Étude de l’imagerie amyloïde cérébrale et de l’élargissement des endosomes dans les cellules sanguines au cours de la maladie d’Alzheimer

Alzheimer’s disease (AD) diagnostic is based on clinical and biological criteria, and is dependent on impairment of the episodic memory together with a marker of the underlying pathophysiologic process. One of the earliest events in AD pathology in the brain is formation of Amyloid deposits in the extracellular space. One of the main subcellular sites of amyloid-β (Aβ) production from amyloid precursor protein (APP) processing is the endosomal compartment. Appearance of endosomal abnormalities precede the formation of amyloid deposits, in the brain areas affected by disease progression in AD. In the present work we first studied brain amyloid load in patients with posterior cortical atrophy using [11C]PiB ligand retention in positron emitting tomography (PET). In a second part we studied the endosomal compartment in peripheral cells (fibroblasts and mononuclear leucocytes, PBMC) from AD patients, and in lymphoblastoid cell lines (LCL) from Down’s syndrome (DS) individuals where a third copy of amyloid-precursor-protein-coding gene located on chromosome 21 is known to initiate early Alzheimer’s pathology in most DS individuals. Our work shows similar profiles in topography and intensity of [PiB] binding in AD and posterior cortical atrophy (PCA), confirming underlying AD pathology in atypical focal presentations of AD. Analysis of endosomes yielded a significant increase in the frequency of cells with large endosomes in all analyzed cell types, and mean endosome volume correlated to [PiB] binding in PBMC. This result indicates that modifications of the endosomal compartment are seen in the periphery of central nervous system and may represent diagnostic tool from blood.Le diagnostic de la maladie d’Alzheimer (MA) s’appuie sur des critères clinico-biologiques combinant un déficit de la mémoire épisodique et un marqueur biologique (dosage dans le liquide céphalorachidien, imagerie nucléaire) indicateur des changements qui signent le début de la maladie. Un phénomène biologique précoce de la maladie est la production de dépôts du peptide amyloïde dont le principal site de production à partir de son précurseur, l’APP, est le compartiment endosomal. L’apparition dans le cerveau d’endosomes élargis précède celle des dépôts amyloïdes.Nous avons analysé deux marqueurs biologiques. D’abord la charge amyloïde cérébrale par fixation du ligand [PiB] en tomographie d’émission de positrons (TEP) dans le cerveau des malades atteints d’une atrophie corticale postérieure (ACP). Puis nous avons étudié les endosomes dans les cellules périphériques (leucocytes mononucléaires et fibroblastes) de patients MA, et dans des lignées lymphoblastoïdes (LCL) d’individus porteurs d’une trisomie 21 dont 45% développent une MA à l’âge de 60 ans (contre 3 % dans la population générale), principalement en raison de la présence d’une troisième copie du gène codant l’APP, localisé sur le chromosome 21. Nos travaux montrent des profils de marquage [PiB] similaires entre la MA et l’atrophie corticale postérieure (ACP) aussi bien en intensité qu’en topographie. L’étude des endosomes montre que les modifications du compartiment endosomal sont détectables en périphérie du système nerveux central et sont corrélées au marquage des dépôts amyloïdes cérébraux. Ces altérations pourraient constituer un outil de diagnostic à partir de prélèvements sanguins

Modifications of the endosomal compartment in peripheral blood mononuclear cells and fibroblasts from Alzheimer’s disease patients

International audienceIdentification of blood-based biomarkers of Alzheimer’s disease (AD) remains a challenge. Neuropathological studies have identified enlarged endosomes in post-mortem brains as the earliest cellular change associated to AD. Here the presence of enlarged endosomes was investigated in peripheral blood mononuclear cells from 48 biologically defined AD patients (25 with mild cognitive impairment and 23 with dementia (AD-D)), and 23 age-matched healthy controls using immunocytochemistry and confocal microscopy. The volume and number of endosomes were not significantly different between AD and controls. However, the percentage of cells containing enlarged endosomes was significantly higher in the AD-D group as compared with controls. Furthermore, endosomal volumes significantly correlated to [C11]PiB cortical index measured by positron emission tomography in the AD group, independently of the APOE genotype, but not to the levels of amyloid-beta, tau and phosphorylated tau measured in the cerebrospinal fluid. Importantly, we confirmed the presence of enlarged endosomes in fibroblasts from six unrelated AD-D patients as compared with five cognitively normal controls. This study is the first, to our knowledge, to report morphological alterations of the endosomal compartment in peripheral cells from AD patients correlated to amyloid load that will now be evaluated as a possible biomarker

Analysis of brain PiB positive amyloid deposits and endosome enlargement in blood cells, in Alzheimer's disease

