Abstract
While previous studies suggest the implication of herpes simplex virus (HSV) in the onset of Alzheimer’s disease (AD), no study has investigated its association with early neuroimaging ...markers of AD. In the Three-City and the AMI cohorts, the associations between HSV infection and (i) hippocampal volume (
n
= 349), (ii) white matter alterations in the parahippocampal cingulum and fornix using diffusion tensor imaging (
n
= 260), and (iii) incidence of AD (
n
= 1599) were assessed according to APOE4 status. Regardless of APOE4 status, infected subjects presented (i) significantly more microstructural alterations of the parahippocampal cingulum and fornix, (ii) lower hippocampal volumes only when their anti-HSV IgG level was in the highest tercile—reflecting possibly more frequent reactivations of the virus (
p
= 0.03 for subjects with a high anti-HSV IgG level while there was no association for all infected subjects,
p
= 0.19), and (iii) had no increased risk of developing AD. Nevertheless, among APOE4 carriers, infected subjects presented lower hippocampal volumes, although not significant (
p
= 0.09), and a two or three times higher risk of developing AD (adjusted Hazard ratio (aHR) = 2.72 1.07–6.91
p
= 0.04 for infected subjects and aHR = 3.87 1.45–10.28
p
= 0.007 for infected subjects with an anti-HSV IgG level in the highest tercile) while no association was found among APOE4 noncarriers. Our findings support an association between HSV infection and AD and a potential interaction between HSV status and APOE4. This reinforces the need to further investigate the infectious hypothesis of AD, especially the associated susceptibility factors and the possibility of preventive treatments.
Early-onset torsion dystonia (TOR1A/DYT1) is a devastating hereditary motor disorder whose pathophysiology remains unclear. Studies in transgenic mice suggested abnormal cholinergic transmission in ...the putamen, but this has not yet been demonstrated in humans. The role of the cerebellum in the pathophysiology of the disease has also been highlighted but the involvement of the intrinsic cerebellar cholinergic system is unknown. In this study, cholinergic neurons were imaged using PET with 18F-fluoroethoxybenzovesamicol, a radioligand of the vesicular acetylcholine transporter (VAChT). Here, we found an age-related decrease in VAChT expression in the posterior putamen and caudate nucleus of DYT1 patients versus matched controls, with low expression in young but not in older patients. In the cerebellar vermis, VAChT expression was also significantly decreased in patients versus controls, but independently of age. Functional connectivity within the motor network studied in MRI and the interregional correlation of VAChT expression studied in PET were also altered in patients. These results show that the cholinergic system is disrupted in the brain of DYT1 patients and is modulated over time through plasticity or compensatory mechanisms.
BACKGROUND AND PURPOSE—The aim of the present study was to evaluate the relationship between normal-appearing white matter (NAWM) integrity and postischemic stroke recovery in 4 main domains ...including cognition, mood, gait, and dependency.
METHODS—A prospective study was conducted, including patients diagnosed for an ischemic supratentorial stroke on a 3T brain MRI performed 24 to 72 hours after symptom onset. Clinical assessment 1 year after stroke included a Montreal Cognitive Assessment, an Isaacs set test, a Zazzo cancelation task, a Hospital Anxiety and Depression scale, a 10-meter walking test, and a modified Rankin Scale (mRS). Diffusion tensor imaging parameters in the NAWM were computed using FMRIB (Functional Magnetic Resonance Imaging of the Brain) Diffusion Toolbox. The relationships between mean NAWM diffusion tensor imaging parameters and the clinical scores were assessed using linear and ordinal regression analyses, including the volumes of white matter hyperintensities, gray matter, and ischemic stroke as radiological covariates.
RESULTS—Two hundred seven subjects were included (66±13 years old; 67% men; median National Institutes of Health Stroke Scale score, 3; interquartile range, 2–6). In the models including only radiological variables, NAWM fractional anisotropy was associated with the mRS and the cognitive scores. After adjusting for demographic confounders, NAWM fractional anisotropy remained a significant predictor of mRS (β=−0.24; P=0.04). Additional path analysis showed that NAWM fractional anisotropy had a direct effect on mRS (β=−0.241; P=0.001) and a less important indirect effect mediating white matter hyperintensity burden. Similar results were found with mean diffusivity, axial diffusivity, and radial diffusivity. In further subgroup analyses, a relationship between NAWM integrity in widespread white matter tracts, mRS, and Isaacs set test was found in right hemispheric strokes.
CONCLUSIONS—NAWM diffusion tensor imaging parameters measured early after an ischemic stroke are independent predictors of functional outcome and may be additional markers to include in studies evaluating poststroke recovery.
