Large-scale longitudinal multi-site MRI brain morphometry studies are becoming increasingly crucial to characterize both normal and clinical population groups using fully automated segmentation ...tools. The test–retest reproducibility of morphometry data acquired across multiple scanning sessions, and for different MR vendors, is an important reliability indicator since it defines the sensitivity of a protocol to detect longitudinal effects in a consortium. There is very limited knowledge about how across-session reliability of morphometry estimates might be affected by different 3T MRI systems. Moreover, there is a need for optimal acquisition and analysis protocols in order to reduce sample sizes. A recent study has shown that the longitudinal FreeSurfer segmentation offers improved within session test–retest reproducibility relative to the cross-sectional segmentation at one 3T site using a nonstandard multi-echo MPRAGE sequence. In this study we implement a multi-site 3T MRI morphometry protocol based on vendor provided T1 structural sequences from different vendors (3D MPRAGE on Siemens and Philips, 3D IR-SPGR on GE) implemented in 8 sites located in 4 European countries. The protocols used mild acceleration factors (1.5–2) when possible. We acquired across-session test–retest structural data of a group of healthy elderly subjects (5 subjects per site) and compared the across-session reproducibility of two full-brain automated segmentation methods based on either longitudinal or cross-sectional FreeSurfer processing. The segmentations include cortical thickness, intracranial, ventricle and subcortical volumes. Reproducibility is evaluated as absolute changes relative to the mean (%), Dice coefficient for volume overlap and intraclass correlation coefficients across two sessions. We found that this acquisition and analysis protocol gives comparable reproducibility results to previous studies that used longer acquisitions without acceleration. We also show that the longitudinal processing is systematically more reliable across sites regardless of MRI system differences. The reproducibility errors of the longitudinal segmentations are on average approximately half of those obtained with the cross sectional analysis for all volume segmentations and for entorhinal cortical thickness. No significant differences in reliability are found between the segmentation methods for the other cortical thickness estimates. The average of two MPRAGE volumes acquired within each test–retest session did not systematically improve the across-session reproducibility of morphometry estimates. Our results extend those from previous studies that showed improved reliability of the longitudinal analysis at single sites and/or with non-standard acquisition methods. The multi-site acquisition and analysis protocol presented here is promising for clinical applications since it allows for smaller sample sizes per MRI site or shorter trials in studies evaluating the role of potential biomarkers to predict disease progression or treatment effects.
•We implemented a multi-site 3T MRI protocol for brain morphometry on 8EU sites.•We acquired across-session test-retest data on 40 healthy elderly subjects.•We calculated the reproducibility of cortical and volumetric FreeSurfer estimates.•Longitudinal segmentation was more reliable than cross-sectional on all sites.
Purpose
Sleep apnoea (SA) is associated with accelerated cognitive decline in patients with mild cognitive impairment (MCI). Treatment of SA by continuous positive airway pressure (CPAP) may slow ...this decline if patients comply with the treatment. The aim of this study was to assess the rate of CPAP compliance in this population.
Methods
In this single-centre retrospective study conducted in a tertiary care institution, patients with a diagnosis of MCI and SA initiating CPAP between January 2015 and August 2021 were included. Data from the initial sleep recording, the 3-month follow-up and compliance with at least 12 months of CPAP were analysed. Compliance was defined as an average CPAP use of at least 4 h per night.
Results
55 patients were included (49% women, age 70.7 ± 8.9 years, body mass index 28.9 ± 6.5 kg/m
2
). Aetiology of MCI was vascular (45.5%), psychiatric (12.7%) and related to Alzheimer’s disease (7.3%), with 47.3% of amnesic disorders and 45.5% of dysexecutive disorders. The MiniMentalState score was 26.7 ± 3.1. SA was mostly obstructive (81.8%) with a mean apnoea-hypopnoea index of 41.1 ± 16.4/h. At 3 months, 38 patients were compliant (69%) with a CPAP median use of 5.9 h per night and 83% of nights. Self-reported tolerance was better in compliant patients (75.7% vs 38.5%
p
= 0.017). Thirty-four patients remained compliant at 12 months (62%).
Conclusion
Our results suggest a high rate of CPAP compliance in patients suffering from MCI. Compliance was related to the device tolerance, emphasizing the need to closely monitor and improve this factor.
Objectives
We aimed to define brain iron distribution patterns in subtypes of early-onset Alzheimer’s disease (EOAD) by the use of quantitative susceptibility mapping (QSM).
