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Background: The cerebral default mode network (DMN) can be mapped onto specific regions in the cerebellum, which are specifically vulnerable to atrophy in Alzheimer's disease (AD) patients.Objective: We set out to determine whether there are specific differences in the interaction between the cerebral and cerebellar DMN in amnestic mild cognitive impairment (aMCI) patients compared to healthy controls using resting-state functional MRI and whether these differences are relevant for memory performance.Methods: Eighteen patients with aMCI were age and education-matched to eighteen older adults and underwent 3T MR-imaging. We performed seed-based functional connectivity analysis between the cerebellar DMN seeds and the cerebral DMN.Results: Our results showed that compared to healthy older adults, aMCI patients showed lower anti-correlation between the cerebellar DMN and several cerebral DMN regions. Additionally, we showed that degradation of the anti-correlation between the cerebellar DMN and the medial frontal cortex is correlated with worse memory performance in aMCI patients.Conclusion: These findings provide evidence that the cerebellar DMN and cerebral DMN are negatively correlated during rest in older individuals, and suggest that the reduced anti-correlated impacts the modulatory role of the cerebellum on cognitive functioning, in particular on the executive component of memory functions in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Cerebral small vessel disease (cSVD) and amyloid-β (Aβ) deposition often co-exist in (prodromal) dementia, and both types of pathology have been associated with neurodegeneration. We examined whether cSVD and Aβ have independent or interactive effects on hippocampal volume (HV) in a memory clinic population. We included 87 individuals with clinical diagnoses of Alzheimer's disease (AD) (n = 24), mild cognitive impairment (MCI) (n = 26), and subjective cognitive complaints (SCC) (n = 37). cSVD magnetic resonance imaging markers included white matter hyperintensity (WMH) volume, lacunar infarct presence, and microbleed presence. Aβ pathology was assessed as cerebrospinal fluid-derived Aβ1 - 42 levels and dichotomized into normal or abnormal, and HV was determined by manual volumetric measurements. A linear hierarchical regression approach was applied for the detection of additive or interaction effects between cSVD and Aβ on HV in the total participant group (n = 87) and in the non-demented group (including SCC and MCI individuals only, n = 63). The results revealed that abnormal Aβ and lacunar infarct presence were independently associated with lower HV in the non-demented individuals. Interestingly, Aβ and WMH pathology interacted in the non-demented individuals, such that WMH had a negative effect on HV in individuals with abnormal CSF Aβ42 levels, but not in individuals with normal CSF Aβ42 levels. These associations were not present when individuals with AD were included in the analyses. Our observations suggest that relatively early on in the disease process older individuals with abnormal Aβ levels are at an increased risk of accelerated disease progression when concomitant cSVD is present. [ABSTRACT FROM AUTHOR]

Background: Research suggests that altered interregional connectivity in specific networks, such as the default mode network (DMN), is associated with cognitive and psychotic symptoms in schizophrenia. In addition, frontal and limbic connectivity alterations have been associated with trauma, drug use and urban upbringing, though these environmental exposures have never been examined in relation to DMN functional connectivity in psychotic disorder. Methods: Resting-state functional MRI scans were obtained from 73 patients with psychotic disorder, 83 non-psychotic siblings of patients with psychotic disorder and 72 healthy controls. Posterior cingulate cortex (PCC) seed-based correlation analysis was used to estimate functional connectivity within the DMN. DMN functional connectivity was examined in relation to group (familial risk), group × environmental exposure (to cannabis, developmental trauma and urbanicity) and symptomatology. Results: There was a significant association between group and PCC connectivity with the inferior parietal lobule (IPL), the precuneus (PCu) and the medial prefrontal cortex (MPFC). Compared to controls, patients and siblings had increased PCC connectivity with the IPL, PCu and MPFC. In the IPL and PCu, the functional connectivity of siblings was intermediate to that of controls and patients. No significant associations were found between DMN connectivity and (subclinical) psychotic/cognitive symptoms. In addition, there were no significant interactions between group and environmental exposures in the model of PCC functional connectivity. Discussion: Increased functional connectivity in individuals with (increased risk for) psychotic disorder may reflect trait-related network alterations. The within-network “connectivity at rest” intermediate phenotype was not associated with (subclinical) psychotic or cognitive symptoms. The association between familial risk and DMN connectivity was not conditional on environmental exposure. [ABSTRACT FROM AUTHOR]

