Network Hyperexcitability in Early Alzheimer's Disease: Is Functional Connectivity a Potential Biomarker?

Network hyperexcitability (NH) is an important feature of the pathophysiology of Alzheimer's disease. Functional connectivity (FC) of brain networks has been proposed as a potential biomarker for NH. Here we use a whole brain computational model and resting-state MEG recordings to investigate the relation between hyperexcitability and FC. Oscillatory brain activity was simulated with a Stuart Landau model on a network of 78 interconnected brain regions. FC was quantified with amplitude envelope correlation (AEC) and phase coherence (PC). MEG was recorded in 18 subjects with subjective cognitive decline (SCD) and 18 subjects with mild cognitive impairment (MCI). Functional connectivity was determined with the corrected AECc and phase lag index (PLI), in the 4-8 Hz and the 8-13 Hz bands. The excitation/inhibition balance in the model had a strong effect on both AEC and PC. This effect was different for AEC and PC, and was influenced by structural coupling strength and frequency band. Empirical FC matrices of SCD and MCI showed a good correlation with model FC for AEC, but less so for PC. For AEC the fit was best in the hyperexcitable range. We conclude that FC is sensitive to changes in E/I balance. The AEC was more sensitive than the PLI, and results were better for the thetaband than the alpha band. This conclusion was supported by fitting the model to empirical data. Our study justifies the use of functional connectivity measures as surrogate markers for E/I balance.

In pursuit of a sensitive EEG functional connectivity outcome measure for clinical trials in Alzheimer's disease.

OBJECTIVE: In clinical trials in Alzheimer's Disease (AD), an improvement of impaired functional connectivity (FC) could provide biological support for the potential efficacy of the drug. Electroencephalography (EEG) analysis of the SAPHIR-trial showed a treatment induced improvement of global relative theta power but not of FC measured by the phase lag index (PLI). We compared the PLI with the amplitude envelope correlation with leakage correction (AEC-c), a presumably more sensitive FC measure. METHODS: Patients with early AD underwent 12 weeks of placebo or treatment with PQ912, a glutaminylcyclase inhibitor. Eyes-closed task free EEG was measured at baseline and follow-up (PQ912 n = 47, placebo n = 56). AEC-c and PLI were measured in multiple frequency bands. Change in FC was compared between treatment groups by using two models of covariates. RESULTS: A significant increase in global AEC-c in the alpha frequency band was found with PQ912 treatment compared to placebo (p = 0.004, Cohen's d = 0.58). The effect remained significant when corrected for sex, country, ApoE ε4 carriage, age, baseline value (model 1; p = 0.006) and change in relative alpha power (model 2; p = 0.004). CONCLUSIONS: Functional connectivity in early AD, measured with AEC-c in the alpha frequency band, improved after PQ912 treatment. SIGNIFICANCE: AEC-c may be a robust and sensitive FC measure for detecting treatment effects.

Medial temporal lobe atrophy relates more strongly to sleep-wake rhythm fragmentation than to age or any other known risk.

Atrophy of the medial temporal lobe of the brain is key to memory function and memory complaints in old age. While age and some morbidities are major risk factors for medial temporal lobe atrophy, individual differences remain, and mechanisms are insufficiently known. The largest combined neuroimaging and whole genome study to date indicates that medial temporal lobe volume is most associated with common polymorphisms in the GRIN2B gene that encodes for the 2B subunit (NR2B) of the NMDA receptor. Because sleep disruption induces a selective loss of NR2B from hippocampal synaptic membranes in rodents, and because of several other reports on medial temporal lobe sensitivity to sleep disruption, we hypothesized a contribution of the typical age-related increase in sleep-wake rhythm fragmentation to medial temporal lobe atrophy. Magnetic resonance imaging and actigraphy in 138 aged individuals showed that individual differences in sleep-wake rhythm fragmentation accounted for more (19%) of the variance in medial temporal lobe atrophy than age did (15%), or any of a list of health and brain structural indicators. The findings suggest a role of sleep-wake rhythm fragmentation in age-related medial temporal lobe atrophy, that might in part be prevented or reversible.

