Chemical shift-encoded multishot EPI for navigator-free prostate DWI.

PURPOSE: DWI is an important contrast for prostate MRI to enable early and accurate detection of cancer. This study introduces a Dixon 3-shot-EPI protocol with structured low-rank reconstruction for navigator-free DWI. The aim is to overcome the limitations of single-shot EPI (ssh-EPI), such as geometric distortions and fat signal interference, while addressing the motion-induced phase variations of multishot EPI and simultaneously allowing water/fat separation. METHODS: DWI data were acquired from 7 healthy volunteers using both Dixon 3-shot EPI and standard fat-suppressed ssh-EPI with similar scan times for comparison. Two readers evaluated image quality using a 5-point Likert scale regarding different aspects. The ADC values were quantitatively compared between protocols. To show feasibility in a clinical setting, the protocol was applied to two patients. RESULTS: From the reader scores, Dixon 3-shot EPI significantly reduced geometric distortion compared with ssh-EPI (p < 0.01), with no significant differences in edge definition, SNR, or overall image quality. There was no significant difference in ADC values between the two protocols. However, the Dixon multishot-EPI protocol offered advantages such as self-referenced B0 map-driven distortion correction, greater flexibility in imaging parameters, and superior fat suppression. In the patient data, the lesion could be clearly identified in both protocols and on the associated ADC maps. CONCLUSION: The proposed Dixon 3-shot-EPI protocol shows promise as an alternative to ssh-EPI for prostate DWI, providing reduced geometric distortions and improved fat suppression. It addresses common DWI issues based on EPI and enhances scanning flexibility, indicating potential for optimized imaging.

The contribution of the vascular architecture and cerebrovascular reactivity to the BOLD signal formation across cortical depth.

Assessment of neuronal activity using blood oxygenation level-dependent (BOLD) is confounded by how the cerebrovascular architecture modulates hemodynamic responses. To understand brain function at the laminar level, it is crucial to distinguish neuronal signal contributions from those determined by the cortical vascular organization. Therefore, our aim was to investigate the purely vascular contribution in the BOLD signal by using vasoactive stimuli and compare that with neuronal-induced BOLD responses from a visual task. To do so, we estimated the hemodynamic response function (HRF) across cortical depth following brief visual stimulations under different conditions using ultrahigh-field (7 Tesla) functional (f)MRI. We acquired gradient-echo (GE)-echo-planar-imaging (EPI) BOLD, containing contributions from all vessel sizes, and spin-echo (SE)-EPI BOLD for which signal changes predominately originate from microvessels, to distinguish signal weighting from different vascular compartments. Non-neuronal hemodynamic changes were induced by hypercapnia and hyperoxia to estimate cerebrovascular reactivity and venous cerebral blood volume ( C B V v O 2 ). Results show that increases in GE HRF amplitude from deeper to superficial layers coincided with increased macrovascular C B V v O 2 . C B V v O 2 -normalized GE-HRF amplitudes yielded similar cortical depth profiles as SE, thereby possibly improving specificity to neuronal activation. For GE BOLD, faster onset time and shorter time-to-peak were observed toward the deeper layers. Hypercapnia reduced the amplitude of visual stimulus-induced signal responses as denoted by lower GE-HRF amplitudes and longer time-to-peak. In contrast, the SE-HRF amplitude was unaffected by hypercapnia, suggesting that these responses reflect predominantly neurovascular processes that are less contaminated by macrovascular signal contributions.

Cognition in (pre)symptomatic Dutch-type hereditary and sporadic cerebral amyloid angiopathy.