Aortic stiffness predicts an excess risk of stroke, supposedly via cerebral small-vessel disease. White matter hyperintensities, silent lacunar infarcts, and brain microbleeds, manifestations of cerebral small-vessel disease on neuroimaging, may precede overt cerebrovascular disease. Therefore, we assessed whether aortic stiffness is also related to such lesions. In 167 hypertensive patients (85 men) without a history of cardiovascular or cerebrovascular disease, a mean age of 51.8+/-13.1 years, and untreated office blood pressure levels of 169+/-25/104+/-12 mm Hg, we determined aortic pulse wave velocity and office and ambulatory 24-hour pulse pressure (off medication), as well as the volume of white matter hyperintensities and the presence of lacunar infarcts and microbleeds using brain MRI. Linear and logistic regression analyses were performed to assess the relationships between the arterial stiffness measures and brain lesions. Aortic stiffness and pulse pressure were significantly related to each of the brain lesions in univariate analyses (P<0.05). Multivariate analyses, adjusted for age, sex, brain volume, mean arterial pressure, and heart rate, showed that a higher pulse wave velocity was significantly associated with a greater volume of white matter hyperintensities (unstandardized regression coefficient: 0.041; 95% CI: 0.005 to 0.078; P<0.05) and the presence of lacunar infarcts (odds ratio [per SD increase in pulse wave velocity]: 1.78; 95% CI: 1.06 to 2.99; P<0.05) but not with microbleeds. The models for pulse pressure failed to reach statistical significance in multivariate analyses. In conclusion, aortic stiffness is independently associated with manifestations of cerebral small-vessel disease in hypertensive patients, linking systemic large- to cerebral small-artery disease. [ABSTRACT FROM AUTHOR]

The vascular and neurodegenerative processes related to clinical dementia cause cell loss which induces, amongst others, an increase in interstitial fluid (ISF). We assessed microvascular, parenchymal integrity, and a proxy of ISF volume alterations with intravoxel incoherent motion imaging in 21 healthy controls and 53 memory clinic patients - mainly affected by neurodegeneration (mild cognitive impairment, Alzheimer's disease dementia), vascular pathology (vascular cognitive impairment), and presumed to be without significant pathology (subjective cognitive decline). The microstructural components were quantified with spectral analysis using a non-negative least squares method. Linear regression was employed to investigate associations of these components with hippocampal and white matter hyperintensity (WMH) volumes. In the normal appearing white matter, a large f int (a proxy of ISF volume) was associated with a large WMH volume and low hippocampal volume. Likewise, a large f int value was associated with a lower hippocampal volume in the hippocampi. Large ISF volume (f int ) was shown to be a prominent factor associated with both WMHs and neurodegenerative abnormalities in memory clinic patients and is argued to play a potential role in impaired glymphatic functioning., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Blood-brain barrier (BBB) leakage is considered an important underlying process in both cerebral small vessel disease (cSVD) and Alzheimer's disease (AD). The objective of this study was to examine associations between BBB leakage, cSVD, neurodegeneration, and cognitive performance across the spectrum from normal cognition to dementia. Leakage was measured with dynamic contrast-enhanced magnetic resonance imaging in 80 older participants (normal cognition, n = 32; mild cognitive impairment, n = 34; clinical AD-type dementia, n = 14). Associations between leakage and white matter hyperintensity (WMH) volume, hippocampal volume, and cognition (information processing speed and memory performance) were examined with multivariable linear regression and mediation analyses. Leakage within the gray and white matter was positively associated with WMH volume (gray matter, p = 0.03; white matter, p = 0.01). A negative association was found between white matter BBB leakage and information processing speed performance, which was mediated by WMH volume. Leakage was not associated with hippocampal volume. WMH pathology is suggested to form a link between leakage and decline of information processing speed in older individuals with and without cognitive impairment., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The underlying pathology of white matter signal abnormalities (WMSAs) is heterogeneous and may vary dependent on the magnetic resonance imaging contrast used to define them. We investigated differences in white matter diffusivity as an indicator for white matter integrity underlying WMSA based on T1-weighted and fluid-attenuated inversion recovery (FLAIR) imaging contrast. In addition, we investigated which white matter region of interest (ROI) could predict clinical diagnosis best using diffusion metrics. One hundred three older individuals with varying cognitive impairment levels were included and underwent neuroimaging. Diffusion metrics were extracted from WMSA areas based on T1 and FLAIR contrast and from their overlapping areas, the border surrounding the WMSA and the normal-appearing white matter (NAWM). Regional diffusivity differences were calculated with linear mixed effects models. Multinomial logistic regression determined which ROI diffusion values classified individuals best into clinically defined diagnostic groups. T1-based WMSA showed lower white matter integrity compared to FLAIR WMSA-defined regions. Diffusion values of NAWM predicted diagnostic group best compared to other ROI's. To conclude, T1- or FLAIR-defined WMSA provides distinct information on the underlying white matter integrity associated with cognitive decline. Importantly, not the "diseased" but the NAWM is a potentially sensitive indicator for cognitive brain health status., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Albuminuria may be a