The cortical distribution of amyloid-β plaques in Alzheimer’s disease strikingly resembles frontal-parietal intrinsic functional connectivity networks. Using a novel method to trace the distribution of amyloid-β plaques within single patients, Myers et al. reveal a marked negative effect on intrinsic connectivity in several networks that have not typically been investigated.

equally contributed to the study.Amyloid-β pathology (Aβ) and impaired cognition characterize Alzheimer's disease (AD); however, neural mechanisms that link Aβ-pathology with impaired cognition are incompletely understood. Large-scale intrinsic connectivity networks (ICNs) are potential candidates for this link: Aβ-pathology affects specific networks in early AD, these networks show disrupted connectivity, and they process specific cognitive functions impaired in AD, like memory or attention. We hypothesized that, in AD, regional changes of ICNs, which persist across rest-and cognitive task-states, might link Aβ-pathology with impaired cognition via impaired intrinsic connectivity. Pittsburgh compound B (PiB)-positron emission tomography reflecting in vivo Aβ-pathology, resting-state fMRI, task-fMRI, and cognitive testing were used in patients with prodromal AD and healthy controls. In patients, default mode network's (DMN) functional connectivity (FC) was reduced in the medial parietal cortex during rest relative to healthy controls, relatively increased in the same region during an attention-demanding task, and associated with patients' cognitive impairment. Local PiB-uptake correlated negatively with DMN connectivity. Importantly, corresponding results were found for the right lateral parietal region of an attentional network. Finally, structural equation modeling confirmed a direct influence of DMN resting-state FC on the association between Aβ-pathology and cognitive impairment. Data provide evidence that disrupted intrinsic network connectivity links Aβ-pathology with cognitive impairment in early AD.

Reserve refers to the phenomenon of relatively preserved cognition in disproportion to the extent of neuropathology, e.g., in Alzheimer’s disease. A putative functional neural substrate underlying reserve is global functional connectivity of the left lateral frontal cortex (LFC, Brodmann Area 6/44). Resting-state fMRI-assessed global LFC-connectivity is associated with protective factors (education) and better maintenance of memory in mild cognitive impairment (MCI). Since the LFC is a hub of the fronto-parietal control network that regulates the activity of other networks, the question arises whether LFC-connectivity to specific networks rather than the whole-brain may underlie reserve. We assessed resting-state fMRI in 24 MCI and 16 healthy controls (HC) and in an independent validation sample (23 MCI/32 HC). Seed-based LFC-connectivity to seven major resting-state networks (i.e., fronto-parietal, limbic, dorsal-attention, somatomotor, default-mode, ventral-attention, visual) was computed, reserve was quantified as residualized memory performance after accounting for age and hippocampal atrophy. In both samples of MCI, LFC-activity was anti-correlated with the default-mode network (DMN), but positively correlated with the dorsal-attention network (DAN). Greater education predicted stronger LFC-DMN-connectivity (anti-correlation) and LFC-DAN-connectivity. Stronger LFC-DMN and LFC-DAN-connectivity each predicted higher reserve, consistently in both MCI samples. No associations were detected for LFC-connectivity to other networks. These novel results extend our previous findings on global functional connectivity of the LFC, showing that LFC-connectivity specifically to the DAN and DMN, two core memory networks, enhances reserve in the memory domain in MCI.

Oxygen extraction (OEF), oxidative metabolism (CMRO), and blood flow (CBF) in the brain, as well as the coupling between CMRO and CBF due to cerebral autoregulation are fundamental to brain's health. We used a clinically feasible MRI protocol to assess impairments of these parameters in the perfusion territories of stenosed carotid arteries. Twenty-nine patients with unilateral high-grade carotid stenosis and thirty age-matched healthy controls underwent multi-modal MRI scans. Pseudo-continuous arterial spin labeling (pCASL) yielded absolute CBF, whereas multi-parametric quantitative blood oxygenation level dependent (mqBOLD) modeling allowed imaging of relative OEF and CMRO. Both CBF and CMRO were significantly reduced in the stenosed territory compared to the contralateral side, while OEF was evenly distributed across both hemispheres similarly in patients and controls. The CMRO-CBF coupling was significantly different between both hemispheres in patients, i.e. significant interhemispheric flow-metabolism uncoupling was observed in patients compared to controls. Given that CBF and CMRO are intimately linked to brain function in health and disease, the proposed easily applicable MRI protocol of pCASL and mqBOLD imaging might serve as a valuable tool for early diagnosis of potentially harmful cerebral hemodynamic and metabolic states with the final aim to select clinically asymptomatic patients who would benefit from carotid revascularization therapy.