INTRODUCTION: Cerebral amyloid angiopathy (CAA) is a main cause of cognitive dysfunction in the elderly. We investigated specific cognitive profiles, cognitive function in the stage before intracerebral hemorrhage (ICH), and the association between magnetic resonance imaging (MRI) based cerebral small vessel disease (cSVD) burden in CAA because data on these topics are limited. METHODS: We included Dutch-type hereditary CAA (D-CAA) mutation carriers with and without ICH, patients with sporadic CAA (sCAA), and age-matched controls. Cognition was measured with a standardized test battery. Linear regression was performed to assess the association between MRI-cSVD burden and cognition. RESULTS: D-CAA ICH- mutation carriers exhibited poorer global cognition and executive function compared to age-matched controls. Patients with sCAA performed worse across all cognitive domains compared to D-CAA ICH+ mutation carriers and age-matched controls. MRI-cSVD burden is associated with decreased processing speed. DISCUSSION: CAA is associated with dysfunction in multiple cognitive domains, even before ICH, with increased MRI-cSVD burden being associated with slower processing speed. HIGHLIGHTS: Cognitive dysfunction is present in early disease stages of cerebral amyloid angiopathy (CAA) before the occurrence of symptomatic intracerebral hemorrhage (sICH). Presymptomatic Dutch-type CAA (D-CAA) mutation carriers show worse cognition than age-matched controls. More early awareness of cognitive dysfunction in CAA before first sICH is needed. Increased cerebral small vessel disease CAA-burden on magnetic resonance imaging is linked to a decrease in processing speed.

One Size Does Not Fit All: Micro-, Meso-, and Macrobleeds in Cerebral Amyloid Angiopathy.

INTRODUCTION: MRI rating criteria for small vessel disease markers include definitions for microbleeds and macrobleeds but do not account for small (<10 mm) hemorrhages with a cystic cavity and/or irregular shape. Such hemorrhages, however, are often present in patients with cerebral amyloid angiopathy (CAA). In this study, we aimed to investigate the frequency, diameter, and volume distribution of these hemorrhages (which we called mesobleeds) in patients with CAA. METHODS: We selected participants with Dutch-type hereditary CAA (D-CAA) and sporadic CAA (sCAA) and scored microbleeds, mesobleeds, and macrobleeds on 3T susceptibility-weighted images MRI. Hemorrhage diameter and volume were calculated in a subset of participants using a semi-automatic tool; their distribution was evaluated on a logarithmic scale. RESULTS: We included 25 participants with D-CAA (mean age 56 years) and 25 with sCAA (mean age 73 years). In total, 11,007 microbleeds, 602 mesobleeds, and 195 macrobleeds were observed. Eighty-two percent of participants had ≥1 mesobleed. Hemorrhage diameter and volume were calculated in four participants with 272 microbleeds (median diameter 1.52 mm, volume 0.004 mL), 84 mesobleeds (median diameter 5.61 mm, volume 0.06 mL), and 37 macrobleeds (median diameter 19.58 mm, volume 1.33 mL). Mesobleed diameter and volume were larger than microbleeds (optimal cut-off 0.02 mL) but showed overlap with macrobleeds. CONCLUSION: Hemorrhages <10 mm with an irregular shape and/or cystic cavity are frequently found in participants with CAA and have a distinct diameter and volume distribution. We propose to name these hemorrhage mesobleeds and to rate them separately from micro- and macrobleeds. Future research is necessary to investigate their pathophysiology and prognostic value.

Advancing 7T perfusion imaging by pulsed arterial spin labeling: Using a parallel transmit coil for enhanced labeling robustness and temporal SNR.

Non-invasive perfusion imaging by Arterial spin labeling (ASL) can be advantageous at Ultra-high field (UHF) MRI, since the image SNR and the T1 relaxation time both increase with the static field. However, ASL implementation, especially at 7T, is not trivial. Especially for ASL, UHF MRI comes with many challenges, mainly due to B1+ inhomogeneities. This study aimed to investigate the effects of different transmit coil configurations on perfusion-weighted imaging at 7T using a flow-sensitive alternating inversion recovery (FAIR) technique with time-resolved frequency offset corrected inversion (TR-FOCI) pulses for labeling and background suppression. We conducted a performance comparison between a parallel transmit (pTx) system equipped with 32 receive (Rx) and 8 transmit (Tx) channels and a standard setup with 32Rx and 2Tx channels. Our findings demonstrate that the pTx system, characterized by a more homogeneous B1 transmit field, resulted in a significantly higher contrast-to-noise ratio, temporal signal-to-noise ratio, and lower coefficient of variance (CoV) than the standard 2Tx setup. Additionally, both setups demonstrated comparable capabilities for functional mapping of the hand region in the motor cortex, achieving reliable results within a short acquisition time of approximately 5 minutes.