Methods
EOAD patients ...prospectively underwent MRI on a 3-T scanner and concomitant clinical and neuropsychological evaluation, between 2016 and 2019. An age-matched control group was constituted of cognitively healthy participants at risk of developing AD. Volumetry of the hippocampus and cerebral cortex was performed on 3DT1 images. EOAD subtypes were defined according to the hippocampal to cortical volume ratio (HV:CTV). Limbic-predominant atrophy (LP
MRI
) is referred to HV:CTV ratios below the 25
th
percentile, hippocampal-sparing (HpSp
MRI
) above the 75
th
percentile, and typical-AD between the 25
th
and 75
th
percentile. Brain iron was estimated using QSM. QSM analyses were made voxel-wise and in 7 regions of interest within deep gray nuclei and limbic structures. Iron distribution in EOAD subtypes and controls was compared using an ANOVA.
Results
Sixty-eight EOAD patients and 43 controls were evaluated. QSM values were significantly higher in deep gray nuclei (
p
< 0.001) and limbic structures (
p
= 0.04) of EOAD patients compared to controls. Among EOAD subtypes, HpSp
MRI
had the highest QSM values in deep gray nuclei (
p
< 0.001) whereas the highest QSM values in limbic structures were observed in LP
MRI
(
p
= 0.005). QSM in deep gray nuclei had an AUC = 0.92 in discriminating HpSp
MRI
and controls.
Conclusions
In early-onset Alzheimer’s disease patients, we observed significant variations of iron distribution reflecting the pattern of brain atrophy. Iron overload in deep gray nuclei could help to identify patients with atypical presentation of Alzheimer’s disease.
Key Points
• In early-onset AD patients, QSM indicated a significant brain iron overload in comparison with age-matched controls.
• Iron load in limbic structures was higher in participants with limbic-predominant subtype.
• Iron load in deep nuclei was more important in participants with hippocampal-sparing subtype.
Predicted age difference (PAD) is a score computed by subtracting chronological age from "brain" age, which is estimated using neuroimaging data. The goal of this study was to evaluate the PAD as a ...marker of phenotypic heterogeneity and severity among early-onset Alzheimer's disease (EOAD) patients.
We first used 3D T1-weighted (3D-T1) magnetic resonance images (MRI) of 3,227 healthy subjects aged between 18 and 85 years to train, optimize, and evaluate the brain age model. A total of 123 participants who met the criteria for early-onset (<65 years) sporadic form of probable Alzheimer's disease (AD) and presented with two distinctive clinical presentations an amnestic form (
= 74) and a non-amnestic form (
= 49) were included at baseline and followed-up for a maximum period of 4 years. All the participants underwent a work-up at baseline and every year during the follow-up period, which included clinical examination, neuropsychological testing and genotyping, and structural MRI. In addition, cerebrospinal fluid biomarker assay was recorded at baseline. PAD score was calculated by applying brain age model to 3D-T1 images of the EOAD patients and healthy controls, who were matched based on age and sex. At baseline, between-group differences for neuropsychological and PAD scores were assessed using linear models. Regarding longitudinal analysis of neuropsychological and PAD scores, differences between amnestic and non-amnestic participants were analyzed using linear mixed-effects modeling.
PAD score was significantly higher for non-amnestic patients (2.35 ± 0.91) when compared to amnestic patients (2.09 ± 0.74) and controls (0.00 ± 1). Moreover, PAD score was linearly correlated with the Mini-Mental State Examination (MMSE) and the Clinical Dementia Rating Sum of Boxes (CDR-SB), for both amnestic and non-amnestic sporadic forms. Longitudinal analyses showed that the gradual development of the disease in patients was accompanied by a significant increase in PAD score over time, for both amnestic and non-amnestic patients.
PAD score was able to separate amnestic and non-amnestic sporadic forms. Regardless of the clinical presentation, as PAD score was a way of quantifying an early brain age acceleration, it was an appropriate method to detect the development of AD and follow the evolution of the disease as a marker of severity as MMSE and CDR-SB.
