Journal of Alzheimer's disease : JAD, Jan 20, 2018
It is an open issue whether blood biomarkers serve to diagnose Alzheimer's disease (AD) or mo... more It is an open issue whether blood biomarkers serve to diagnose Alzheimer's disease (AD) or monitor its progression over time from prodromal stages. Here, we addressed this question starting from data of the European FP7 IMI-PharmaCog/E-ADNI longitudinal study in amnesic mild cognitive impairment (aMCI) patients including biological, clinical, neuropsychological (e.g., ADAS-Cog13), neuroimaging, and electroencephalographic measures. PharmaCog/E-ADNI patients were classified as "positive" (i.e., "prodromal AD" n = 76) or "negative" (n = 52) based on a diagnostic cut-off of Aβ42/P-tau in cerebrospinal fluid as well as APOE ε 4 genotype. Blood was sampled at baseline and at two follow-ups (12 and 18 months), when plasma amyloid peptide 42 and 40 (Aβ42, Aβ40) and apolipoprotein J (clusterin, CLU) were assessed. Linear Mixed Models found no significant differences in plasma molecules between the "positive" (i.e., prodromal AD) and "negative...
Early Alzheimer's disease (AD) detection using cerebrospinal fluid (CSF) biomarkers has been ... more Early Alzheimer's disease (AD) detection using cerebrospinal fluid (CSF) biomarkers has been recommended as enrichment strategy for trials involving mild cognitive impairment (MCI) patients. To model a prodromal AD trial for identifying MRI structural biomarkers to improve subject selection and to be used as surrogate outcomes of disease progression. APOE ɛ4 specific CSF Aβ42/P-tau cut-offs were used to identify MCI with prodromal AD (Aβ42/P-tau positive) in the WP5-PharmaCog (E-ADNI) cohort. Linear mixed models were performed 1) with baseline structural biomarker, time, and biomarker×time interaction as factors to predict longitudinal changes in ADAS-cog13, 2) with Aβ42/P-tau status, time, and Aβ42/P-tau status×time interaction as factors to explain the longitudinal changes in MRI measures, and 3) to compute sample size estimation for a trial implemented with the selected biomarkers. Only baseline lateral ventricle volume was able to identify a subgroup of prodromal AD patients...
Neuroimaging biomarkers differ between patients with early-onset Alzheimer's disease (EOAD) a... more Neuroimaging biomarkers differ between patients with early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD). Whether these changes reflect cognitive heterogeneity or differences in disease severity is still unknown. This study aimed at investigating changes in neuroimaging biomarkers, according to the age of onset of the disease, in mild amnestic Alzheimer's disease patients with positive amyloid biomarkers in cerebrospinal fluid. Both patient groups were impaired on tasks assessing verbal and visual recognition memory. EOAD patients showed greater executive and linguistic deficits, while LOAD patients showed greater semantic memory impairment. In EOAD and LOAD, hypometabolism involved the bilateral temporoparietal junction and the posterior cingulate cortex. In EOAD, atrophy was widespread, including frontotemporoparietal areas, whereas it was limited to temporal regions in LOAD. Atrophic volumes were greater in EOAD than in LOAD. Hypometabolic...
We investigated whether dementia risk factors were associated with prodromal Alzheimer's dise... more We investigated whether dementia risk factors were associated with prodromal Alzheimer's disease (AD) according to the International Working Group-2 and National Institute of Aging-Alzheimer's Association criteria, and with cognitive decline. A total of 1394 subjects with mild cognitive impairment from 14 different studies were classified according to these research criteria, based on cognitive performance and biomarkers. We compared the frequency of 10 risk factors between the subgroups, and used Cox-regression to examine the effect of risk factors on cognitive decline. Depression, obesity, and hypercholesterolemia occurred more often in individuals with low-AD-likelihood, compared with those with a high-AD-likelihood. Only alcohol use increased the risk of cognitive decline, regardless of AD pathology. These results suggest that traditional risk factors for AD are not associated with prodromal AD or with progression to dementia, among subjects with mild cognitive impairmen...