Neural network topology in ADHD; evidence for maturational delay and default-mode network alterations.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) has been associated with widespread brain abnormalities in white and grey matter, affecting not only local, but global functional networks as well. In this study, we explored these functional networks using source-reconstructed electroencephalography in ADHD and typically developing (TD) children. We expected evidence for maturational delay, with underlying abnormalities in the default mode network. METHODS: Electroencephalograms were recorded in ADHD (n=42) and TD (n=43) during rest, and functional connectivity (phase lag index) and graph (minimum spanning tree) parameters were derived. Dependent variables were global and local network metrics in theta, alpha and beta bands. RESULTS: We found evidence for a more centralized functional network in ADHD compared to TD children, with decreased diameter in the alpha band (ηp2=0.06) and increased leaf fraction (ηp2=0.11 and 0.08) in the alpha and beta bands, with underlying abnormalities in hub regions of the brain, including default mode network. CONCLUSIONS: The finding of a more centralized network is in line with maturational delay models of ADHD and should be replicated in longitudinal designs. SIGNIFICANCE: This study contributes to the literature by combining high temporal and spatial resolution to construct EEG network topology, and associates maturational-delay and default-mode interference hypotheses of ADHD.

Functional and effective whole brain connectivity using magnetoencephalography to identify monozygotic twin pairs.

Resting-state functional connectivity patterns are highly stable over time within subjects. This suggests that such 'functional fingerprints' may have strong genetic component. We investigated whether the functional (FC) or effective (EC) connectivity patterns of one monozygotic twin could be used to identify the co-twin among a larger sample and determined the overlap in functional fingerprints within monozygotic (MZ) twin pairs using resting state magnetoencephalography (MEG). We included 32 cognitively normal MZ twin pairs from the Netherlands Twin Register who participate in the EMIF-AD preclinAD study (average age 68 years). Combining EC information across multiple frequency bands we obtained an identification rate over 75%. Since MZ twin pairs are genetically identical these results suggest a high genetic contribution to MEG-based EC patterns, leading to large similarities in brain connectivity patterns between two individuals even after 60 years of life or more.

Directional information flow in patients with Alzheimer's disease. A source-space resting-state MEG study.

In a recent magnetoencephalography (MEG) study, we found posterior-to-anterior information flow over the cortex in higher frequency bands in healthy subjects, with a reversed pattern in the theta band. A disruption of information flow may underlie clinical symptoms in Alzheimer's disease (AD). In AD, highly connected regions (hubs) in posterior areas are mostly disrupted. We therefore hypothesized that in AD the information flow from these hub regions would be disturbed. We used resting-state MEG recordings from 27 early-onset AD patients and 26 healthy controls. Using beamformer-based virtual electrodes, we estimated neuronal oscillatory activity for 78 cortical regions of interest (ROIs) and 12 subcortical ROIs of the AAL atlas, and calculated the directed phase transfer entropy (dPTE) as a measure of information flow between these ROIs. Group differences were evaluated using permutation tests and, for the AD group, associations between dPTE and general cognition or CSF biomarkers were determined using Spearman correlation coefficients. We confirmed the previously reported posterior-to-anterior information flow in the higher frequency bands in the healthy controls, and found it to be disturbed in the beta band in AD. Most prominently, the information flow from the precuneus and the visual cortex, towards frontal and subcortical structures, was decreased in AD. These disruptions did not correlate with cognitive impairment or CSF biomarkers. We conclude that AD pathology may affect the flow of information between brain regions, particularly from posterior hub regions, and that changes in the information flow in the beta band indicate an aspect of the pathophysiological process in AD.

2016 Comprehensive Update of the Banff Working Group on Liver Allograft Pathology: Introduction of Antibody-Mediated Rejection.

The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.

Interplay of co-inherited diseases can turn benign syndromes in a deadly combination: haemoglobinopathy and bilirubin transport disorder.

We present a case about a 25-year-old male patient suffering from a rare genetic disorder called Mizuho haemoglobin. He was admitted to the Intensive Care Unit with acute liver and renal failure. During admission he also developed a cardiac tamponade twice. Finally he received a liver transplantation. Hereafter the patient stabilised and his liver and renal functions improved. His symptoms could not be explained solely by his known disease. After searching the literature, similarities between his symptoms and a rare complication of sickle cell disease were found. Molecular diagnostics showed that the patient also suffered from Gilbert's syndrome. Due to his chronic haemolysis, symptoms of this other disease were masked. This stresses the importance of always looking for other causes if symptoms or changes cannot be explained by a known rare disorder.