Le diagnostic de la maladie d’Alzheimer (MA) s’appuie sur des critères clinico-biologiques combinant un déficit de la mémoire épisodique et un marqueur biologique (dosage dans le liquide céphalorachidien, imagerie nucléaire) indicateur des changements qui signent le début de la maladie. Un phénomène biologique précoce de la maladie est la production de dépôts du peptide amyloïde dont le principal site de production à partir de son précurseur, l’APP, est le compartiment endosomal. L’apparition dans le cerveau d’endosomes élargis précède celle des dépôts amyloïdes.Nous avons analysé deux marqueurs biologiques. D’abord la charge amyloïde cérébrale par fixation du ligand [PiB] en tomographie d’émission de positrons (TEP) dans le cerveau des malades atteints d’une atrophie corticale postérieure (ACP). Puis nous avons étudié les endosomes dans les cellules périphériques (leucocytes mononucléaires et fibroblastes) de patients MA, et dans des lignées lymphoblastoïdes (LCL) d’individus porteurs d’une trisomie 21 dont 45% développent une MA à l’âge de 60 ans (contre 3 % dans la population générale), principalement en raison de la présence d’une troisième copie du gène codant l’APP, localisé sur le chromosome 21. Nos travaux montrent des profils de marquage [PiB] similaires entre la MA et l’atrophie corticale postérieure (ACP) aussi bien en intensité qu’en topographie. L’étude des endosomes montre que les modifications du compartiment endosomal sont détectables en périphérie du système nerveux central et sont corrélées au marquage des dépôts amyloïdes cérébraux. Ces altérations pourraient constituer un outil de diagnostic à partir de prélèvements sanguins.Alzheimer’s disease (AD) diagnostic is based on clinical and biological criteria, and is dependent on impairment of the episodic memory together with a marker of the underlying pathophysiologic process. One of the earliest events in AD pathology in the brain is formation of Amyloid deposits in the extracellular space. One of the main subcellular sites of amyloid-β (Aβ) production from amyloid precursor protein (APP) processing is the endosomal compartment. Appearance of endosomal abnormalities precede the formation of amyloid deposits, in the brain areas affected by disease progression in AD. In the present work we first studied brain amyloid load in patients with posterior cortical atrophy using [11C]PiB ligand retention in positron emitting tomography (PET). In a second part we studied the endosomal compartment in peripheral cells (fibroblasts and mononuclear leucocytes, PBMC) from AD patients, and in lymphoblastoid cell lines (LCL) from Down’s syndrome (DS) individuals where a third copy of amyloid-precursor-protein-coding gene located on chromosome 21 is known to initiate early Alzheimer’s pathology in most DS individuals. Our work shows similar profiles in topography and intensity of [PiB] binding in AD and posterior cortical atrophy (PCA), confirming underlying AD pathology in atypical focal presentations of AD. Analysis of endosomes yielded a significant increase in the frequency of cells with large endosomes in all analyzed cell types, and mean endosome volume correlated to [PiB] binding in PBMC. This result indicates that modifications of the endosomal compartment are seen in the periphery of central nervous system and may represent diagnostic tool from blood

Data_Sheet_1_Principal component analysis suggests multiple dimensions of memory inhibition that are differentially affected by age.PDF

BackgroundCognitive inhibition is among the executive functions that decline early in the course of normal aging. Failures to be able to inhibit irrelevant information from memory may represent an essential factor of age-associated memory impairment. While a variety of elaborate behavioral tasks have been developed that presumably all index memory inhibition, the extent to which these different tasks measure the same underlying cognitive construct that declines with age has not been well explored.MethodsIn the current study, 100 and 75 cognitively healthy younger (n = 71; age = 30.7 ± 5.4 years, 56.7% female) and older (n = 104, age = 69.3 ± 5.9 years, 66.2% female) adults with equivalent educational attainment performed three computer-based memory inhibition tasks: the Retrieval Induced Forgetting task, the Suppress task, and the Directed Forgetting task. We conducted a principal component analysis using scores derived from different components of these tasks to explore whether and how the tasks relate to one another. We further investigated how age, sex and education, along with, in a subsample of the participants, a neuropsychological measure of episodic memory, impacted both the task scores individually, and the principal components derived from the exploratory analysis.ResultsWe identified 3 distinct sources of variability which represent potentially independent cognitive processes: memory retrieval facilitation, and two memory inhibition processes that distinguished themselves by the degree of volitional initiation of memory suppression. Only the memory retrieval component correlated with a neuropsychologically-derived episodic memory score, and both memory inhibition principal components were age dependent.ConclusionOur findings provide support for a distinction in memory suppression processes between those ‘instructed’ to be performed and those which happen without explicit instruction. This distinction adds nuance to the dichotomous classification of controlled vs. automatic inhibitory mechanisms, which have been shown in previous work to vary as a function of the degree of frontal involvement. Our findings further demonstrate that while both of these measures of inhibition were affected by age, the episodic memory component was not, suggesting that inhibitory impairments may precede memory deficits in healthy aging.</p

Improved accuracy of the diagnosis of early Alzheimer’s disease using combined measures of hippocampal volume and sulcal morphology

International audienc

Association Between Cognitive Test Performance and Subjective Cognitive Decline in a Diverse Cohort of Older Adults: Findings From the KHANDLE Study.