biomarker of generalized (i.e., microvascular and macrovascular) endothelial dysfunction. According to this concept, endothelial dysfunction of the renal microcirculation causes albuminuria by increasing glomerular capillary wall permeability and intraglomerular pressure, the latter eventually leading to glomerular capillary dropout (rarefaction) and further increases in intraglomerular pressure. However, direct evidence for an association between capillary rarefaction and albuminuria is lacking. Therefore, we examined the cross-sectional association between the recruitment of capillaries after arterial occlusion (capillary density during postocclusive peak reactive hyperemia) and during venous occlusion (venous congestion), as assessed with skin capillaroscopy, and albuminuria in 741 participants of the Maastricht Study, including 211 participants with type 2 diabetes. Overall, 57 participants had albuminuria, which was defined as a urinary albumin excretion ≥30 mg/24 h. After adjustment for potential confounders, participants in the lowest tertile of skin capillary recruitment during postocclusive peak reactive hyperemia had an odds ratio for albuminuria of 2.27 (95% confidence interval, 1.07 to 4.80) compared with those in the highest tertile. Similarly, a comparison between the lowest and the highest tertiles of capillary recruitment during venous congestion yielded an odds ratio of 2.89 (95% confidence interval, 1.27 to 6.61) for participants in the lowest tertile. In conclusion, lower capillary density of the skin microcirculation independently associated with albuminuria, providing direct support for a role of capillary rarefaction in the pathogenesis of albuminuria., (Copyright © 2016 by the American Society of Nephrology.)

Introduction: Dorsal pathway dysfunctions are thought to underlie visuospatial processing problems in Alzheimer disease (AD). Prior studies reported compensatory mechanisms in the dorsal or ventral pathway in response to these functional changes. Since functional and structural connectivity are interrelated, these functional changes could be interpreted as a disconnection between both pathways. To better understand functional alterations in the dorsal pathway, we combined functional imaging with diffusion tensor imaging (DTI) in patients with mild cognitive impairment (MCI), a likely prodromal stage of AD., Methods: Eighteen older male individuals with amnestic MCI (aMCI) and 18 male cognitively healthy individuals, matched for age (range 59-75 years) and education, performed an object recognition task in the Magnetic Resonance Imaging (MRI) scanner. Neural activation was measured during recognition of non-canonically versus canonically oriented objects. Regions showing activation differences between groups were also investigated by DTI., Results: Recognition of non-canonical objects elicited increased frontal, temporal and parietal activation. Combining the functional MRI (fMRI) with the DTI results showed less deactivation in areas with decreased diffusion (mediolateral parietal and orbitofrontal) and increased activation in areas with increased diffusion (parietal and temporal) in aMCI patients. Finally, in aMCI patients decreased diffusion was found in the hippocampal cingulum, connecting both pathways., Conclusions: Our results showed increased activation in early AD patients in ventral and dorsal pathways. A decrease in deactivation and diffusion suggests functional reorganization, while increased activation and diffusion suggests compensatory processes. This is the first study showing structural evidence for functional reorganization, which may be related to connectivity loss in the cingulum., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Neuropathology suggests an important role for the locus coeruleus (LC) in Alzheimer's disease (AD) pathophysiology. Neuropathology and structural damage in the LC appears to be one of the earliest changes. We hypothesize that reduced functional integration of the LC reflected by lower brain functional connectivity contributes to early memory dysfunction. To test this, we examined resting-state functional connectivity from the LC in 18 healthy older individuals and 18 mildly cognitively impaired patients with possible AD. Connectivity measures were correlated with memory scores. The left LC showed strong connectivity to the left parahippocampal gyrus that correlated with memory performance in healthy persons. This connectivity was reduced in aMCI patients. Lateralization of connectivity-memory correlations was altered in less impaired aMCI patients: greater right LC-left parahippocampal gyrus connectivity was associated with better memory performance, in particular for encoding. Our results provide new evidence that the LC, in interaction with the parahippocampal gyrus, may contribute to episodic memory formation. They suggest functional impairment and the possibility that associated compensatory changes contribute to preserved memory functions in early AD. Structural and functional LC-related measures may provide early AD markers., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Alzheimer's disease-related pathology results in tremendous structural and functional changes in the brain. These morphological changes might lead to a less precise performance of automated brain segmentation techniques in AD-patients, which in turn could possibly lead to false allocations of gray matter, white matter or cerebrospinal fluid. FreeSurfer has been shown to operate as an accurate and reliable instrument to measure cortical thickness and volume of neuroanatomical structures. Considering the principal role