Awareness of cognitive decline trajectories in asymptomatic individuals at risk for AD

Background: Lack of awareness of cognitive decline (ACD) is common in late-stage Alzheimer’s disease (AD). Recent studies showed that ACD can also be reduced in the early stages. Methods: We described different trends of evolution of ACD over 3 years in a cohort of memory-complainers and their association to amyloid burden and brain metabolism. We studied the impact of ACD at baseline on cognitive scores’ evolution and the association between longitudinal changes in ACD and in cognitive score. Results: 76.8% of subjects constantly had an accurate ACD (reference class). 18.95% showed a steadily heightened ACD and were comparable to those with accurate ACD in terms of demographic characteristics and AD biomarkers. 4.25% constantly showed low ACD, had significantly higher amyloid burden than the reference class, and were mostly men. We found no overall effect of baseline ACD on cognitive scores’ evolution and no association between longitudinal changes in ACD and in cognitive scores. Conclusions: ACD begins to decrease during the preclinical phase in a group of individuals, who are of great interest and need to be further characterized. Trial registration: The present study was conducted as part of the INSIGHT-PreAD study. The identification number of INSIGHT-PreAD study (ID-RCB) is 2012-A01731-42

Low Cognitive Awareness, but Not Complaint, is a Good Marker of Preclinical Alzheimer's Disease

Subjective cognitive decline (SCD) may result from many conditions, including Alzheimer's disease (AD)

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Gray matter network disruptions and regional amyloid beta in cognitively normal adults

The accumulation of amyloid plaques is one of the earliest pathological changes in Alzheimer's disease (AD) and may occur 20 years before the onset of symptoms. Examining associations between amyloid pathology and other early brain changes is critical for understanding the pathophysiological underpinnings of AD. Alterations in gray matter networks might already start at early preclinical stages of AD. In this study, we examined the regional relationship between amyloid aggregation measured with positron emission tomography (PET) and gray matter network measures in elderly subjects with subjective memory complaints. Single-subject gray matter networks were extracted from T1-weigthed structural MRI in cognitively normal subjects (n = 318, mean age 76.1 ± 3.5, 64% female, 28% amyloid positive). Degree, clustering, path length and small world properties were computed. Global and regional amyloid load was determined using [18F]-Florbetapir PET. Associations between standardized uptake value ratio (SUVr) values and network measures were examined using linear regression models. We found that higher global SUVr was associated with lower clustering (ß = -0.12, p < 0.05), and small world values (ß = -0.16, p < 0.01). Associations were most prominent in orbito- and dorsolateral frontal and parieto-occipital regions. Local SUVr values showed less anatomical variability and did not convey additional information beyond global amyloid burden. In conclusion, we found that in cognitively normal elderly subjects, increased global amyloid pathology is associated with alterations in gray matter networks that are indicative of incipient network breakdown towards AD dementia

Gray matter network disruptions and regional amyloid beta in cognitively normal adults

The accumulation of amyloid plaques is one of the earliest pathological changes in Alzheimer's disease (AD) and may occur 20 years before the onset of symptoms. Examining associations between amyloid pathology and other early brain changes is critical for understanding the pathophysiological underpinnings of AD. Alterations in gray matter networks might already start at early preclinical stages of AD. In this study, we examined the regional relationship between amyloid aggregation measured with positron emission tomography (PET) and gray matter network measures in elderly subjects with subjective memory complaints. Single-subject gray matter networks were extracted from T1-weigthed structural MRI in cognitively normal subjects (n = 318, mean age 76.1 ± 3.5, 64% female, 28% amyloid positive). Degree, clustering, path length and small world properties were computed. Global and regional amyloid load was determined using [18F]-Florbetapir PET. Associations between standardized uptake value ratio (SUVr) values and network measures were examined using linear regression models. We found that higher global SUVr was associated with lower clustering (Ã\u9f = -0.12, p < 0.05), and small world values (Ã\u9f = -0.16, p < 0.01). Associations were most prominent in orbito- and dorsolateral frontal and parieto-occipital regions. Local SUVr values showed less anatomical variability and did not convey additional information beyond global amyloid burden. In conclusion, we found that in cognitively normal elderly subjects, increased global amyloid pathology is associated with alterations in gray matter networks that are indicative of incipient network breakdown towards AD dementia

Effect of Alzheimer's disease risk and protective factors on cognitive trajectories in subjective memory complainers: An INSIGHT-preAD study