Arterial input function estimation compensating for inflow and partial voluming in dynamic contrast-enhanced MRI.

Both inflow and the partial volume effect (PVE) are sources of error when measuring the arterial input function (AIF) in dynamic contrast-enhanced (DCE) MRI. This is relevant, as errors in the AIF can propagate into pharmacokinetic parameter estimations from the DCE data. A method was introduced for flow correction by estimating and compensating the number of the perceived pulse of spins during inflow. We hypothesized that the PVE has an impact on concentration-time curves similar to inflow. Therefore, we aimed to study the efficiency of this method to compensate for both effects simultaneously. We first simulated an AIF with different levels of inflow and PVE contamination. The peak, full width at half-maximum (FWHM), and area under curve (AUC) of the reconstructed AIFs were compared with the true (simulated) AIF. In clinical data, the PVE was included in AIFs artificially by averaging the signal in voxels surrounding a manually selected point in an artery. Subsequently, the artificial partial volume AIFs were corrected and compared with the AIF from the selected point. Additionally, corrected AIFs from the internal carotid artery (ICA), the middle cerebral artery (MCA), and the venous output function (VOF) estimated from the superior sagittal sinus (SSS) were compared. As such, we aimed to investigate the effectiveness of the correction method with different levels of inflow and PVE in clinical data. The simulation data demonstrated that the corrected AIFs had only marginal bias in peak value, FWHM, and AUC. Also, the algorithm yielded highly correlated reconstructed curves over increasingly larger neighbourhoods surrounding selected arterial points in clinical data. Furthermore, AIFs measured from the ICA and MCA produced similar peak height and FWHM, whereas a significantly larger peak and lower FWHM was found compared with the VOF. Our findings indicate that the proposed method has high potential to compensate for PVE and inflow simultaneously. The corrected AIFs could thereby provide a stable input source for DCE analysis.

Time-encoded ASL reveals lower cerebral blood flow in the early AD continuum.

INTRODUCTION: Cerebral blood flow (CBF) is reduced in cognitively impaired (CI) Alzheimer's disease (AD) patients. We checked the sensitivity of time-encoded arterial spin labeling (te-ASL) in measuring CBF alterations in individuals with positive AD biomarkers and associations with relevant biomarkers in cognitively unimpaired (CU) individuals. METHODS: We compared te-ASL with single-postlabel delay (PLD) ASL in measuring CBF in 59 adults across the AD continuum, classified as CU amyloid beta (Aß) negative (-), CU Aß positive (+), and CI Aß+. We sought associations of CBF with biomarkers of AD, cerebrovascular disease, synaptic dysfunction, neurodegeneration, and cognition in CU participants. RESULTS: te-ASL was more sensitive at detecting CBF reduction in the CU Aß+ and CI Aß+ groups. In CU participants, lower CBF was associated with altered biomarkers of Aß, tau, synaptic dysfunction, and neurodegeneration. DISCUSSION: CBF reduction occurs early in the AD continuum. te-ASL is more sensitive than single-PLD ASL at detecting CBF changes in AD. HIGHLIGHTS: Lower CBF can be detected in CU subjects in the early AD continuum. te-ASL is more sensitive than single-PLD ASL at detecting CBF alterations in AD. CBF is linked to biomarkers of AD, synaptic dysfunction, and neurodegeneration.