In this article, we present an innovative MRI‐based method for Alzheimer disease (AD) detection and mild cognitive impairment (MCI) prognostic, using lifespan trajectories of brain structures. After ...a full screening of the most discriminant structures between AD and normal aging based on MRI volumetric analysis of 3,032 subjects, we propose a novel Hippocampal‐Amygdalo‐Ventricular Atrophy score (HAVAs) based on normative lifespan models and AD lifespan models. During a validation on three external datasets on 1,039 subjects, our approach showed very accurate detection (AUC ≥ 94%) of patients with AD compared to control subjects and accurate discrimination (AUC = 78%) between progressive MCI and stable MCI (during a 3‐year follow‐up). Compared to normative modeling, classical machine learning methods and recent state‐of‐the‐art deep learning methods, our method demonstrated better classification performance. Moreover, HAVAs simplicity makes it fully understandable and thus well‐suited for clinical practice or future pharmaceutical trials.
In this article, we present an innovative MRI‐based method for Alzheimer disease (AD) detection and mild cognitive impairment (MCI) prognostic, using lifespan trajectories of brain structures. Compared to normative modeling and recent state‐of‐the‐art deep learning methods, our method demonstrated better classification performance. Moreover, it simplicity makes it fully understandable and thus well‐suited for clinical practice or future pharmaceutical trials.
Learning involves distributed but coordinated activity among the widespread connected brain areas. Increase in areas connections' strength may be established offline, that is, aside from the task ...itself, in a resting‐state. The resulting functional connectivity may hence constitute a neural trace of the learning episode. The present study examined whether a conditional visuomotor learning task previously shown to activate the cerebellum would modify cerebellar intrinsic connectivity in groups of young and older male subjects. In the group of young subjects, resting‐state connectivity within several cerebellar networks (fronto‐cerebellar, temporo‐cerebellar, cerebello‐cerebellar) was modified following the task. In most cases, modulation resulted in increased anticorrelations between cerebellar and cortical areas and the amplitude of changes was correlated with learning efficacy. The group of older subjects drastically differed, with sparser modifications of resting‐state functional connectivity and no cerebellar networks involved. The findings of this exploratory study indicate that associative learning modifies the strength of intrinsic connectivity in young subjects but to a lesser degree in older subjects. They further suggest that functional connectivity within cerebellar networks may play an operative role in this kind of learning.
The figure illustrates the Resting State Connectivity changes in young male subjects. Following a conditional visuo‐motor learning task, increased anticorrelations between cerebellar and cortical areas were found. All together, our results suggest that the connectivity changes play an operative role in learning.
Abstract
The chronological progression of brain atrophy over decades, from pre-symptomatic to dementia stages, has never been formally depicted in Alzheimer’s disease. This is mainly due to the lack ...of cohorts with long enough MRI follow-ups in cognitively unimpaired young participants at baseline. To describe a spatiotemporal atrophy staging of Alzheimer’s disease at the whole-brain level, we built extrapolated lifetime volumetric models of healthy and Alzheimer’s disease brain structures by combining multiple large-scale databases (n = 3512 quality controlled MRI from 9 cohorts of subjects covering the entire lifespan, including 415 MRI from ADNI1, ADNI2 and AIBL for Alzheimer’s disease patients). Then, we validated dynamic models based on cross-sectional data using external longitudinal data. Finally, we assessed the sequential divergence between normal aging and Alzheimer’s disease volumetric trajectories and described the following staging of brain atrophy progression in Alzheimer’s disease: (i) hippocampus and amygdala; (ii) middle temporal gyrus; (iii) entorhinal cortex, parahippocampal cortex and other temporal areas; (iv) striatum and thalamus and (v) middle frontal, cingular, parietal, insular cortices and pallidum. We concluded that this MRI scheme of atrophy progression in Alzheimer’s disease was close but did not entirely overlap with Braak staging of tauopathy, with a ‘reverse chronology’ between limbic and entorhinal stages. Alzheimer’s disease structural progression may be associated with local tau accumulation but may also be related to axonal degeneration in remote sites and other limbic-predominant associated proteinopathies.
Using extrapolated lifetime volumetric models of healthy and Alzheimer’s disease brain structures, Planche et al. propose a staging of atrophy progression in Alzheimer’s disease including (i) hippocampus and amygdala; (ii) middle temporal gyrus; (iii) entorhinal cortex and other temporal areas; (iv) striatum and thalamus and (v) middle frontal, cingular, parietal, insular cortices and pallidum.
Graphical Abstract
Graphical Abstract
BACKGROUND AND PURPOSE—Cortical cerebral microinfarcts (CMIs) have been associated with vascular dementia and Alzheimer disease. The aim of the present study was to evaluate the role of cortical CMI ...detected on 3T magnetic resonance imaging, on the evolution of cognition during the year following an acute ischemic stroke.
METHODS—We conducted a prospective and monocentric study, including patients diagnosed for a supratentorial ischemic stroke with a National Institutes of Health Stroke Scale score ≥1, without prestroke dementia or neurological disability. Cortical CMIs were assessed on a brain 3T magnetic resonance imaging realized at baseline, as well as markers of small vessel disease, stroke characteristics, and hippocampal atrophy. Cognitive assessment was performed at 3 time points (baseline, 3 months, and 1 year) using the Montreal Cognitive Assessment, the Isaacs set test, and the Zazzo’s cancellation task. Generalized linear mixed models were performed to evaluate the relationships between the number of cortical CMI and changes in cognitive scores over 1 year.
