog=0.050, p<.0001) through lower neurodegeneration (direct βres_nd=‐0.128, p<.0001). White matter hyperintensities volume, CSF Aβ42/Aβ40 ratio, and CSF phosphorylated tau were not involved in the association between resilience and cognition. Conclusion: Resilience preserves cognitive functions both directly and indirectly through an apparent protection against neurodegeneration. Beside, AD and small vessel disease markers are not associated with resilience and they do not mediate the protective effect of resilience on cognition. [ABSTRACT FROM AUTHOR]

Background: Since the new ATN classification system positing a biological definition of Alzheimer's disease (AD), cerebrospinal fluid (CSF) biomarkers are the keystone of AD diagnosis in countries where amyloid and tau positron emission tomography (PET) are not available. However, data confronting CSF biomarkers with pathology are still scarce. Method: Among the 242 patients within Lille Brain bank, 23 patients had both CSF biomarkers and a neuropathologically confirmed AD. CSF collection was performed during follow up at the Lille Memory Clinic. CSF Ab42, Tau and pTau were measured and classified as pathological or normal regarding the cutoff at the time. The ATN profile (where A+ stands for pathological Ab42, T+ for pathological pTau and N+ for pathological Tau) was then determined. Result: 21/23 patients had early onset AD, the age at first symptoms, the delay between the first symptoms and the lumbar puncture (LP) as well as the the delay between the autopsy and the LP were not different between groups. The MMSE at LP was above 15 in the A+T+N‐ (23.8 ± 4.5), the A‐T‐N+ (22) and the A+T+N+ group, and was statistically different between A+T+N‐ vs A‐T‐N+ (p = 0.03) and A+T+N‐ vs A‐T+N+ (P = 0.01) groups. Among our pathologically proved AD cases, 14/23 were A+T+N+, while 7 patients had 2 pathological biomarkers (4 were A+T+N‐ and 3 were A‐T+N+) and 2 patients had one (one was A+T‐N‐ and one was A‐T‐N+). AD was the main neuropathological diagnosis in all cases except for the A‐T+N‐ case where progressive supranuclear palsy was the main diagnosis (Figure 1). Conclusion: Despite neuropathological evidence of amyloid deposition, neuronal death and neurodegeneration at autopsy, only 60% of our AD patients had a full A+T+N+ CSF profile. CSF Ab42/40 ratio may improve correlations between biomarkers and pathology by reincorporating some of our A‐T+ patients into the A+T+ group. We are currently confirming these data by repeating the measures using modern fully‐automated assays, including CSF Ab42/40 ratio. [ABSTRACT FROM AUTHOR]

Background: There is an unmet need for an accurate, non‐invasive biomarker test for the diagnosis of early Alzheimer's disease (AD). To identify new biomarkers, we focused on long non‐coding RNAs (lncRNAs) as they are tissue‐ specific to identify lncRNA panel candidates for diagnostic of early Alzheimer's disease (AD) and other dementia types. Method: We performed a screening using NGS RNA‐Sequencing to quantify over 127000 lncRNAs in human postmortem brain tissue and blood samples including whole blood, PBMCs and, plasma samples collected in prospective clinical studies that recruited patients with early AD, patients with late AD, patients with one of the other 5 dementia types and healthy controls. Result: We identified for the first time several panels (i) a panel of brain‐enriched lncRNAs never described before, (ii) panels of brain‐enriched lncRNAs that are either expressed in whole blood or circulating in plasma. (iii) Interestingly, out of these, we also identified panels of lncRNAs that are differentially expressed in the blood of patients with AD or with other dementia types as compared to healthy control subjects. The most accurate lncRNA panel to detect early AD is selected for use as Research‐Use‐Only test and is being further validated to compile the data dossier for submission to regulatory agencies for approval as an in‐vitro diagnostic (IVD) tool diagnostic of AD. Additional clinical applications are for prognostic or theragnostic purposes. Conclusion: Our results from studies combining the use of high‐quality samples from well‐designed prospective clinical studies, cutting edge technologies and scientific knowhow enabled to translate novel brain specific lncRNA panels measurable in blood as new non‐invasive and accurate diagnostic approaches using highly specific and low represented sequences specific to neurodegenerative diseases. This project is funded by the Alzheimer's Drug Discovery Foundation (ADDF) Diagnostics Accelerator, a fund set up in collaboration with Bill Gates and other philanthropic partners, By H2020 SMEINST (GA#674474) and by EuroTransBio (ETB‐2014‐63 supported by Region Grand Est). [ABSTRACT FROM AUTHOR]