Modulation of histone deacetylase (HDAC) activity has been implicated as a potential therapeutic strategy for multiple diseases. However, it has been difficult to dissect the role of individual HDACs ...due to a lack of selective small-molecule inhibitors. Here, we report the synthesis of a series of highly potent and isoform-selective class I HDAC inhibitors, rationally designed by exploiting minimal structural changes to the clinically experienced HDAC inhibitor CI-994. We used this toolkit of isochemogenic or chemically matched inhibitors to probe the role of class I HDACs in β-cell pathobiology and demonstrate for the first time that selective inhibition of an individual HDAC isoform retains beneficial biological activity and mitigates mechanism-based toxicities. The highly selective HDAC3 inhibitor BRD3308 suppressed pancreatic β-cell apoptosis induced by inflammatory cytokines, as expected, or now glucolipotoxic stress, and increased functional insulin release. In addition, BRD3308 had no effect on human megakaryocyte differentiation, while inhibitors of HDAC1 and 2 were toxic. Our findings demonstrate that the selective inhibition of HDAC3 represents a potential path forward as a therapy to protect pancreatic β-cells from inflammatory cytokines and nutrient overload in diabetes.
Due to heterogeneous clinical presentation, difficult differential diagnosis with Alzheimer's disease (AD) and psychiatric disorders, and evolving clinical criteria, the epidemiology and natural ...history of frontotemporal lobar degeneration (FTD) remain elusive. In order to better characterize FTD patients, we relied on the database of a regional memory clinic network with standardized diagnostic procedures and chose AD patients as a comparator.
Patients that were first referred to our network between January 2010 and December 2016 and whose last clinical diagnosis was degenerative or vascular dementia were included. Comparisons were conducted between FTD and AD as well as between the different FTD syndromes, divided into language variants (lvFTD), behavioral variant (bvFTD), and FTD with primarily motor symptoms (mFTD). Cognitive progression was estimated with the yearly decline in Mini Mental State Examination (MMSE).
Among the patients that were referred to our network in the 6-year time span, 690 were ultimately diagnosed with FTD and 18,831 with AD. Patients with FTD syndromes represented 2.6% of all-cause dementias. The age-standardized incidence was 2.90 per 100,000 person-year and incidence peaked between 75 and 79 years. Compared to AD, patients with FTD syndromes had a longer referral delay and delay to diagnosis. Patients with FTD syndromes had a higher MMSE score than AD at first referral while their progression was similar. mFTD patients had the shortest survival while survival in bvFTD, lvFTD, and AD did not significantly differ. FTD patients, especially those with the behavioral variant, received more antidepressants, anxiolytics, and antipsychotics than AD patients.
FTD syndromes differ with AD in characteristics at baseline, progression rate, and treatment. Despite a broad use of the new diagnostic criteria in an organized memory clinic network, FTD syndromes are longer to diagnose and account for a low proportion of dementia cases, suggesting persistent underdiagnosis. Congruent with recent publications, the late peak of incidence warns against considering FTD as being exclusively a young-onset dementia.
Bipolar disorder is associated with an increased risk of dementia with aging. Little is known regarding this association, limiting appropriate diagnosis and management. We aimed to describe the ...characteristics of bipolar patients with late cognitive impairment for whom the hypothesis of an underlying neurodegenerative disease had been raised. We performed a retrospective multicenter study, recruiting bipolar patients over 50 years old from five French tertiary memory centers who had undergone cerebrospinal fluid (CSF) biomarker assessment for Alzheimer’s disease (AD). Clinical, neuropsychological, and paraclinical characteristics were analyzed and 78 patients were included. The mean age at the onset of cognitive impairment was 62.4 years (±9.2). The mean MMSE score was 22.8 (±4.5), the mean FAB was 11.7 (±3.9), and the mean FCRST was 15.8 (±7.4)/36.8 (±9.7) (free/total recall). A total of 48.6% of the patients displayed cognitive fluctuations, and 38.2% showed cognitive improvement during follow-ups; and 56.3% of the patients showed Parkinsonism, of which 12.7% had never received antipsychotics. Among patients who underwent DAT-scans, 35.3% displayed dopaminergic denervation; 10.3% of patients had CSF AD biological signature (“A+ T+” profile), while 56.4% had other abnormal CSF profiles. Thus, clinical presentation was dominated by executive dysfunction, episodic memory impairment, fluctuating cognition, and a high frequency of Parkinsonism. Specifically, high frequency of delusional episodes suggests limited tolerance of psychotropic drugs. Most patients had abnormal CSF biomarker profiles, but only a minority displayed AD’s specific biomarker signature. Therefore, while our results unveil shared common neurocognitive features in bipolar patients with cognitive impairment of suspected neurodegenerative origin they suggest a participation of various underlying pathologies rather than a common degenerative mechanism in the pathophysiology of this condition.
