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)

Precision medicine - the golden gate for detection, treatment and prevention of Alzheimer's disease

During this decade, breakthrough conceptual shifts have commenced to emerge in the field of Alzheimer’s disease (AD) recognizing risk factors and the non-linear dynamic continuum of complex pathophysiologies amongst a wide dimensional spectrum of multi-factorial brain proteinopathies/neurodegenerative diseases. As is the case in most fields of medicine, substantial advancements in detecting, treating and preventing AD will likely evolve from the generation and implementation of a systematic precision medicine strategy. This approach will likely be based on the success found from more advanced research fields, such as oncology. Precision medicine will require integration and transfertilization across fragmented specialities of medicine and direct reintegration of Neuroscience, Neurology and Psychiatry into a continuum of medical sciences away from the silo approach. Precision medicine is biomarker-guided medicine on systems-levels that takes into account methodological advancements and discoveries of the comprehensive pathophysiological profiles of complex multi-factorial neurodegenerative diseases, such as late-onset sporadic AD. This will allow identifying and characterizing the disease processes at the asymptomatic preclinical stage, where pathophysiological and topographical abnormalities precede overt clinical symptoms by many years to decades. In this respect, the uncharted territory of the AD preclinical stage has become a major research challenge as the field postulates that early biomarker guided customized interventions may offer the best chance of therapeutic success. Clarification and practical operationalization is needed for comprehensive dissection and classification of interacting and converging disease mechanisms, description of genomic and epigenetic drivers, natural history trajectories through space and time, surrogate biomarkers and indicators of risk and progression, as well as considerations about the regulatory, ethical, political and societal consequences of early detection at asymptomatic stages. In this scenario, the integrated roles of genome sequencing, investigations of comprehensive fluid-based biomarkers and multimodal neuroimaging will be of key importance for the identification of distinct molecular mechanisms and signaling pathways in subsets of asymptomatic people at greatest risk for progression to clinical milestones due to those specific pathways. The precision medicine strategy facilitates a paradigm shift in Neuroscience and AD research and development away from the classical “one-size-fits-all” approach in drug discovery towards biomarker guided “molecularly” tailored therapy for truly effective treatment and prevention options. After the long and winding decade of failed therapy trials progress towards the holistic systems-based strategy of precision medicine may finally turn into the new age of scientific and medical success curbing the global AD epidemic

Obtaining representative core streamlines for white matter tractometry of the human brain

Diffusion MRI infers information about the micro-structural architecture of the brain by probing the diffusion of water molecules. The process of virtually reconstructing brain pathways based on these measurements is called tractography. Various metrics can be mapped onto pathways to study their micro-structural properties. Tractometry is an along-tract profiling technique that often requires the extraction of a representative streamline for a given bundle. This is traditionally computed by local averaging of the spatial coordinates of the vertices, and constructing a single streamline through those averages. However, the resulting streamline can end up being highly non-representative of the shape of the individual streamlines forming the bundle. In particular, this occurs when there is variation in the topology of streamlines within a bundle (e.g., differences in length, shape or branching). We propose an envelope-based method to compute a representative streamline that is robust to these individual differences. We demonstrate that this method produces a more representative core streamline, which in turn should lead to more reliable and interpretable tractometry analyses

Pandora: 4-D White Matter Bundle Population-Based Atlases Derived from Diffusion MRI Fiber Tractography

Brain atlases have proven to be valuable neuroscience tools for localizing regions of interest and performing statistical inferences on populations. Although many human brain atlases exist, most do not contain information about white matter structures, often neglecting them completely or labelling all white matter as a single homogenous substrate. While few white matter atlases do exist based on diffusion MRI fiber tractography, they are often limited to descriptions of white matter as spatially separate "regions" rather than as white matter "bundles" or fascicles, which are well-known to overlap throughout the brain. Additional limitations include small sample sizes, few white matter pathways, and the use of outdated diffusion models and techniques. Here, we present a new population-based collection of white matter atlases represented in both volumetric and surface coordinates in a standard space. These atlases are based on 2443 subjects, and include 216 white matter bundles derived from 6 different automated state-of-the-art tractography techniques. This atlas is freely available and will be a useful resource for parcellation and segmentation

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

Basal forebrain volume, but not hippocampal volume, is a predictor of global cognitive decline in patients with alzheimer's disease treated with cholinesterase inhibitors

Background: Predicting the progression of cognitive decline in Alzheimer's disease (AD) is important for treatment selection and patient counseling. Structural MRI markers such as hippocampus or basal forebrain volumes might represent useful instruments for the prediction of cognitive decline. The primary objective was to determine the predictive value of hippocampus and basal forebrain volumes for global and domain specific cognitive decline in AD dementia during cholinergic treatment. Methods: We used MRI and cognitive data from 124 patients with the clinical diagnosis of AD dementia, derived from the ADNI-1 cohort, who were on standard of care cholinesterase inhibitor treatment during a follow-up period between 0.4 and 3.1 years. We used linear mixed effects models with cognitive function as outcome to assess the main effects as well as two-way interactions between baseline volumes and time controlling for age, sex, and total intracranial volume. This model accounts for individual variation in follow-up times. Results: Basal forebrain volume, but not hippocampus volume, was a significant predictor of rates of global cognitive decline. Larger volumes were associated with smaller rates of cognitive decline. Left hippocampus volume had a modest association with rates of episodic memory decline. Baseline performance in global cognition and memory was significantly associated with hippocampus and basal forebrain volumes; in addition, basal forebrain volume was associated with baseline performance in executive function. Conclusions: Our findings indicate that in AD dementia patients, basal forebrain volume may be a useful marker to predict subsequent cognitive decline during cholinergic treatment