of FreeSurfer in the imaging field of AD, the present study aims to investigate the robustness of FreeSurfer to capture morphological changes in the brain against varying processing variables in comparison to manual measurements (the gold standard). T1-weighted MRI scan data were used pertaining to a sample of 53 individuals (18 healthy participants, 18 patients with mild cognitive impairment, and 18 patients with mild AD). Data were analyzed with different FreeSurfer versions (v4.3.1, v4.5.0, v5.0.0, v5.1.0), on a custom-built cluster (LINUX) and a Macintosh (UNIX) workstation. Group differences across versions and workstations were most consistent for both the hippocampus and posterior cingulate, regions known to be affected in the earliest stages of the disease. The results showed that later versions of FreeSurfer were more sensitive to identify group differences and corresponded best with the results of gold standard manual volumetric methods. In conclusion, later versions of FreeSurfer were more accurate than earlier versions, especially in medial temporal and posterior parietal regions. This development is very promising for future applications of FreeSurfer in research studies and encourages the future role of FreeSurfer output as a candidate marker in clinical practice.

White matter hyperintensities are associated with an increased risk of Alzheimer's disease (AD). White matter hyperintensities are believed to disconnect brain areas. We examined the topographical association between white matter hyperintensities and cortical thickness in controls, mild cognitive impairment (MCI), and AD patients. We examined associations between white matter hyperintensities and cortical thickness among 18 older cognitively healthy participants, 18 amnestic MCI, and 17 mild AD patients. These associations were cluster-size corrected for multiple comparisons. In controls, a positive association between white matter hyperintensities and cortical thickness was found in lateral temporal gyri. In MCI patients, white matter hyperintensities were positively related to cortical thickness in frontal, temporal, and parietal areas. Positive associations between white matter hyperintensities and cortical thickness in AD patients were confined to parietal areas. The results of the interaction group by white matter hyperintensities on cortical thickness were consistent with the findings of positive associations in the parietal lobe for MCI and AD patients separately. In the frontal areas, controls and AD patients showed inverse associations between white matter hyperintensities and cortical thickness, while MCI patients still showed a positive association. These results suggest that a paradoxical relationship between white matter hyperintensities and cortical thickness could be a consequence of neuroinflammatory processes induced by AD-pathology and white matter hyperintensities. Alternatively, it might reflect a region-specific and disease-stage dependent compensatory hypertrophy in response to a compromised network.

Background: Gray matter atrophy, an important biomarker for early Alzheimer's disease, might be due to white matter changes within gray matter., Methods: Twenty older participants with significant memory decline over a 12-year period (T12) were matched to 20 nondeclining participants. All participants were magnetic resonance imaging scanned at T12. Cortical thickness and diffusion tensor imaging analyses were performed., Results: Lower cortical thickness values were associated with lower diffusion values in frontal and parietal gray matter areas. This association was only present in the memory decline group. The cortical thickness-diffusion tensor imaging correlations showed significant group differences in the posterior cingulate gyrus, precuneus, and superior frontal gyrus., Conclusions: Decreased gray matter diffusivity in the posterior cingulate/precuneus area might be a disease-specific process and a potential new biomarker for early Alzheimer's disease. Future studies should validate its potential as a biomarker and focus on cellular changes underlying diffusivity changes in gray matter., (Copyright © 2013 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Structural brain changes precede cognitive and clinical symptoms in Alzheimer's disease (AD). We aimed to examine the gray and white matter tissue changes in individuals with memory decline over a 12-year period, who might be at risk for AD. The participants were selected from the longitudinal Maastricht Aging Study based on their scores on the verbal word learning task. A group with profound memory decline over a 12-year period (n = 20) was identified and matched with a group that did not meet this criterion (n = 20). All of the participants underwent MRI scanning. Diffusion tensor imaging and cortical thickness analyses were performed to investigate the white and gray matter differences respectively. We found decreased white matter integrity in the memory decline group compared to the control group in frontal and parietal brain regions and in several cortico-cortical and cortico-subcortical tracts. Cortical thinning in the memory decline group was found in frontal, parietal, medial temporal and occipital areas. These results showed similarities with the structural brain changes observed in early AD. Thus, not only may cognitive changes be detected years before the clinical diagnosis, but typical gray and white matter changes appear to be present in older people with memory decline as well. This suggests that a combination of cognitive decline and structural brain changes might be an ideal biomarker for AD pathogenesis.