Depuis les nouveaux critères diagnostiques des différents syndromes de dégénérescence lobaire fronto temporales (DLFT) peu d’études en population ont été réalisées.
L’objectif de cette étude est ...d’identifier les caractéristiques des DLFT ainsi que leur profil d’évolution au sein du réseau des consultations mémoire du Nord Pas-de-Calais (Méotis) entre 2010 et 2016.
La population DLFT a été divisée en 3 groupes : les DLFT comportementales (DFTc), les langagières (DFTla) et les motrices (DFTm), et a été comparée aux patients avec une maladie d’Alzheimer (MA) ainsi qu’aux autre pathologies neurodégénératives. 690 DLFT ont été suivies au sein du réseau Méotis, 446 DFTc, 118 DFTla et 126 DFTm, ainsi que 18831 MA. 600 DLFT et 900 MA avaient au moins 2 scores de MMSE avec un premier ≥10.
Les patients DLFT représentent 3 % de la population de l’étude, composé majoritairement de DLFTc (64 %). En comparaison aux patients MA, les DLFT sont plus jeunes en début de pathologie avec un MMSE plus élevé et une errance diagnostique plus importante, particulièrement pour les DFTc. L’évolution du MMSE en fonction du temps ne montre pas de différence significative entre les DFTc et les MA.
À notre connaissance aucune autre étude n’a comparé les caractéristiques des 3 groupes de DLFT depuis 2011 avec un tel effectif. Néanmoins notre recrutement n’avait pas vocation à être exhaustif, nous n’avons pas inclus les patients suivis dans d’autres filières ou non diagnostiqués.
Les DLFT sont sous diagnostiquées notamment la DFTc qui pose le plus grand enjeu diagnostique. De façon inattendue, la progression cognitive des DLFT semble comparable à celle de la MA.
Large-scale longitudinal multi-site MRI brain morphometry studies are becoming increasingly crucial to characterize both normal and clinical population groups using fully automated segmentation ...tools. The testaretest reproducibility of morphometry data acquired across multiple scanning sessions, and for different MR vendors, is an important reliability indicator since it defines the sensitivity of a protocol to detect longitudinal effects in a consortium. There is very limited knowledge about how across-session reliability of morphometry estimates might be affected by different 3 T MRI systems. Moreover, there is a need for optimal acquisition and analysis protocols in order to reduce sample sizes. A recent study has shown that the longitudinal FreeSurfer segmentation offers improved within session testaretest reproducibility relative to the cross-sectional segmentation at one 3 T site using a nonstandard multi-echo MPRAGE sequence. In this study we implement a multi-site 3 T MRI morphometry protocol based on vendor provided T1 structural sequences from different vendors (3D MPRAGE on Siemens and Philips, 3D IR-SPGR on GE) implemented in 8 sites located in 4 European countries. The protocols used mild acceleration factors (1.5a2) when possible. We acquired across-session testaretest structural data of a group of healthy elderly subjects (5 subjects per site) and compared the across-session reproducibility of two full-brain automated segmentation methods based on either longitudinal or cross-sectional FreeSurfer processing. The segmentations include cortical thickness, intracranial, ventricle and subcortical volumes. Reproducibility is evaluated as absolute changes relative to the mean (%), Dice coefficient for volume overlap and intraclass correlation coefficients across two sessions. We found that this acquisition and analysis protocol gives comparable reproducibility results to previous studies that used longer acquisitions without acceleration. We also show that the longitudinal processing is systematically more reliable across sites regardless of MRI system differences. The reproducibility errors of the longitudinal segmentations are on average approximately half of those obtained with the cross sectional analysis for all volume segmentations and for entorhinal cortical thickness. No significant differences in reliability are found between the segmentation methods for the other cortical thickness estimates. The average of two MPRAGE volumes acquired within each testaretest session did not systematically improve the across-session reproducibility of morphometry estimates. Our results extend those from previous studies that showed improved reliability of the longitudinal analysis at single sites and/or with non-standard acquisition methods. The multi-site acquisition and analysis protocol presented here is promising for clinical applications since it allows for smaller sample sizes per MRI site or shorter trials in studies evaluating the role of potential biomarkers to predict disease progression or treatment effects.
PDF