Introduction: Cognitive change in people at risk of Alzheimer's disease (AD) such as subjective memory complainers is highly variable across individuals. Methods: We used latent class growth modeling to identify distinct classes of nonlinear trajectories of cognitive change over 2 years follow-up from 265 subjective memory complainers individuals (age 70 years and older) of the INSIGHT-preAD cohort. We determined the effect of cortical amyloid load, hippocampus and basal forebrain volumes, and education on the cognitive trajectory classes. Results: Latent class growth modeling identified distinct nonlinear cognitive trajectories. Education was associated with higher performing trajectories, whereas global amyloid load and basal forebrain atrophy were associated with lower performing trajectories. Discussion: Distinct classes of cognitive trajectories were associated with risk and protective factors of AD. These associations support the notion that the identified cognitive trajectories reflect different risk for AD that may be useful for selecting high-risk individuals for intervention trials

Differential default mode network trajectories in asymptomatic individuals at risk for Alzheimer's disease

Introduction:The longitudinal trajectories of functional brain dynamics and the impact of geneticrisk factors in individuals at risk for Alzheimer\u2019s disease are poorly understood.Methods:In a large-scale monocentric cohort of 224 amyloid stratified individuals at risk forAlzheimer\u2019s disease, default mode network (DMN) resting state functional connectivity (FC) wasinvestigated between two serial time points across 2 years.Results:Widespread DMN FC changes were shown in frontal and posterior areas, as well as in theright hippocampus. There were no cross-sectional differences, however, apolipoprotein E\u3b54(APOE\u3b54) carriers demonstrated slower increase in FC in frontal lobes. There was no impact ofindividual brain amyloid load status.Discussion:For the first time, we demonstrated that the pleiotropic biological effect of theAPOE\u3b54allele impacts the dynamic trajectory of the DMN during aging. Dynamic functional biomarkersmay become useful surrogate outcomes for the development of preclinical targeted therapeuticinterventions

Association of cerebrospinal fluid α-synuclein with total and phospho-tau181 protein concentrations and brain amyloid load in cognitively normal subjective memory complainers stratified by Alzheimer's disease biomarkers