Improved understanding of complex hemodynamic impairments in asymptomatic internal carotid artery stenosis (ICAS) is crucial to better assess stroke risks. Multimodal MRI is ideal for measuring brain hemodynamics and has the potential to improve diagnostics and treatment selections. We applied MRI-based perfusion and oxygenation-sensitive imaging in ICAS with the hypothesis that the sensitivity to hemodynamic impairments will improve within individual watershed areas (iWSA). We studied cerebral blood flow (CBF), cerebrovascular reactivity (CVR), relative cerebral blood volume (rCBV), relative oxygen extraction fraction (rOEF), oxygen extraction capacity (OEC) and capillary transit-time heterogeneity (CTH) in 29 patients with asymptomatic, unilateral ICAS (age 70.3 ± 7.0 y) and 30 age-matched healthy controls. In ICAS, we found significant impairments of CBF, CVR, rCBV, OEC, and CTH (strongest lateralization ΔCVR = –24%), but not of rOEF. Although the spatial overlap of compromised hemodynamic parameters within each patient varied in a complex manner, most pronounced changes of CBF, CVR and rCBV were detected within iWSAs (strongest effect ΔCVR = +117%). At the same time, CTH impairments were iWSA independent, indicating widespread dysfunction of capillary-level oxygen diffusivity. In summary, complementary MRI-based perfusion and oxygenation parameters offer deeper perspectives on complex microvascular impairments in individual patients. Furthermore, knowledge about iWSAs improves the sensitivity to hemodynamic impairments.

Results demonstrate feasibility of individual WSA delineation by TTP maps in healthy elderly and carotid stenosis patients. Data indicate necessity of individual segmentation approaches especially in patients with hemodynamic compromise to detect critical regions of impaired hemodynamics.

Relative oxygen extraction fraction (rOEF) is a fundamental indicator of cerebral metabolic function. An easily applicable method for magnetic resonance imaging (MRI) based rOEF mapping is the multi-parametric quantitative blood oxygenation level dependent (mq-BOLD) approach with separate acquisitions of transverse relaxation times [Formula: see text] and T2 and dynamic susceptibility contrast (DSC) based relative cerebral blood volume (rCBV). Given that transverse relaxation and rCBV in white matter (WM) strongly depend on nerve fiber orientation, mq-BOLD derived rOEF is expected to be affected as well. To investigate fiber orientation related rOEF artefacts, we present a methodological study characterizing anisotropy effects of WM as measured by diffusion tensor imaging (DTI) on mq-BOLD in 30 healthy volunteers. Using a 3T clinical MRI-scanner, we performed a comprehensive correlation of all parameters ([Formula: see text], T2, [Formula: see text], rCBV, rOEF, where [Formula: see text]=1/[Formula: see text]–1/T2) with DTI-derived fiber orientation towards the main magnetic field (B0). Our results confirm strong dependencies of transverse relaxation and rCBV on the nerve fiber orientation towards B0, with anisotropy-driven variations up to 37%. Comparably weak orientation-dependent variations of mq-BOLD derived rOEF (3.8%) demonstrate partially counteracting influences of [Formula: see text] and rCBV effects, possibly suggesting applicability of rOEF as an oxygenation sensitive biomarker. However, unresolved issues warrant caution when applying mq-BOLD to WM.

Hypoxia plays an important role for the prognosis and therapy response of cancer. Thus, hypoxia imaging would be a valuable tool for pre-therapeutic assessment of tumor malignancy. However, there is no standard validated technique for clinical application available yet. Therefore, we performed a study in 12 patients with high-grade glioma, where we directly compared the two currently most promising techniques, namely the MR-based relative oxygen extraction fraction (MR-rOEF) and the PET hypoxia marker H-1-(3-[ F]-fluoro-2-hydroxypropyl)-2-nitroimidazole ([ F]-FMISO). MR-rOEF was determined from separate measurements of T , T * and relative cerebral blood volume (rCBV) employing a multi-parametric approach for quantification of the blood-oxygenation-level-dependent (BOLD) effect. With respect to [ F]-FMISO-PET, besides the commonly used late uptake between 120 and 130 min ([ F]-FMISO ), we also analyzed the hypoxia specific uptake rate [ F]-FMISO-k , as obtained by pharmacokinetic modeling of dynamic uptake data. Since pharmacokinetic modeling of partially acquired dynamic [ F]-FMISO data was sensitive to a low signal-to-noise-ratio, analysis was restricted to high-uptake tumor regions. Individual spatial analyses of deoxygenation and hypoxia-related parameter maps revealed that high MR-rOEF values clustered in (edematous) peritumoral tissue, while areas with high [ F]-FMISO concentrated in and around active tumor with disrupted blood-brain barrier, i.e. contrast enhancement in T -weighted MRI. Volume-of-interest-based correlations between MR-rOEF and [ F]-FMISO as well as [ F]-FMISO-k , and voxel-wise analyses in individual patients, yielded limited correlations, supporting the notion that [ F]-FMISO uptake, even after 2 h, might still be influenced by perfusion while [ F]-FMISO-k was severely hampered by noise. According to these results, vascular deoxygenation, as measured by MR-rOEF, and severe tissue hypoxia, as measured by [ F]-FMISO, show a poor spatial correspondence. Overall, the two methods appear to rather provide complementary than redundant information about high-grade glioma biology.