Water exchange across the blood-brain barrier and epilepsy: Review on pathophysiology and neuroimaging.

The blood-brain barrier (BBB) is a barrier protecting the brain and a milieu of continuous exchanges between blood and brain. There is emerging evidence that the BBB plays a major role in epileptogenesis and drug-resistant epilepsy, through several mechanisms, such as water homeostasis dysregulation, overexpression of drug transporters, and inflammation. Studies have shown abnormal water homeostasis in epileptic tissue and altered aquaporin-4 water channel expression in animal epilepsy models. This review focuses on abnormal water exchange in epilepsy and describes recent non-invasive MRI methods of quantifying water exchange. PLAIN LANGUAGE SUMMARY: Abnormal exchange between blood and brain contribute to seizures and epilepsy. The authors describe why correct water balance is necessary for healthy brain functioning and how it is impacted in epilepsy. This review also presents recent MRI methods to measure water exchange in human brain. These measures would improve our understanding of factors leading to seizures.

On the influence of the vascular architecture on Gradient Echo and Spin Echo BOLD fMRI signals across cortical depth: a simulation approach based on realistic 3D vascular networks.

GE-BOLD contrast stands out as the predominant technique in functional MRI experiments for its high sensitivity and straightforward implementation. GE-BOLD exhibits rather similar sensitivity to vessels independent of their size at submillimeter resolution studies like those examining cortical columns and laminae. However, the presence of nonspecific macrovascular contributions poses a challenge to accurately isolate neuronal activity. SE-BOLD increases specificity towards small vessels, thereby enhancing its specificity to neuronal activity, due to the effective suppression of extravascular contributions caused by macrovessels with its refocusing pulse. However, even SE-BOLD measurements may not completely remove these macrovascular contributions. By simulating hemodynamic signals across cortical depth, we gain insights into vascular contributions to the laminar BOLD signal. In this study, we employed four realistic 3D vascular models to simulate oxygen saturation states in various vascular compartments, aiming to characterize both intravascular and extravascular contributions to GE and SE signals, and corresponding BOLD signal changes, across cortical depth at 7T. Simulations suggest that SE-BOLD cannot completely reduce the macrovascular contribution near the pial surface. Simulations also show that both the specificity and signal amplitude of BOLD signals at 7T depend on the spatial arrangement of large vessels throughout cortical depth and on the pial surface.

A fully synthetic three-dimensional human cerebrovascular model based on histological characteristics to investigate the hemodynamic fingerprint of the layer BOLD fMRI signal formation.

Recent advances in functional magnetic resonance imaging (fMRI) at ultra-high field (≥7 tesla), novel hardware, and data analysis methods have enabled detailed research on neurovascular function, such as cortical layer-specific activity, in both human and nonhuman species. A widely used fMRI technique relies on the blood oxygen level-dependent (BOLD) signal. BOLD fMRI offers insights into brain function by measuring local changes in cerebral blood volume, cerebral blood flow, and oxygen metabolism induced by increased neuronal activity. Despite its potential, interpreting BOLD fMRI data is challenging as it is only an indirect measurement of neuronal activity. Computational modeling can help interpret BOLD data by simulating the BOLD signal formation. Current developments have focused on realistic 3D vascular models based on rodent data to understand the spatial and temporal BOLD characteristics. While such rodent-based vascular models highlight the impact of the angioarchitecture on the BOLD signal amplitude, anatomical differences between the rodent and human vasculature necessitate the development of human-specific models. Therefore, a computational framework integrating human cortical vasculature, hemodynamic changes, and biophysical properties is essential. Here, we present a novel computational approach: a three-dimensional VAscular MOdel based on Statistics (3D VAMOS), enabling the investigation of the hemodynamic fingerprint of the BOLD signal within a model encompassing a fully synthetic human 3D cortical vasculature and hemodynamics. Our algorithm generates microvascular and macrovascular architectures based on morphological and topological features from the literature on human cortical vasculature. By simulating specific oxygen saturation states and biophysical interactions, our framework characterizes the intravascular and extravascular signal contributions across cortical depth and voxel-wise levels for gradient-echo and spin-echo readouts. Thereby, the 3D VAMOS computational framework demonstrates that using human characteristics significantly affects the BOLD fingerprint, making it an essential step in understanding the fundamental underpinnings of layer-specific fMRI experiments.