Hypercholesterolaemia and hepatosplenomegaly: two manifestations of cholesteryl ester storage disease.

Cholesteryl ester storage disease (CESD) is a rare autosomal recessive disease caused by mutations in LIPA. Here we describe two different clinical presentations of this disease: one case with a clear phenotype of familial hypercholesterolaemia and one case with hepatosplenomegaly from childhood onwards. These two cases exemplify the diversity of clinical phenotypes of patients with CESD. Knowledge on the phenotypic variability of the disease is of clinical relevance in light of enzyme replacement therapy (sebelipase alpha) for patients with mutations in LIPA, which is currently under development.

Ex vivo normothermic machine perfusion and viability testing of discarded human donor livers.

In contrast to traditional static cold preservation of donor livers, normothermic machine perfusion may reduce preservation injury, improve graft viability and potentially allows ex vivo assessment of graft viability before transplantation. We have studied the feasibility of normothermic machine perfusion in four discarded human donor livers. Normothermic machine perfusion consisted of pressure and temperature controlled pulsatile perfusion of the hepatic artery and continuous portal perfusion for 6 h. Two hollow fiber membrane oxygenators provided oxygenation of the perfusion fluid. Biochemical markers in the perfusion fluid reflected minimal hepatic injury and improving function. Lactate levels decreased to normal values, reflecting active metabolism by the liver (mean lactate 10.0 ± 2.3 mmol/L at 30 min to 2.3 ± 1.2 mmol/L at 6 h). Bile production was observed throughout the 6 h perfusion period (mean rate 8.16 ± 0.65 g/h after the first hour). Histological examination before and after 6 h of perfusion showed well-preserved liver morphology without signs of additional hepatocellular ischemia, biliary injury or sinusoidal damage. In conclusion, this study shows that normothermic machine perfusion of human donor livers is technically feasible. It allows assessment of graft viability before transplantation, which opens new avenues for organ selection, therapeutic interventions and preconditioning.

Brain atrophy accelerates cognitive decline in cerebral small vessel disease: the LADIS study.

OBJECTIVE: To examine the independent contributions and combined interactions of medial temporal lobe atrophy (MTA), cortical and subcortical atrophy, and white matter lesion (WML) volume in longitudinal cognitive performance. METHODS: A total of 477 subjects with age-related WML were evaluated with brain MRI and annual neuropsychological examinations in 3-year follow-up. Baseline MRI determinants of cognitive decline were analyzed with linear mixed models controlling for multiple confounders. RESULTS: MTA and subcortical atrophy predicted significantly steeper rate of decline in global cognitive measures as well as compound scores for psychomotor speed, executive functions, and memory after adjusting for age, gender, education, lacunes/infarcts, and WML volume. Cortical atrophy independently predicted decline in psychomotor speed. WML volume remained significantly associated with cognitive decline even after controlling for the atrophy scores. Moreover, significant synergistic interactions were found between WML and atrophy measures in overall cognitive performance across time and the rate of cognitive decline. Synergistic effects were also observed between baseline lacunar infarcts and all atrophy measures on change in psychomotor speed. The main results remained robust after exclusion of subjects with clinical stroke or incident dementia, and after additional adjustments for progression of WML and lacunes. CONCLUSIONS: Brain atrophy and WML are independently related to longitudinal cognitive decline in small vessel disease. MTA, subcortical, and cortical atrophy seem to potentiate the effect of WML and lacunes on cognitive decline.

The spatial distribution of age-related white matter changes as a function of vascular risk factors--results from the LADIS study.