Abstract: Background: The assessment of total tau, phosphorylated tau (pTau-181) and amyloid beta (Aβ 1–42) concentrations in the cerebrospinal fluid (CSF) of subjects has been validated for the diagnosis of Alzheimer’s disease (AD). Although these measurements have shown some variability, little is known about their intersite variability in clinical settings. Methods: A total of 880 subjects (AD, n = 515; non-AD, n = 365) from three French memory centers were included. Receiver–operating characteristic analyses were performed to computerized area under curves (AUCs) and optimal thresholds for each biomarker in the three centers. A test–retest study was performed in a group of 32 CSF samples by repeated blind analysis of the three biomarkers using the same immunoassay batches in the three centers. Results: In the three centers, tau (AUC, 0.82–0.88) and pTau-181 (AUC, 0.83–0.89) outperformed Aβ 1–42 (AUC, 0.70 –0.73) to discriminate subjects with AD from those without AD. An intersite variation of mean levels and cutoffs was observed for the three biomarkers. This variation was higher for Aβ 1–42 (range of cutoff, 368–582 pg/mL) than for tau (range of cutoff, 289–353 pg/mL). In a test–retest study, the mean interlaboratory coefficients of variation were 12.2% for Aβ 1–42, 11.3% for tau, and 11.5% for pTau-181. Conclusion: Intercenter variability of CSF biomarkers has been confirmed in a multisite cohort of subjects and can be improved in clinical settings. Efforts on harmonization of procedures should be encouraged to optimize the accuracy of CSF biomarkers in AD. [Copyright &y& Elsevier]

1 Diacetolol is the N-acetylated metabolite of acebutolol and possesses beta-adrenergic receptor blocking properties. 2 Its antihypertensive action was assessed in accordance with a double-blind randomised cross- over scheme in 17 patients with moderate essential hypertension previously well controlled with acebutolol. 3 Significant reductions in lying mean arterial blood pressure were observed with daily doses of 200 mg (- 9%), 400 mg (- 10%) and 800 mg (- 14%), and were associated with significant decreases in heart rate and plasma renin activity. 4 The diacetolol mean plasma level measured 8 to 10 h after drug ingestion was proportional to the dose (207 +/- 27, 394 +/- 63 and 823 +/- 135 ng/ml for respectively 200, 400 and 800 mg/day). [ABSTRACT FROM AUTHOR]