Is CAA a perivascular brain clearance disease? A discussion of the evidence to date and outlook for future studies.

The brain's network of perivascular channels for clearance of excess fluids and waste plays a critical role in the pathogenesis of several neurodegenerative diseases including cerebral amyloid angiopathy (CAA). CAA is the main cause of hemorrhagic stroke in the elderly, the most common vascular comorbidity in Alzheimer's disease and also implicated in adverse events related to anti-amyloid immunotherapy. Remarkably, the mechanisms governing perivascular clearance of soluble amyloid ß-a key culprit in CAA-from the brain to draining lymphatics and systemic circulation remains poorly understood. This knowledge gap is critically important to bridge for understanding the pathophysiology of CAA and accelerate development of targeted therapeutics. The authors of this review recently converged their diverse expertise in the field of perivascular physiology to specifically address this problem within the framework of a Leducq Foundation Transatlantic Network of Excellence on Brain Clearance. This review discusses the overarching goal of the consortium and explores the evidence supporting or refuting the role of impaired perivascular clearance in the pathophysiology of CAA with a focus on translating observations from rodents to humans. We also discuss the anatomical features of perivascular channels as well as the biophysical characteristics of fluid and solute transport.

Human brain clearance imaging: Pathways taken by magnetic resonance imaging contrast agents after administration in cerebrospinal fluid and blood.

Over the last decade, it has become evident that cerebrospinal fluid (CSF) plays a pivotal role in brain solute clearance through perivascular pathways and interactions between the brain and meningeal lymphatic vessels. Whereas most of this fundamental knowledge was gained from rodent models, human brain clearance imaging has provided important insights into the human system and highlighted the existence of important interspecies differences. Current gold standard techniques for human brain clearance imaging involve the injection of gadolinium-based contrast agents and monitoring their distribution and clearance over a period from a few hours up to 2 days. With both intrathecal and intravenous injections being used, which each have their own specific routes of distribution and thus clearance of contrast agent, a clear understanding of the kinetics associated with both approaches, and especially the differences between them, is needed to properly interpret the results. Because it is known that intrathecally injected contrast agent reaches the blood, albeit in small concentrations, and that similarly some of the intravenously injected agent can be detected in CSF, both pathways are connected and will, in theory, reach the same compartments. However, because of clear differences in relative enhancement patterns, both injection approaches will result in varying sensitivities for assessment of different subparts of the brain clearance system. In this opinion review article, the "EU Joint Programme - Neurodegenerative Disease Research (JPND)" consortium on human brain clearance imaging provides an overview of contrast agent pharmacokinetics in vivo following intrathecal and intravenous injections and what typical concentrations and concentration-time curves should be expected. This can be the basis for optimizing and interpreting contrast-enhanced MRI for brain clearance imaging. Furthermore, this can shed light on how molecules may exchange between blood, brain, and CSF.

Influence of arterial transit time delays on the differentiation between tumor progression and pseudoprogression in glioblastoma by arterial spin labeling magnetic resonance imaging.