White matter hyperintensities (WMH) are a frequent finding on brain MRI of elderly subjects, and have been associated with various risk factors, as well as with development of cognitive and functional impairment. While an overall association between WMH load and risk factors is well described, possible spatially restricted vulnerability remains to be established. The aim of this study was to investigate the spatial distribution of WMH in normally functioning elderly subjects. We introduce a voxel-based approach in which lesion probability is mapped as a function of clinical risk factors using logistic regression, and validate the method using simulated datasets. The method was then applied in a total of 605 participants of the LADIS study (age 74 ± 5 years, all with WMH), and the location of manually delineated WMH was investigated after spatial normalisation. Particularly strong and widespread associations were found for age, gender and hypertension. Different distribution patterns were found for men and women. Further, increased probability was found in association with self-reported alcohol and tobacco consumption, as well as in those with a history of migraine. It is concluded that the location of WMH is dependent on the risk factors involved pointing towards a regionally different pathogenesis and/or vulnerability of the white matter.

Incident lacunes influence cognitive decline: the LADIS study.

BACKGROUND: In cerebral small vessel disease, the core MRI findings include white matter lesions (WML) and lacunar infarcts. While the clinical significance of WML is better understood, the contribution of lacunes to the rate of cognitive decline has not been established. This study investigated whether incident lacunes on MRI determine longitudinal cognitive change in elderly subjects with WML. METHODS: Within the Leukoaraiosis and Disability Study (LADIS), 387 subjects were evaluated with repeated MRI and neuropsychological assessment at baseline and after 3 years. Predictors of change in global cognitive function and specific cognitive domains over time were analyzed with multivariate linear regression. RESULTS: After controlling for demographic factors, baseline cognitive performance, baseline lacunar and WML lesion load, and WML progression, the number of new lacunes was related to subtle decrease in compound scores for executive functions (p = 0.021) and speed and motor control (p = 0.045), but not for memory or global cognitive function. Irrespective of lacunes, WML progression was associated with decrease in executive functions score (p = 0.016). CONCLUSION: Incident lacunes on MRI parallel a steeper rate of decline in executive functions and psychomotor speed. Accordingly, in addition to WML, lacunes determine longitudinal cognitive impairment in small vessel disease. Although the individual contribution of lacunes on cognition was modest, they cannot be considered benign findings, but indicate a risk of progressive cognitive impairment.

Location of lacunar infarcts correlates with cognition in a sample of non-disabled subjects with age-related white-matter changes: the LADIS study.

OBJECTIVES: In cerebral small vessel disease, white-matter hyperintensities (WMH) and lacunes are both related to cognition. Still, their respective contribution in older people remains unclear. The purpose of this study is to assess the topographic distribution of lacunes and determine whether it has an impact on cognitive functions in a sample of non-disabled patients with age-related white-matter changes. METHODS: Data were drawn from the baseline evaluation of the LADIS (Leucoaraioisis and Disability study) cohort of non-disabled subjects beyond 65 years of age. The neuropsychological evaluation was based on the Mini Mental Status Examination (MMSE), a modified Alzheimer Diseases Assessment Scale for global cognitive functions, and compound Z scores for memory, executive functions, speed and motor control. WMH were rated according to the Fazekas scale; the number of lacunes was assessed in the following areas: lobar white matter, putamen/pallidum, thalamus, caudate nucleus, internal/external capsule, infratentorial areas. An analysis of covariance was performed after adjustment for possible confounders. RESULTS: Among 633 subjects, 47% had at least one lacune (31% at least one within basal ganglia). The presence of lacunes in the thalamus was associated with lower scores of MMSE (beta = -0.61; p = 0.043), and worse compound scores for speed and motor control (beta = -0.25; p = 0.006), executive functions (beta = -0.19; p = 0.022) independently of the cognitive impact of WMH. There was also a significant negative association between the presence of lacunes in putamen/pallidum and the memory compound Z score (beta = -0.13; p = 0.038). By contrast, no significant negative association was found between cognitive parameters and the presence of lacunes in internal capsule, lobar white matter and caudate nucleus. CONCLUSION: In non-disabled elderly subjects with leucoaraisosis, the location of lacunes within subcortical grey matter is a determinant of cognitive impairment, independently of the extent of WMH.

Hypoxia inducible factor-1-alpha (HIF-1alpha) is related to both angiogenesis and inflammation in rheumatoid arthritis.