Cortical grey matter atrophy patterns have been reported in healthy ageing and Alzheimer disease (AD), but less consistently in the parietal regions of the brain. We investigated cortical grey matter volume patterns in parietal areas. The grey matter of the somatosensory cortex, superior and inferior parietal lobule was measured in 75 older adults (38 cognitively stable and 37 individuals with cognitive decline after 3 years). Dementia screening 6 years after scanning resulted in nine AD cases from the cognitively stable (n=3) and cognitive decline group (n=6), who were assigned to a third group, the preclinical AD group. When regional differences in cortical volume in the parietal lobe areas were compared between groups, significant differences were found between either the cognitive decline or stable group on the one hand and preclinical AD individuals on the other hand in the inferior parietal lobule. Group membership was best predicted by the grey matter volume of the inferior parietal lobule, compared to the other parietal lobe areas. The parietal lobe was characterised by a differential atrophy pattern based on cognitive status, which is in agreement with the 'last-developed-first-atrophied' principle. Future studies should investigate the surplus value of the inferior parietal lobe as a potential marker for the diagnosis of AD compared to other brain regions, such as the medial temporal lobe and the prefrontal lobe., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Medial temporal lobe (MTL) atrophy is considered to be one of the most important predictors of Alzheimer's disease (AD). This study investigates whether atrophy in parietal and prefrontal areas increases the predictive value of MTL atrophy in three groups of different cognitive status. Seventy-five older adults were classified as cognitively stable (n = 38) or cognitively declining (n = 37) after three years follow-up. At follow-up, the grey matter of the MTL, inferior prefrontal cortex (IPC), and inferior parietal lobule (IPL) was delineated on MRI scans. Six years later, a dementia assessment resulted in distinguishing and separating a third group (n = 9) who can be considered as preclinical AD cases at scan time. Ordinal logistic regressions analysis showed that the left and right MTL, as well as the right IPC and IPL accurately predicted group membership. Receiver Operating Curves showed that the MTL was best in distinguishing cognitively stable from cognitively declining individuals. The accuracy of the differentiation between preclinical AD and cognitively stable participants improved when MTL and IPL volumes were combined, while differentiating preclinical AD and cognitively declined participants was accomplished most accurately by the combined volume of all three areas. We conclude that depending on the current cognitive status of an individual, adding IPL or IPC atrophy improved the accuracy of predicting conversion to AD by up to 22%. Diagnosis of preclinical AD may lead to more false positive outcomes if only the MTL atrophy is considered.

In this study, we present an accurate, reliable, robust, and time-efficient technique for a semi-automatic segmentation of neuroanatomically defined cortical structures in Magnetic Resonance Imaging (MRI) scans. It involves manual drawing of the border of a region of interest (ROI), supported by three-dimensional (3D) visualization techniques (rendering), and a subsequent automatic tracing of the gray matter voxels inside the ROI by means of an automatic tissue classifier. The approach has been evaluated on a set of MRI scans of 75 participants selected from the Maastricht Aging Study (MAAS) and applied to cortical brain structures for both the left and right hemispheres, viz., the inferior prefrontal cortex (PFC); the orbital PFC; the dorsolateral PFC; the anterior cingulate cortex; and the posterior cingulate cortex. The use of a 3D surface-rendered brain can be rotated in any direction was invaluable in identifying anatomical landmarks on the basis of gyral and sulcal topography. This resulted in a high accuracy (anatomical correctness) and reliability: the intra-rater intra-class correlation coefficient (ICC) was between 0.96 and 0.99. Furthermore, the obtained time savings were substantial, i.e., up to a factor of 7.5 compared with fully manual segmentations., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)