Microvascular Phenotyping in the Maastricht Study: Design and Main Findings, 2010-2018.

Microvascular dysfunction (MVD) is a common pathophysiological change that occurs in various diseases, such as type 2 diabetes mellitus (T2DM), heart failure, dementia, and depression. Recent technical advances have enabled noninvasive measurement and quantification of microvascular changes in humans. In this paper, we describe the protocols of the microvascular measurements applied in the Maastricht Study, an ongoing prospective, population-based cohort study of persons aged 40-75 years being carried out in the southern part of the Netherlands (baseline data assessment, November 2010-January 2020). The study includes a variety of noninvasive measurements in skin, retina, brain, and sublingual tissue, as well as plasma and urine biomarker assessments. Following this, we summarize our main findings involving these microvascular measurements through the end of 2018. Finally, we provide a brief perspective on future microvascular investigations within the framework of the Maastricht Study.

Capillary Rarefaction Associates with Albuminuria: The Maastricht Study.

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.

Decreased gray matter diffusivity: a potential early Alzheimer's disease biomarker?

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.

Atrophy of the parietal lobe in preclinical dementia.

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.

Associations of increased interstitial fluid with vascular and neurodegenerative abnormalities in a memory clinic sample.

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 fint (a proxy of ISF volume) was associated with a large WMH volume and low hippocampal volume. Likewise, a large fint value was associated with a lower hippocampal volume in the hippocampi. Large ISF volume (fint) 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.

A time-saving and facilitating approach for segmentation of anatomically defined cortical regions: MRI volumetry.

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.

Associations between pattern separation and hippocampal subfield structure and function vary along the lifespan: A 7 T imaging study.

Pattern separation (PS) describes the process by which the brain discriminates similar stimuli from previously encoded stimuli. This fundamental process requires the intact processing by specific subfields in the hippocampus and can be examined using mnemonic discrimination tasks. Previous studies reported different patterns for younger and older individuals between mnemonic discrimination performance and hippocampal subfield activation. Here, we investigated the relationship between the lure discrimination index (LDI) and hippocampal subfield volume and activity across the adult lifespan (20-70 years old). Using ultra-high field functional and structural magnetic resonance imaging at 7 T, we found that lower DG volume and higher CA3 activation was associated with worse LDI performance in individuals (>60 years), suggesting that this higher activation may be an indication of aberrant neurodegenerative-related processes. In fact, higher activation in the CA1 and DG was associated with lower volumes in these subfields. For individuals around 40-50 years old, we observed that greater left and right DG volume, and greater activity in the CA3 was associated with lower LDI performance. Taken together, these results suggest that the relationship between memory and hippocampal subfield structure or function varies nonlinearly and possibly reciprocally with age, with midlife being a critically vulnerable period in life.

Contributions of Cerebro-Cerebellar Default Mode Connectivity Patterns to Memory Performance in Mild Cognitive Impairment.

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.

Increase in blood-brain barrier leakage in healthy, older adults.

Blood-brain barrier (BBB) breakdown can disrupt nutrient supply and waste removal, which affects neuronal functioning. Currently, dynamic contrast-enhanced (DCE) MRI is the preferred in-vivo method to quantify BBB leakage. Dedicated DCE MRI studies in normal aging individuals are lacking, which could hamper value estimation and interpretation of leakage rate in pathological conditions. Therefore, we applied DCE MRI to investigate the association between BBB disruption and age in a healthy sample. Fifty-seven cognitively and neurologically healthy, middle-aged to older participants (mean age: 66 years, range: 47-91 years) underwent MRI, including DCE MRI with intravenous injection of a gadolinium-based contrast agent. Pharmacokinetic modeling was applied to contrast concentration time-curves to estimate BBB leakage rate in each voxel. Subsequently, leakage rate was calculated in the white and gray matter, and primary (basic sensory and motor functions), secondary (association areas), and tertiary (higher-order cognition) brain regions. A difference in vulnerability to deterioration was expected between these regions, with especially tertiary regions being affected by age. Higher BBB leakage rate was significantly associated with older age in the white and gray matter, and also in tertiary, but not in primary or secondary brain regions. Even in healthy individuals, BBB disruption was stronger in older persons, which suggests BBB disruption is a normal physiologically aging phenomenon. Age-related increase in BBB disruption occurred especially in brain regions most vulnerable to age-related deterioration, which may indicate that BBB disruption is an underlying mechanism of normal age-related decline.Netherlands Trial Register number: NL6358, date of registration: 2017-03-24.

White matter hyperintensities mediate the association between blood-brain barrier leakage and information processing speed.

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.

The prevalence of cortical gray matter atrophy may be overestimated in the healthy aging brain.