Few studies have examined the relationship between CSF and structural biomarkers, and cognitive f... more Few studies have examined the relationship between CSF and structural biomarkers, and cognitive function in MCI. We examined the relationship between cognitive function, hippocampal volume and cerebrospinal fluid (CSF) Aβ42 and tau in 145 patients with MCI. Patients were assessed on cognitive tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB), the Geriatric Depression Scale and the Functional Activities Questionnaire. Hippocampal volume was measured using magnetic resonance imaging (MRI), and CSF markers of Aβ42, tau and p-tau181 were also measured. Worse performance on a wide range of memory and sustained attention tasks were associated with reduced hippocampal volume, higher CSF tau and p-tau181 and increased tau/Aβ42 ratio. Memory tasks were also associated with lower ability to conduct functional activities of daily living, providing a link between AD biomarkers, memory performance and functional outcome. These results suggest that biomarkers of Aβ and t...
Free water elimination (FWE) in brain diffusion MRI has been shown to improve tissue specificity ... more Free water elimination (FWE) in brain diffusion MRI has been shown to improve tissue specificity in human white matter characterization both in health and in disease. Relative to the classical diffusion tensor imaging (DTI) model, FWE is also expected to increase sensitivity to microstructural changes in longitudinal studies. However, it is not clear if these two models differ in their test-retest reproducibility. This study compares a bi-tensor model for FWE with DTI by extending a previous longitudinal-reproducibility 3T multisite study (10 sites, 7 different scanner models) of 50 healthy elderly participants (55-80 years old) scanned in two sessions at least 1 week apart. We computed the reproducibility of commonly used DTI metrics (FA: fractional anisotropy, MD: mean diffusivity, RD: radial diffusivity, and AXD: axial diffusivity), derived either using a DTI model or a FWE model. The DTI metrics were evaluated over 48 white-matter regions of the JHU-ICBM-DTI-81 white-matter labe...
OBJECTIVE : To examine if patients with sporadic early-onset Alzheimer’s disease (EOAD) and those... more OBJECTIVE : To examine if patients with sporadic early-onset Alzheimer’s disease (EOAD) and those with late-onset Alzheimer’s disease (LOAD) exhibit distinct patterns of impairment across memory subdomains. METHOD : One group of EOAD patients (n=20, MMSE = 21, mean age: 60.6), one group of LOAD patients (n=20, MMSE = 22, mean age: 77.9) and two groups of matched younger and older controls (n=40) participated. All patients presented with mild dementia (CDR=1). The diagnosis of AD was supported by evidence of both amyloidopathy and neuronal injury from CSF biomarkers (Innotest). All participants underwent a detailed neuropsychological assessment, a MRI scan and a FDG-PET scan. For each neuropsychological test, individual z-scores were calculated and then averaged into a global patient group z-score (EOAD/LOAD) for each cognitive domain. RESULTS : Both EOAD and LOAD groups were impaired in all the cognitive domains when compared to their respective control groups. Concerning memory domains both groups were similarly affected on measures of verbal episodic memory, short term memory and working memory. The EOAD group was not more affected than the LOAD group in any memory domain. By contrast LOAD patients showed significantly poorer performance than EOAD patients in semantic memory (p < 0.0001). VBM analysis with MRI and SPM with PET-FDG showed that impaired semantic performance in patients was associated with reduced gray matter volume in the anterior temporal lobe region bilaterally and greater hypometabolism in the left temporoparietal region, both areas being key regions of the semantic network. DISCUSSION : Contrary to previous studies, our results do not support the view that EOAD patients show a preservation of memory in the early stage of the disease. EOAD and LOAD patients present with distinct patterns of memory impairment, and LOAD patients show a prominent semantic memory impairment Disclosure: Dr. Ceccaldi has received personal compensation for activities with Novartis, Eli Lilly, Ipsen, Nutricia, Pharnext, and Piramal as a consultant, scientific advisory board member and/or speaker. Dr. Joubert has nothing to disclose. Dr. Gour has nothing to disclose. Dr. Koric has nothing to disclose. Dr. Didic has nothing to disclose. Dr. Gueriot has nothing to disclose. Dr. Ranjeva has nothing to disclose. Dr. Guedj has nothing to disclose. Dr. Felician has nothing to disclose.
Understanding how to reduce the influence of physiological noise in resting state fMRI data is im... more Understanding how to reduce the influence of physiological noise in resting state fMRI data is important for the interpretation of functional brain connectivity. Limited data is currently available to assess the performance of physiological noise correction techniques, in particular when evaluating longitudinal changes in the default mode network (DMN) of healthy elderly participants. In this 3T harmonized multisite fMRI study, we investigated how different retrospective physiological noise correction (rPNC) methods influence the within-site test-retest reliability and the across-site reproducibility consistency of DMN-derived measurements across 13 MRI sites. Elderly participants were scanned twice at least a week apart (five participants per site). The rPNC methods were: none (NPC), Tissue-based regression, PESTICA and FSL-FIX. The DMN at the single subject level was robustly identified using ICA methods in all rPNC conditions. The methods significantly affected the mean z-scores ...