Arterial spin labeling (ASL) and dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) have shown potential for differentiating tumor progression from pseudoprogression. For pseudocontinuous ASL with a single postlabeling delay, the presence of delayed arterial transit times (ATTs) could affect the evaluation of ASL-MRI perfusion data. In this study, the influence of ATT artifacts on the perfusion assessment and differentiation between tumor progression and pseudoprogression were studied. This study comprised 66 adult patients (mean age 60 ± 13 years; 40 males) with a histologically confirmed glioblastoma who received postoperative radio (chemo)therapy. ASL-MRI and DSC-MRI scans were acquired at 3 months postradiotherapy as part of the standard clinical routine. These scans were visually scored regarding (i) the severity of ATT artifacts (%) on the ASL-MRI scans only, scored by two neuroradiologists; (ii) perfusion of the enhancing tumor lesion; and (iii) radiological evaluation of tumor progression versus pseudoprogression by one neuroradiologist. The final outcome was based on combined clinical and radiological follow-up until 9 months postradiotherapy. ATT artifacts were identified in all patients based on the mean scores of two raters. A significant difference between the radiological evaluation of ASL-MRI and DSC-MRI was observed only for ASL images with moderate ATT severity (30%-65%). The perfusion assessment showed ASL-MRI tending more towards hyperperfusion than DSC-MRI in the case of moderate ATT artifacts. In addition, there was a significant difference between the prediction of tumor progression with ASL-MRI and the final outcome in the case of severe ATT artifacts (McNemar test, p = 0.041). Despite using ASL imaging parameters close to the recommended settings, ATT artifacts frequently occur in patients with treated brain tumors. Those artifacts could hinder the radiological evaluation of ASL-MRI data and the detection of true disease progression, potentially affecting treatment decisions for patients with glioblastoma.

Serum and cerebrospinal fluid neurofilament light chain and glial fibrillary acid protein levels in early and advanced stages of cerebral amyloid Angiopathy.

BACKGROUND: Neurofilament light chain (NFL) is a biomarker for neuroaxonal damage and glial fibrillary acidic protein (GFAP) for reactive astrocytosis. Both processes occur in cerebral amyloid angiopathy (CAA), but studies investigating the potential of NFL and GFAP as markers for CAA are lacking. We aimed to investigate NFL and GFAP as biomarkers for neuroaxonal damage and astrocytosis in CAA. METHODS: For this cross-sectional study serum and cerebrospinal fluid (CSF) samples were collected between 2010 and 2020 from controls, (pre)symptomatic Dutch-type hereditary (D-CAA) mutation-carriers and participants with sporadic CAA (sCAA) from two prospective CAA studies at two University hospitals in the Netherlands. NFL and GFAP levels were measured with Simoa-assays. The association between NFL and GFAP levels and age, cognitive performance (MoCA), CAA-related MRI markers (CAA-CSVD-burden) and Aß40 and Aß42 levels in CSF were assessed with linear regression adjusted for confounders. The control group was divided in age < 55 and ≥55 years to match the specific groups. RESULTS: We included 187 participants: 28 presymptomatic D-CAA mutation-carriers (mean age 40 years), 29 symptomatic D-CAA participants (mean age 58 years), 59 sCAA participants (mean age 72 years), 33 controls < 55 years (mean age 42 years) and 38 controls ≥ 55 years (mean age 65 years). In presymptomatic D-CAA, only GFAP in CSF (7.7*103pg/mL vs. 4.4*103pg/mL in controls; P<.001) was increased compared to controls. In symptomatic D-CAA, both serum (NFL:26.2pg/mL vs. 12.5pg/mL; P=0.008, GFAP:130.8pg/mL vs. 123.4pg/mL; P=0.027) and CSF (NFL:16.8*102pg/mL vs. 7.8*102pg/mL; P=0.01 and GFAP:11.4*103pg/mL vs. 7.5*103pg/mL; P<.001) levels were higher than in controls and serum levels (NFL:26.2pg/mL vs. 6.7pg/mL; P=0.05 and GFAP:130.8pg/mL vs. 66.0pg/mL; P=0.004) were higher than in pre-symptomatic D-CAA. In sCAA, only NFL levels were increased compared to controls in both serum (25.6pg/mL vs. 12.5pg/mL; P=0.005) and CSF (20.0*102pg/mL vs 7.8*102pg/mL; P=0.008). All levels correlated with age. Serum NFL correlated with MoCA (P=0.008) and CAA-CSVD score (P<.001). NFL and GFAP in CSF correlated with Aß42 levels (P=0.01/0.02). CONCLUSIONS: GFAP level in CSF is an early biomarker for CAA and is increased years before symptom onset. NFL and GFAP levels in serum and CSF are biomarkers for advanced CAA.