BackgroundSubjective cognitive decline (SCD) may represent a low-burden indicator of dementia risk. The value of SCD as a proxy marker, however, depends on the consistency of associations between subjective and objective cognitive measures across sociodemographic and psychological factors.MethodsWe evaluated baseline data from the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) study (n=1615). SCD was measured using the 12-item Everyday Cognition (ECog) scale. Using linear regression models with interaction terms, we evaluated 6 potential modifiers (age, sex, race/ethnicity, educational attainment, family history of dementia, and depressive symptoms) of the association between cognitive performance (episodic memory, executive function) and SCD.ResultsLower episodic memory and executive function scores were associated with higher log(ECog scores) (more SCD). Older age and elevated depressive symptoms were associated with higher log(ECog scores). Age (interaction P=0.002) and education (interaction P=0.01) modified the association between executive function and log(ECog scores). Specifically, associations between executive function and log(ECog scores) were stronger among participants with more education and less pronounced among older participants.ConclusionsThe association between cognitive performance and log(ECog scores) differed little across sociodemographic and psychological factors. SCD as measured by the ECog may be a valuable proxy for cognitive performance in diverse older adults

Sulcal morphology in Alzheimer's disease: an effective marker of diagnosis and cognition

Julien Lagarde and Fabian Corlier contributed equally.International audienceMeasuring the morphology of brain sulci has been recently proposed as a novel imaging approach in AD. We aimed to investigate the relevance of such an approach in AD, by exploring its (1) clinical relevance in comparison with traditional imaging methods, (2) relationship with amyloid deposition, (3) association with cognitive functions. Here, 51 patients (n=32 MCI/mild dementia-AD, n=19 moderate/severe dementia-AD) diagnosed according to clinical-biological criteria (CSF biomarkers and amyloid-PET) and 29 controls (with negative amyloid-PET) underwent neuropsychological and 3T-MRI examinations. Mean sulcal width (SW) & mean cortical thickness around the sulcus (CT-S) were automatically measured. We found higher SW and lower CT-S in AD patients than in controls. These differences were more pronounced at later stages of the disease and provided the best diagnostic accuracies among the imaging markers. Correlations were not found between CT-S or SW and amyloid deposition but between specific cognitive functions and regional CT-S/SW in key associated regions. Sulcal morphology is a good supporting diagnosis tool, that reflects the main cognitive impairments in AD. It could be considered as a good surrogate marker to evaluate the efficacy of new drugs

ENDO-LYSOSOMAL ALTERATIONS IN DOWN SYNDROME BEFORE AND AFTER ALZHEIMER'S DISEASE

info:eu-repo/semantics/publishe

Distinct patterns of antiamyloid-β antibodies in typical and atypical Alzheimer disease

International audienceOBJECTIVE: To compare serum antiamyloid-β (Aβ) antibodies in typical and atypical Alzheimer disease (AD). DESIGN: Preliminary observations. SUBJECTS: Thirteen patients with AD, 8 patients with posterior cortical atrophy with evidence of AD (PCA-AD) pathophysiological process by both cerebrospinal fluid (CSF) biomarkers and amyloid imaging, and 12 age-matched control individuals. INTERVENTIONS: The class and subclass levels of serum anti-Aβ antibodies were measured using an oligomer-based enzyme-linked immunosorbent assay. This method allowed measuring both free antibodies and, after acidic treatment, the total fraction that includes all antibodies complexed with circulating Aβ40/42 and any cross-reacting antigen. RESULTS: Anti-Aβ IgG were restricted to the IgG1 and IgG3 subclasses. Their total levels were strikingly lower and more homogeneous in patients with PCA compared with both typical AD and controls, while biomarkers of amyloid deposition (CSF Aβ42 and positron emission tomography amyloid imaging) were similar in patients with AD and patients with PCA. CONCLUSIONS: Serum anti-Aβ IgG1 and IgG3 antibodies differ between distinct forms of AD. Its significance is discussed for possible implications as immune effectors in the specific pathophysiology of AD variants