To date, limited data are available regarding the inter-site consistency of test-retest reproduci... more To date, limited data are available regarding the inter-site consistency of test-retest reproducibility of functional connectivity measurements, in particular with regards to integrity of the default mode network (DMN) in elderly participants. We implemented a harmonized resting-state fMRI protocol on 13 clinical scanners at 3.0 Tesla using vendor-provided sequences. Each site scanned a group of 5 healthy elderly participants twice, at least a week apart. We evaluated inter-site differences and test-retest reproducibility of both temporal signal-to-noise ratio (tSNR) and functional connectivity measurements derived from: i) seed-based analysis (SBA) with seed in the posterior cingulate cortex (PCC), ii) group independent component analysis (ICA) separately for each site (site ICA), and iii) consortium ICA, with group ICA across the whole consortium. Despite protocol harmonization, significant and quantitatively important inter-site differences remained in the tSNR of resting-state f...
An increasing number of studies indicate that semantic memory is impaired in mild cognitive impai... more An increasing number of studies indicate that semantic memory is impaired in mild cognitive impairment (MCI). However, the extent and the neural basis of this impairment remain unknown. The aim of the present study was: 1) to evaluate whether all or only a subset of semantic domains are impaired in MCI patients; and 2) to assess the neural substrate of the semantic impairment in MCI patients using voxel-based analysis of MR grey matter density and SPECT perfusion. 29 predominantly amnestic MCI patients and 29 matched control subjects participated in this study. All subjects underwent a full neuropsychological assessment, along with a battery of five tests evaluating different domains of semantic memory. A semantic memory composite Z-score was established on the basis of this battery and was correlated with MRI grey matter density and SPECT perfusion measures. MCI patients were found to have significantly impaired performance across all semantic tasks, in addition to their anterograd...
Journal of Alzheimer's disease : JAD, Jan 20, 2018
It is an open issue whether blood biomarkers serve to diagnose Alzheimer's disease (AD) or mo... more It is an open issue whether blood biomarkers serve to diagnose Alzheimer's disease (AD) or monitor its progression over time from prodromal stages. Here, we addressed this question starting from data of the European FP7 IMI-PharmaCog/E-ADNI longitudinal study in amnesic mild cognitive impairment (aMCI) patients including biological, clinical, neuropsychological (e.g., ADAS-Cog13), neuroimaging, and electroencephalographic measures. PharmaCog/E-ADNI patients were classified as "positive" (i.e., "prodromal AD" n = 76) or "negative" (n = 52) based on a diagnostic cut-off of Aβ42/P-tau in cerebrospinal fluid as well as APOE ε 4 genotype. Blood was sampled at baseline and at two follow-ups (12 and 18 months), when plasma amyloid peptide 42 and 40 (Aβ42, Aβ40) and apolipoprotein J (clusterin, CLU) were assessed. Linear Mixed Models found no significant differences in plasma molecules between the "positive" (i.e., prodromal AD) and "negative...
Early Alzheimer's disease (AD) detection using cerebrospinal fluid (CSF) biomarkers has been ... more Early Alzheimer's disease (AD) detection using cerebrospinal fluid (CSF) biomarkers has been recommended as enrichment strategy for trials involving mild cognitive impairment (MCI) patients. To model a prodromal AD trial for identifying MRI structural biomarkers to improve subject selection and to be used as surrogate outcomes of disease progression. APOE ɛ4 specific CSF Aβ42/P-tau cut-offs were used to identify MCI with prodromal AD (Aβ42/P-tau positive) in the WP5-PharmaCog (E-ADNI) cohort. Linear mixed models were performed 1) with baseline structural biomarker, time, and biomarker×time interaction as factors to predict longitudinal changes in ADAS-cog13, 2) with Aβ42/P-tau status, time, and Aβ42/P-tau status×time interaction as factors to explain the longitudinal changes in MRI measures, and 3) to compute sample size estimation for a trial implemented with the selected biomarkers. Only baseline lateral ventricle volume was able to identify a subgroup of prodromal AD patients...