Prevailing opinion holds that normal brain aging is characterized by substantial atrophy of cortical gray matter. However, this conclusion is based on earlier studies whose findings may be influenced by the inclusion of subjects with subclinical cognitive disorders like preclinical dementia. The present magnetic resonance imaging study tested this hypothesis. Cognitively healthy subjects (mean age 72 years, range 52-82) who remained cognitively stable over a 3-year period were compared to subjects with significant cognitive decline. Subjects who developed dementia within 6 years after the scan session were excluded. The gray matter volumes of seven cortical regions were delineated on T1-weighted magnetic resonance imaging scans. Participants without cognitive decline did not exhibit an age effect on the gray matter volume. Conversely, participants with cognitive decline exhibited a significant age effect in all the seven areas. These results suggest that cortical gray matter atrophy may have been overestimated in studies on healthy aging, since most studies were unable to exclude participants with a substantial atypical cognitive decline or preclinical dementia. Our results underscore the importance of establishing stringent inclusion criteria for future studies on normal aging.

The use of faces as stimuli in neuroimaging and psychological experiments: a procedure to standardize stimulus features.

In psychological experiments involving facial stimuli, it is of great importance that the basic perceptual or psychological characteristics that are investigated are not confounded by factors such as brightness and contrast, head size, hair cut and color, skin color, and the presence of glasses and earrings. Standardization of facial stimulus materials reduces the effect of these confounding factors. We therefore employed a set of basic image processing techniques to deal with this issue. The processed images depict the faces in grayscale, all at the same size, brightness, and contrast, and confined to an oval mask revealing only the basic features such as the eyes, nose, and mouth. The standardization was successfully applied to four different face databases, consisting of male and female faces and including neutral as well as happy facial expressions. An important advantage of the proposed standardization is that featural as well as configurational information is retained. We also consider the procedure to be a major contribution to the development of a de facto standard for the use of facial stimuli in psychological experiments. Such methodological standardization would allow a better comparison of the results of these studies.

Shades of white: diffusion properties of T1- and FLAIR-defined white matter signal abnormalities differ in stages from cognitively normal to dementia.

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.

The Relationship between Cerebral Small Vessel Disease, Hippocampal Volume and Cognitive Functioning in Patients with COPD: An MRI Study.

The neural correlates of cognitive impairment in chronic obstructive pulmonary disease (COPD) are not yet understood. Structural brain abnormalities could possibly be associated with the presence of cognitive impairment through cigarette smoke, inflammation, vascular disease, or hypoxemia in these patients. This study aimed to investigate whether macrostructural brain magnetic resonance imaging (MRI) features of cerebral small vessel disease (SVD) and hippocampal volume (HCV) are related to cognitive performance in patients with COPD. A subgroup of cognitively high and low-performing COPD patients of the COgnitive-PD study, underwent a brain 3T MRI. SVD as a marker of vascular damage was assessed using qualitative visual rating scales. HCV as a marker of neurodegeneration was assessed using the learning embedding for atlas propagation (LEAP) method. Features of SVD and HCV were compared between cognitively high and low-performing individuals using Mann Whitney U tests and independent samples t-tests, respectively. No group differences were reported between 25 high-performing (mean age 60.3 (standard deviation [SD] 9.7) years; 40.0% men; forced expiratory volume in first second [FEV1] 50.1% predicted) and 30 low-performing patients with COPD (mean age 60.6 (SD 6.8) years; 53.3% men; FEV1 55.6% predicted) regarding demographics, clinical characteristics, comorbidities and the presence of the SVD features and HCV. To conclude, the current study does not provide evidence for a relationship between cerebral SVD and HCV and cognitive functioning in patients with COPD. Additional studies will be needed to determine other possible mechanisms of cognitive impairment in patients with COPD, including microstructural brain changes and inflammatory-, hormonal-, metabolic- and (epi)genetic factors.

Reduced specialized processing in psychotic disorder: a graph theoretical analysis of cerebral functional connectivity.

BACKGROUND: Previous research has shown that the human brain can be represented as a complex functional network that is characterized by specific topological properties, such as clustering coefficient, characteristic path length, and global/local efficiency. Patients with psychotic disorder may have alterations in these properties with respect to controls, indicating altered efficiency of network organization. This study examined graph theoretical changes in relation to differential genetic risk for the disorder and aimed to identify clinical correlates. METHODS: Anatomical and resting-state MRI brain scans were obtained from 73 patients with psychotic disorder, 83 unaffected siblings, and 72 controls. Topological measures (i.e., clustering coefficient, characteristic path length, and small-worldness) were used as dependent variables in a multilevel random regression analysis to investigate group differences. In addition, associations with (subclinical) psychotic/cognitive symptoms were examined. RESULTS: Patients had a significantly lower clustering coefficient compared to siblings and controls, with no difference between the latter groups. No group differences were observed for characteristic path length and small-worldness. None of the topological properties were associated with (sub)clinical psychotic and cognitive symptoms. CONCLUSIONS: The reduced ability for specialized processing (reflected by a lower clustering coefficient) within highly interconnected brain regions observed in the patient group may indicate state-related network alterations. There was no evidence for an intermediate phenotype and no evidence for psychopathology-related alterations.

Relevance of parahippocampal-locus coeruleus connectivity to memory in early dementia.

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.

Default mode network connectivity as a function of familial and environmental risk for psychotic disorder.

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.

Can FreeSurfer Compete with Manual Volumetric Measurements in Alzheimer's Disease?

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.

Visuospatial processing in early Alzheimer's disease: a multimodal neuroimaging study.

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.

White matter hyperintensities are positively associated with cortical thickness in Alzheimer's disease.

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.