OBJECTIVES: Despite the important role of the transcription factor HIF-1alpha in angiogenesis and inflammation, only a few studies on HIF-1alpha expression have been performed in RA patients. The aim of the present study was to identify the layer in synovial tissue of RA patients where HIF1a is expressed and to find out whether HIF-1alpha expression is related to both angiogenesis and inflammation in synovium from RA patients. METHODS: A reproducible staining method for HIF-1alpha was developed. HIF-1alpha -positive cells were quantified in synovial tissue from patients with RA. As control we used synovial tissue from patients with osteoarthritis (OA). The number of HIF-1alpha-positive cells was compared with the number of blood vessels present and was correlated with the amount of inflammation. The amount of inflammation was determined by counting inflammatory cells, by estimating the proliferation marker Ki67 in inflamed tissue, and by using a recently published synovitis score which gives an accurate estimate of the amount of inflammation present. RESULTS: HIF-1alpha was expressed weakly in the lining layer and strongly in the sublining layer in RA synovial tissue. In contrast, HIF-1alpha was only weakly expressed in OA synovial tissue. The number of HIF-1alpha -positive cells correlated strongly with the number of blood vessels in RA synovial tissue and with inflammatory endothelial cell infiltration (blood vessels), cell proliferation (Ki67) and the synovitis score. CONCLUSIONS: HIF-1alpha expression is strongest in the sub-lining layer of RA synovium and is related to both angiogenesis and inflammation in synovium from RA patients. These results thus suggest that HIF-1alpha could serve as an important new therapeutic target in RA, targeting both angiogenesis and inflammation.

Heterogeneity of white matter hyperintensities in Alzheimer's disease: post-mortem quantitative MRI and neuropathology.

White matter hyperintensities (WMH) are frequently seen on T(2)-weighted MRI scans of elderly subjects with and without Alzheimer's disease. WMH are only weakly and inconsistently associated with cognitive decline, which may be explained by heterogeneity of the underlying neuropathological substrates. The use of quantitative MRI could increase specificity for these neuropathological changes. We assessed whether post-mortem quantitative MRI is able to reflect differences in neuropathological correlates of WMH in tissue samples obtained post-mortem from Alzheimer's disease patients and from non-demented elderly. Thirty-three formalin-fixed, coronal brain slices from 11 Alzheimer's disease patients (mean age: 83 +/- 10 years, eight females) and 15 slices from seven non-demented controls (mean age: 78 +/- 10 years, four females) with WMH were scanned at 1.5 T using qualitative (fluid-attenuated inversion recovery, FLAIR) and quantitative MRI [diffusion tensor imaging (DTI) including estimation of apparent diffusion coefficient (ADC) and fractional anisotropy (FA), and T(1)-relaxation time mapping based on flip-angle array). A total of 104 regions of interest were defined on FLAIR images in WMH and normal appearing white matter (NAWM). Neuropathological examination included (semi-)quantitative assessment of axonal density (Bodian), myelin density (LFB), astrogliosis (GFAP) and microglial activation (HLA-DR). Patient groups (Alzheimer's disease versus controls) and tissue types (WMH versus NAWM) were compared with respect to QMRI and neuropathological measures. Overall, Alzheimer's disease patients had significantly lower FA (P < 0.01) and higher T(1)-values than controls (P = 0.04). WMH showed lower FA (P < 0.01) and higher T(1)-values (P < 0.001) than NAWM in both patient groups. A significant interaction between patient group and tissue type was found for the T(1) measurements, indicating that the difference in T(1)-relaxation time between NAWM and WMH was larger in Alzheimer's disease patients than in non-demented controls. All neuropathological measures showed differences between WMH and NAWM, although the difference in microglial activation was specific for Alzheimer's disease. Multivariate regression models revealed that in Alzheimer's disease, axonal density was an independent determinant of FA, whereas T(1) was independently determined by axonal and myelin density and microglial activation. Quantitative MRI techniques reveal differences in WMH between Alzheimer's disease and non-demented elderly, and are able to reflect the severity of the neuropathological changes involved.

Cerebral blood flow by using pulsed arterial spin-labeling in elderly subjects with white matter hyperintensities.