Neuroimaging biomarkers differ between patients with early-onset Alzheimer's disease (EOAD) a... more Neuroimaging biomarkers differ between patients with early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD). Whether these changes reflect cognitive heterogeneity or differences in disease severity is still unknown. This study aimed at investigating changes in neuroimaging biomarkers, according to the age of onset of the disease, in mild amnestic Alzheimer's disease patients with positive amyloid biomarkers in cerebrospinal fluid. Both patient groups were impaired on tasks assessing verbal and visual recognition memory. EOAD patients showed greater executive and linguistic deficits, while LOAD patients showed greater semantic memory impairment. In EOAD and LOAD, hypometabolism involved the bilateral temporoparietal junction and the posterior cingulate cortex. In EOAD, atrophy was widespread, including frontotemporoparietal areas, whereas it was limited to temporal regions in LOAD. Atrophic volumes were greater in EOAD than in LOAD. Hypometabolic...
We investigated whether dementia risk factors were associated with prodromal Alzheimer's dise... more We investigated whether dementia risk factors were associated with prodromal Alzheimer's disease (AD) according to the International Working Group-2 and National Institute of Aging-Alzheimer's Association criteria, and with cognitive decline. A total of 1394 subjects with mild cognitive impairment from 14 different studies were classified according to these research criteria, based on cognitive performance and biomarkers. We compared the frequency of 10 risk factors between the subgroups, and used Cox-regression to examine the effect of risk factors on cognitive decline. Depression, obesity, and hypercholesterolemia occurred more often in individuals with low-AD-likelihood, compared with those with a high-AD-likelihood. Only alcohol use increased the risk of cognitive decline, regardless of AD pathology. These results suggest that traditional risk factors for AD are not associated with prodromal AD or with progression to dementia, among subjects with mild cognitive impairmen...
Few studies have examined the relationship between CSF and structural biomarkers, and cognitive f... more Few studies have examined the relationship between CSF and structural biomarkers, and cognitive function in MCI. We examined the relationship between cognitive function, hippocampal volume and cerebrospinal fluid (CSF) Aβ42 and tau in 145 patients with MCI. Patients were assessed on cognitive tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB), the Geriatric Depression Scale and the Functional Activities Questionnaire. Hippocampal volume was measured using magnetic resonance imaging (MRI), and CSF markers of Aβ42, tau and p-tau181 were also measured. Worse performance on a wide range of memory and sustained attention tasks were associated with reduced hippocampal volume, higher CSF tau and p-tau181 and increased tau/Aβ42 ratio. Memory tasks were also associated with lower ability to conduct functional activities of daily living, providing a link between AD biomarkers, memory performance and functional outcome. These results suggest that biomarkers of Aβ and t...
Free water elimination (FWE) in brain diffusion MRI has been shown to improve tissue specificity ... more Free water elimination (FWE) in brain diffusion MRI has been shown to improve tissue specificity in human white matter characterization both in health and in disease. Relative to the classical diffusion tensor imaging (DTI) model, FWE is also expected to increase sensitivity to microstructural changes in longitudinal studies. However, it is not clear if these two models differ in their test-retest reproducibility. This study compares a bi-tensor model for FWE with DTI by extending a previous longitudinal-reproducibility 3T multisite study (10 sites, 7 different scanner models) of 50 healthy elderly participants (55-80 years old) scanned in two sessions at least 1 week apart. We computed the reproducibility of commonly used DTI metrics (FA: fractional anisotropy, MD: mean diffusivity, RD: radial diffusivity, and AXD: axial diffusivity), derived either using a DTI model or a FWE model. The DTI metrics were evaluated over 48 white-matter regions of the JHU-ICBM-DTI-81 white-matter labe...