147siIntroduction Several neurodegenerative brain proteinopathies, including Alzheimer's disease (AD), are associated with cerebral deposition of insoluble aggregates of α-synuclein. Previous studies reported a trend toward increased cerebrospinal fluid (CSF) α-synuclein (α-syn) concentrations in AD compared with other neurodegenerative diseases and healthy controls. Methods The pathophysiological role of CSF α-syn in asymptomatic subjects at risk of AD has not been explored. We performed a large-scale cross-sectional observational monocentric study of preclinical individuals at risk for AD (INSIGHT-preAD). Results We found a positive association between CSF α-syn concentrations and brain β-amyloid deposition measures as mean cortical standard uptake value ratios. We demonstrate positive correlations between CSF α-syn and both CSF t-tau and p-tau181 concentrations. Discussion Animal models presented evidence, indicating that α-syn may synergistically and directly induce fibrillization of both tau and β-amyloid. Our data indicate an association of CSF α-syn with AD-related pathophysiological mechanisms, during the preclinical phase of the disease.partially_openopenVergallo A.; Bun R.-S.; Toschi N.; Baldacci F.; Zetterberg H.; Blennow K.; Cavedo E.; Lamari F.; Habert M.-O.; Dubois B.; Floris R.; Garaci F.; Lista S.; Hampel H.; Audrain C.; Auffret A.; Bakardjian H.; Baldacci F.; Batrancourt B.; Benakki I.; Benali H.; Bertin H.; Bertrand A.; Boukadida L.; Cacciamani F.; Causse V.; Cavedo E.; Cherif Touil S.; Chiesa P.A.; Colliot O.; Dalla Barba G.; Depaulis M.; Dos Santos A.; Dubois B.; Dubois M.; Epelbaum S.; Fontaine B.; Francisque H.; Gagliardi G.; Genin A.; Genthon R.; Glasman P.; Gombert F.; Habert M.O.; Hampel H.; Hewa H.; Houot M.; Jungalee N.; Kas A.; Kilani M.; La Corte V.; Le Roy F.; Lehericy S.; Letondor C.; Levy M.; Lista S.; Lowrey M.; Ly J.; Makiese O.; Masetti I.; Mendes A.; Metzinger C.; Michon A.; Mochel F.; Nait Arab R.; Nyasse F.; Perrin C.; Poirier F.; Poisson C.; Potier M.C.; Ratovohery S.; Revillon M.; Rojkova K.; Santos-Andrade K.; Schindler R.; Servera M.C.; Seux L.; Simon V.; Skovronsky D.; Thiebaut M.; Uspenskaya O.; Vlaincu M.; Aguilar L.F.; Babiloni C.; Baldacci F.; Benda N.; Black K.L.; Bokde A.L.W.; Bonuccelli U.; Broich K.; Bun R.S.; Cacciola F.; Castrillo J.; Cavedo E.; Ceravolo R.; Chiesa P.A.; Colliot O.; Coman C.M.; Corvol J.C.; Cuello A.C.; Cummings J.L.; Depypere H.; Dubois B.; Duggento A.; Durrleman S.; Escott-Price V.; Federoff H.; Ferretti M.T.; Fiandaca M.; Frank R.A.; Garaci F.; Genthon R.; George N.; Giorgi F.S.; Graziani M.; Haberkamp M.; Habert M.O.; Hampel H.; Herholz K.; Karran E.; Kim S.H.; Koronyo Y.; Koronyo-Hamaoui M.; Lamari F.; Langevin T.; Lehericy S.; Lista S.; Lorenceau J.; Mapstone M.; Neri C.; Nistico R.; Nyasse-Messene F.; O'Bryant S.E.; Perry G.; Ritchie C.; Rojkova K.; Rossi S.; Santarnecchi E.; Schneider L.S.; Sporns O.; Toschi N.; Verdooner S.R.; Vergallo A.; Villain N.; Welikovitch L.; Woodcock J.; Younesi E.Vergallo, A.; Bun, R. -S.; Toschi, N.; Baldacci, F.; Zetterberg, H.; Blennow, K.; Cavedo, E.; Lamari, F.; Habert, M. -O.; Dubois, B.; Floris, R.; Garaci, F.; Lista, S.; Hampel, H.; Audrain, C.; Auffret, A.; Bakardjian, H.; Baldacci, F.; Batrancourt, B.; Benakki, I.; Benali, H.; Bertin, H.; Bertrand, A.; Boukadida, L.; Cacciamani, F.; Causse, V.; Cavedo, E.; Cherif Touil, S.; Chiesa, P. A.; Colliot, O.; Dalla Barba, G.; Depaulis, M.; Dos Santos, A.; Dubois, B.; Dubois, M.; Epelbaum, S.; Fontaine, B.; Francisque, H.; Gagliardi, G.; Genin, A.; Genthon, R.; Glasman, P.; Gombert, F.; Habert, M. O.; Hampel, H.; Hewa, H.; Houot, M.; Jungalee, N.; Kas, A.; Kilani, M.; La Corte, V.; Le Roy, F.; Lehericy, S.; Letondor, C.; Levy, M.; Lista, S.; Lowrey, M.; Ly, J.; Makiese, O.; Masetti, I.; Mendes, A.; Metzinger, C.; Michon, A.; Mochel, F.; Nait Arab, R.; Nyasse, F.; Perrin, C.; Poirier, F.; Poisson, C.; Potier, M. C.; Ratovohery, S.; Revillon, M.; Rojkova, K.; Santos-Andrade, K.; Schindler, R.; Servera, M. C.; Seux, L.; Simon, V.; Skovronsky, D.; Thiebaut, M.; Uspenskaya, O.; Vlaincu, M.; Aguilar, L. F.; Babiloni, C.; Baldacci, F.; Benda, N.; Black, K. L.; Bokde, A. L. W.; Bonuccelli, U.; Broich, K.; Bun, R. S.; Cacciola, F.; Castrillo, J.; Cavedo, E.; Ceravolo, R.; Chiesa, P. A.; Colliot, O.; Coman, C. M.; Corvol, J. C.; Cuello, A. C.; Cummings, J. L.; Depypere, H.; Dubois, B.; Duggento, A.; Durrleman, S.; Escott-Price, V.; Federoff, H.; Ferretti, M. T.; Fiandaca, M.; Frank, R. A.; Garaci, F.; Genthon, R.; George, N.; Giorgi, F. S.; Graziani, M.; Haberkamp, M.; Habert, M. O.; Hampel, H.; Herholz, K.; Karran, E.; Kim, S. H.; Koronyo, Y.; Koronyo-Hamaoui, M.; Lamari, F.; Langevin, T.; Lehericy, S.; Lista, S.; Lorenceau, J.; Mapstone, M.; Neri, C.; Nistico, R.; Nyasse-Messene, F.; O'Bryant, S. E.; Perry, G.; Ritchie, C.; Rojkova, K.; Rossi, S.; Santarnecchi, E.; Schneider, L. S.; Sporns, O.; Toschi, N.; Verdooner, S. R.; Vergallo, A.; Villain, N.; Welikovitch, L.; Woodcock, J.; Younesi, E

Effect of Alzheimer's disease risk and protective factors on cognitive trajectories in subjective memory complainers: An INSIGHT‐preAD study

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