Background: Amyotrophic lateral sclerosis (ALS) is a sporadic or familial fatal neurodegenerative condition that affects motor neurons in primary motor cortex, brainstem and spinal cord. While predominantly a motor disorder, ALS is frequently associated with cognitive impairment, mostly of frontal type. Hippocampic syndrome is not recognized as part of the cognitive phenotype of ALS. Method: After a national translational survey, we report a French multicentric case series of three patients that presented with an association of definite Alzheimer disease (AD) and ALS. A systematic review of the literature was carried out in January 2020 to explore already reported similar cases. Result: Patient n°1 had a history of behavioral variant of AD followed seven years later by onset of bulbar ALS. Cerebro‐Spinal Fluid (CSF) AD biomarkers displayed AD biological profile associated with ApoE4E4 genotype. Genetic testing for C9ORF72 expansion was negative. Patient n° 2 was diagnosed with ALS, associated with dysexecutive syndrome and CSF AD biological profile (Wallon et al, 2012). Patient n°3 had clinical AD and ALS. Post‐mortem analysis was available, confirming motoneuron disease and Alzheimer type pathology. Review of the literature retrieved only few other cases of co‐occurrence of AD and ALS (Nijboer et al, 2019; Farid et al, 2015; Müller et al, 1993). More frequently, association of amyloid pathology to ALS lesions at post‐mortem examination has been described in ALS patients with or without cognitive impairment. Nevertheless, the relationship between these findings and clinical manifestations is still unclear. The mechanisms that account for the underlying neurodegenerative processes that occurred in our patients remain to be comprehended. Conclusion: We report a series of cases associating AD and ALS and discuss the hypothesis of it being an under recognized phenotype. [ABSTRACT FROM AUTHOR]

Background: The abundance of patient data collected during clinical routine is rarely harnessed towards progress in neuroscience. However, multimodal real‐life data may provide significant insights into pathophysiology, disease progression and prognosis, in particular in the field of Alzheimer's disease. The aim of the Medical Informatics Platform (MIP) within the Human Brain Project is to create an intuitive interface that allows remote computational analyses of clinical data stored in the respective medical centers. Method: The concept of federated analyses refers to the statistical processing of physically separate and non‐aggregated data sets in a single user interface. The MIP interface provides advanced statistical approaches, remote data access and local user regulations. Authorized MIP users are able to test their hypotheses using a flexible portfolio of data sets, modalities and data processing tools. Result: At the present stage, three memory clinics have contributed to the MIP: the Leenaards Memory Centre at the University Hospital Lausanne, Switzerland; the University Hospital Lille Memory Centre, France; and the IRCCS Istituto Centro San Giovanni Di Dio Fatebenefratelli di Brescia, Italy. The data sets contain demographic, neuropsychological and volumetric MRI data from 5154 individuals with subjective and mild cognitive impairment or dementia. The data include clinically probable Alzheimer's etiology according to CSF biomarkers. Proof‐of‐concept and validation analyses will be presented. Reference data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), which can be downloaded by MIP users in accordance with ADNI rules, can be compared with the clinical data in the MIP. Conclusion: Federated analyses such as afforded by the MIP within the Human Brain Project do not only allow novel scientific insights due to a substantial increase in sample size and cross‐validation, but also ensure a high level of data protection. The MIP has a considerable potential for discovery in clinical neuroscience. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a heterogeneous illness, with a common clinical presentation of progressive amnesia and less common « atypical » presentations which may be misdiagnosed with a pathology of the frontotemporal lobar degeneration (FTLD) spectrum. This study sought to characterize which phenotypes of AD are difficult to distinguish from FTLD. Method: Among the patients followed in the Lille Memory Clinic (France) between 1993 and 2018 and having a neuropathologic diagnosis of AD, the clinical phenotypes of those for whom there was a diagnostic hesitation between AD and FTLD (« doubt group », n = 13) were compared with the clinical phenotypes of those for whom there was no hesitation in diagnosing AD (« no doubt group », n = 40). Result: A primary progressive aphasia (PPA) phenotype and a corticobasal syndrome (CBS) phenotype are most likely to be found in the « doubt group » (PPA n = 8/13, 62,5% ; CBS n = 2/13, 15,4%) than in the « no doubt group » (PPA n = 1/40, 2,5% ; CBS n = 0/40, 0%). In this study, no patient with confirmed AD fulfilled precociously the Rascovsky criteria for possible behavioural variant of frontotemporal dementia (bvFTD). Conclusion: As reported, PPA and CBS phenotypes are syndromes that can be observed in AD as in FTLD. Frontal variant of AD seems very uncommon. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Predictors of cardiac events in high-risk patients undergoing emergency surgery," published in a 2009 issue.