RESULTS—Among 199 patients (65±13 years old, 68% men), 88 (44%) had at least one cortical CMI. Hypertension was the main predictor of a higher cortical CMI load (B=0.58, P=0.005). The number of cortical CMI was associated with an increase time at the Zazzo’s cancellation task over 1 year (B=3.84, P=0.01), regardless of the other magnetic resonance imaging markers, stroke severity, and demographic factors.
CONCLUSIONS—Cortical CMIs are additional magnetic resonance imaging markers of poorer processing speed after ischemic stroke. These results indicate that a high load of cortical CMI in patients with stroke can be considered as a cerebral frailty condition which counteracts to the recovery process, suggesting a reduced brain plasticity among these patients.
Although aging is associated with alterations of both activity/rest cycle and brain structure, few studies have evaluated associations between these processes. The aim of this study was to examine ...relationship between activity/rest cycle quality and brain structural integrity in aging subjects by exploring both grey and white matter compartments.
Fifty-eight elderly subjects (76±0.5 years; 41% female) without dementia, sleep disorders and medications were included in the analysis. Actigraphy was used to measure parameters of activity/rest cycle (24-h amplitude, 24-h fragmentation and 24-h stability) and sleep (total sleep time and sleep fragmentation) over a minimal period of 5 days. Whole brain linear regression analyses were performed on grey matter volumes maps using voxel based morphometry and on white matter integrity using tract based statistics analyses.
A lower 24-h amplitude and a higher sleep fragmentation were independently associated with a reduction of white matter integrity in models including age and gender as covariates. The association between 24-h amplitude and white matter integrity decreased but remained significant in a model accounted for sleep fragmentation, indicating a specific effect of 24-h cycle disturbances. No association with grey matter volumes was observed.
In elderly, not only sleep but also 24-h cycle disturbances were associated with altered structural connectivity. This alteration of structural backbone networks related to activity/rest cycle disturbances in aging might constitute a cerebral frailty factor for the development of cognitive impairment.
•Sleep fragmentation is related to WM integrity of the aging brain.•A disturbed 24-h cycle is associated with alterations of WM integrity.•Activity/rest cycle is not associated with age-related GM atrophy.•Activity/rest cycle alterations may contribute to age-related WM cerebral frailty.
Abstract
INTRODUCTION
Alzheimer's disease is associated with sleep disturbances and accumulation of cerebral amyloid beta. The objective was to examine whether actigraphy‐detected sleep parameters ...might be biomarkers for early amyloid burden.
METHODS
Participants underwent a week of actigraphy and an amyloid positron emission tomography (PET) scan. Sleep duration and continuity disruption (sleep fragmentation and nocturnal awakenings) were extracted and compared between amyloid‐positive and amyloid‐negative participants. Then multiple linear regressions were used between mean or night‐to‐night intra‐individual variability (standard deviation) of sleep parameters and brain amyloid burden in a voxel‐wise analysis.
RESULTS
Eighty‐six subjects were included (80.3 ± 5.4 years; 48.8% of women). Amyloid‐positive participants had a higher variability of sleep fragmentation compared to amyloid‐negative participants. This parameter was associated with a higher amyloid burden in the frontal and parietal regions, and in the precuneus, in the whole sample.
DISCUSSION
This study highlights the relevance of using variability in sleep continuity as a potential biomarker of early amyloid pathogenesis.
BACKGROUND AND PURPOSE—Several markers of poststroke cognitive impairment have been reported. The role of brain cortical volume remains uncertain. The aim of this study was to evaluate the influence ...of brain cortical volume on cognitive outcomes using a voxel-based morphometry approach in subjects without prestroke dementia.
METHODS—Ischemic stroke patients were prospectively recruited 24 to 72 hours post stroke (M0). Cognition was evaluated at M0, 3 months, and 1 year (M12) using the Montreal Cognitive Assessment, the Isaacs set test, and the Zazzo’s cancellation task. A 3-T brain magnetic resonance imaging was performed at M0. Grey matter (GM) was segmented using Statistical Parametric Mapping 12 software. Association between global GM volume and cognitive score slopes between M0 and M12 was evaluated using a linear mixed model. Correlations between focal GM volumes and changes in cognitive performance were evaluated using Statistical Parametric Mapping 12.
RESULTS—Two-hundred forty-eight patients were included (mean age 65±SD 14 years old, 66% men). Global GM volume was significantly associated with changes in Montreal Cognitive Assessment scores (β=0.01; P=0.04) and in the number of errors on the Zazzo’s cancellation task (β=−0.02; P=0.04) independently of other clinical/radiological confounders. Subjects with lower GM volumes in the left fronto-temporo-insular cortex were more vulnerable to transient Montreal Cognitive Assessment and Isaacs set test impairment. Subjects with lower GM volumes in right temporo-insular cortex, together with basal ganglia, were more vulnerable to transient cognitive impairment on the Zazzo’s cancellation task.
CONCLUSIONS—Smaller cortical volumes in fronto-temporo-insular areas measured 24 to 72 hours post stroke are associated with cognitive vulnerability in the subacute stroke phase.
PDF