OBJECTIVE : To examine if patients with sporadic early-onset Alzheimer’s disease (EOAD) and those... more OBJECTIVE : To examine if patients with sporadic early-onset Alzheimer’s disease (EOAD) and those with late-onset Alzheimer’s disease (LOAD) exhibit distinct patterns of impairment across memory subdomains. METHOD : One group of EOAD patients (n=20, MMSE = 21, mean age: 60.6), one group of LOAD patients (n=20, MMSE = 22, mean age: 77.9) and two groups of matched younger and older controls (n=40) participated. All patients presented with mild dementia (CDR=1). The diagnosis of AD was supported by evidence of both amyloidopathy and neuronal injury from CSF biomarkers (Innotest). All participants underwent a detailed neuropsychological assessment, a MRI scan and a FDG-PET scan. For each neuropsychological test, individual z-scores were calculated and then averaged into a global patient group z-score (EOAD/LOAD) for each cognitive domain. RESULTS : Both EOAD and LOAD groups were impaired in all the cognitive domains when compared to their respective control groups. Concerning memory domains both groups were similarly affected on measures of verbal episodic memory, short term memory and working memory. The EOAD group was not more affected than the LOAD group in any memory domain. By contrast LOAD patients showed significantly poorer performance than EOAD patients in semantic memory (p < 0.0001). VBM analysis with MRI and SPM with PET-FDG showed that impaired semantic performance in patients was associated with reduced gray matter volume in the anterior temporal lobe region bilaterally and greater hypometabolism in the left temporoparietal region, both areas being key regions of the semantic network. DISCUSSION : Contrary to previous studies, our results do not support the view that EOAD patients show a preservation of memory in the early stage of the disease. EOAD and LOAD patients present with distinct patterns of memory impairment, and LOAD patients show a prominent semantic memory impairment Disclosure: Dr. Ceccaldi has received personal compensation for activities with Novartis, Eli Lilly, Ipsen, Nutricia, Pharnext, and Piramal as a consultant, scientific advisory board member and/or speaker. Dr. Joubert has nothing to disclose. Dr. Gour has nothing to disclose. Dr. Koric has nothing to disclose. Dr. Didic has nothing to disclose. Dr. Gueriot has nothing to disclose. Dr. Ranjeva has nothing to disclose. Dr. Guedj has nothing to disclose. Dr. Felician has nothing to disclose.
Understanding how to reduce the influence of physiological noise in resting state fMRI data is im... more Understanding how to reduce the influence of physiological noise in resting state fMRI data is important for the interpretation of functional brain connectivity. Limited data is currently available to assess the performance of physiological noise correction techniques, in particular when evaluating longitudinal changes in the default mode network (DMN) of healthy elderly participants. In this 3T harmonized multisite fMRI study, we investigated how different retrospective physiological noise correction (rPNC) methods influence the within-site test-retest reliability and the across-site reproducibility consistency of DMN-derived measurements across 13 MRI sites. Elderly participants were scanned twice at least a week apart (five participants per site). The rPNC methods were: none (NPC), Tissue-based regression, PESTICA and FSL-FIX. The DMN at the single subject level was robustly identified using ICA methods in all rPNC conditions. The methods significantly affected the mean z-scores ...
To date, limited data are available regarding the inter-site consistency of test-retest reproduci... more To date, limited data are available regarding the inter-site consistency of test-retest reproducibility of functional connectivity measurements, in particular with regards to integrity of the default mode network (DMN) in elderly participants. We implemented a harmonized resting-state fMRI protocol on 13 clinical scanners at 3.0 Tesla using vendor-provided sequences. Each site scanned a group of 5 healthy elderly participants twice, at least a week apart. We evaluated inter-site differences and test-retest reproducibility of both temporal signal-to-noise ratio (tSNR) and functional connectivity measurements derived from: i) seed-based analysis (SBA) with seed in the posterior cingulate cortex (PCC), ii) group independent component analysis (ICA) separately for each site (site ICA), and iii) consortium ICA, with group ICA across the whole consortium. Despite protocol harmonization, significant and quantitatively important inter-site differences remained in the tSNR of resting-state f...
An increasing number of studies indicate that semantic memory is impaired in mild cognitive impai... more An increasing number of studies indicate that semantic memory is impaired in mild cognitive impairment (MCI). However, the extent and the neural basis of this impairment remain unknown. The aim of the present study was: 1) to evaluate whether all or only a subset of semantic domains are impaired in MCI patients; and 2) to assess the neural substrate of the semantic impairment in MCI patients using voxel-based analysis of MR grey matter density and SPECT perfusion. 29 predominantly amnestic MCI patients and 29 matched control subjects participated in this study. All subjects underwent a full neuropsychological assessment, along with a battery of five tests evaluating different domains of semantic memory. A semantic memory composite Z-score was established on the basis of this battery and was correlated with MRI grey matter density and SPECT perfusion measures. MCI patients were found to have significantly impaired performance across all semantic tasks, in addition to their anterograd...
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