BACKGROUND AND PURPOSE: On MR imaging, white matter hyperintensities (WMH) on T2-weighted images are generally considered as a surrogate marker of ischemic small vessel disease in elderly subjects. Pulsed arterial spin-labeling (PASL) is a noninvasive MR perfusion-weighted technique. We hypothesized that elderly subjects with diffuse confluent WMH should have lower cerebral blood flow (CBF) measurements than subjects with punctiform or beginning confluent WMH. MATERIALS AND METHODS: MR images of 21 subjects (13 women; mean age, 76 years; SD, 5), stratified for the degree of WMH, from a single center within the multinational Leukoaraiosis and Disability (LADIS) study, were investigated. CBF images were obtained by means of quantitative imaging of perfusion by using a single-subtraction second version, with thin-section TI periodic saturation PASL. Values of cortical gray matter, subcortical (including white matter and deep gray matter), and global CBF were calculated. CBF measurements of subjects with diffuse confluent WMH (n = 7) were compared with those of subjects with punctiform or beginning confluent WMH (n = 14). RESULTS: Subjects with diffuse confluent WMH were found to have approximately 20% lower mean global CBF (43.5 mL/100 mL/min; SD, 6.3) than subjects with punctiform or beginning confluent WMH (57.9 mL/100 mL/min; SD, 8.6; P < .01), as well as approximately 20% lower mean subcortical (P < .01) and cortical gray matter CBF (P < .05). CONCLUSION: PASL revealed a significant reduction of CBF measurements in elderly subjects with diffuse confluent WMH.

Reliability and sensitivity of visual scales versus volumetry for evaluating white matter hyperintensity progression.

BACKGROUND: Investigating associations between the change of white matter hyperintensities (WMH) and clinical symptoms over time is crucial for establishing a causal relationship. However, the most suitable method for measuring WMH progression has not been established yet. We compared the reliability and sensitivity of cross-sectional and longitudinal visual scales with volumetry for measuring WMH progression. METHODS: Twenty MRI scan pairs (interval 2 years) were included from the Amsterdam center of the LADIS study. Semi-automated volumetry of WMH was performed twice by one rater. Three cross-sectional scales (Fazekas Scale, Age-Related White Matter Changes Scale, Scheltens Scale) and two progression scales (Rotterdam Progression Scale, Schmidt Progression Scale) were scored by 4 and repeated by 2 raters. RESULTS: Mean WMH volume (24.6 +/- 27.9 ml at baseline) increased by 4.6 +/- 5.1 ml [median volume change (range) = 2.7 (-0.6 to 15.7) ml]. Measuring volumetric change in WMH was reliable (intraobserver:intraclass coefficient = 0.88). All visual scales showed significant change of WMH over time, although the sensitivity was highest for both of the progression scales. Proportional volumetric change of WMH correlated best with the Rotterdam Progression Scale (Spearman's r = 0.80, p < 0.001) and the Schmidt Progression Scale (Spearman's r = 0.64, p < 0.01). Although all scales were reliable for assessment of WMH cross-sectionally, WMH progression assessment using visual scales was less reliable, except for the Rotterdam Progression scale which had moderate to good reliability [weighted Cohen's kappa = 0.63 (intraobserver), 0.59 (interobserver)]. CONCLUSION: To determine change in WMH, dedicated progression scales are more sensitive and/or reliable and correlate better with volumetric volume change than cross-sectional scales.

Distortions in rest-activity rhythm in aging relate to white matter hyperintensities.

Distortions in the rest-activity rhythm in aging are commonly observed. Neurodegenerative changes of the suprachiasmatic nucleus have been proposed to underlie this disrupted rhythm. However, based on previous studies, it can be proposed that white matter hyperintensities (WMH) may also play a role in the altered rest-activity rhythm in aging. The present study focused on the rest-activity rhythm, as assessed with actigraphy, and WMH in nondemented aging. With regard to the rest-activity rhythm, the interdaily stability (IS), intradaily variability (IV) and the amplitude (AMP) of the rhythm were of interest. The white matter hyperintensities were examined separately for the periventricular (PVH) and deep white matter (DWMH) regions, while distinguishing between the various locations within these regions (e.g. occipital PVH). The results indicated that frontal DWMH related to both IS and AMP. A reduction in the most active 10-h period mediated the relationship between frontal DWMH and AMP. Possible underlying mechanisms of these associations are discussed.