Recommendations for quantitative cerebral perfusion MRI using multi-timepoint arterial spin labeling: Acquisition, quantification, and clinical applications.

Accurate assessment of cerebral perfusion is vital for understanding the hemodynamic processes involved in various neurological disorders and guiding clinical decision-making. This guidelines article provides a comprehensive overview of quantitative perfusion imaging of the brain using multi-timepoint arterial spin labeling (ASL), along with recommendations for its acquisition and quantification. A major benefit of acquiring ASL data with multiple label durations and/or post-labeling delays (PLDs) is being able to account for the effect of variable arterial transit time (ATT) on quantitative perfusion values and additionally visualize the spatial pattern of ATT itself, providing valuable clinical insights. Although multi-timepoint data can be acquired in the same scan time as single-PLD data with comparable perfusion measurement precision, its acquisition and postprocessing presents challenges beyond single-PLD ASL, impeding widespread adoption. Building upon the 2015 ASL consensus article, this work highlights the protocol distinctions specific to multi-timepoint ASL and provides robust recommendations for acquiring high-quality data. Additionally, we propose an extended quantification model based on the 2015 consensus model and discuss relevant postprocessing options to enhance the analysis of multi-timepoint ASL data. Furthermore, we review the potential clinical applications where multi-timepoint ASL is expected to offer significant benefits. This article is part of a series published by the International Society for Magnetic Resonance in Medicine (ISMRM) Perfusion Study Group, aiming to guide and inspire the advancement and utilization of ASL beyond the scope of the 2015 consensus article.

Temporal Ordering of Biomarkers in Dutch-Type Hereditary Cerebral Amyloid Angiopathy.

BACKGROUND: The temporal ordering of biomarkers for cerebral amyloid angiopathy (CAA) is important for their use in trials and for the understanding of the pathological cascade of CAA. We investigated the presence and abnormality of the most common biomarkers in the largest (pre)symptomatic Dutch-type hereditary CAA (D-CAA) cohort to date. METHODS: We included cross-sectional data from participants with (pre)symptomatic D-CAA and controls without CAA. We investigated CAA-related cerebral small vessel disease markers on 3T-MRI, cerebrovascular reactivity with functional 7T-MRI (fMRI) and amyloid-ß40 and amyloid-ß42 levels in cerebrospinal fluid. We calculated frequencies and plotted biomarker abnormality according to age to form scatterplots. RESULTS: We included 68 participants with D-CAA (59% presymptomatic, mean age, 50 [range, 26-75] years; 53% women), 53 controls (mean age, 51 years; 42% women) for cerebrospinal fluid analysis and 36 controls (mean age, 53 years; 100% women) for fMRI analysis. Decreased cerebrospinal fluid amyloid-ß40 and amyloid-ß42 levels were the earliest biomarkers present: all D-CAA participants had lower levels of amyloid-ß40 and amyloid-ß42 compared with controls (youngest participant 30 years). Markers of nonhemorrhagic injury (>20 enlarged perivascular spaces in the centrum semiovale and white matter hyperintensities Fazekas score, ≥2, present in 83% [n=54]) and markers of impaired cerebrovascular reactivity (abnormal BOLD amplitude, time to peak and time to baseline, present in 56% [n=38]) were present from the age of 30 years. Finally, markers of hemorrhagic injury were present in 64% (n=41) and only appeared after the age of 41 years (first microbleeds and macrobleeds followed by cortical superficial siderosis). CONCLUSIONS: Our results suggest that amyloid biomarkers in cerebrospinal fluid are the first to become abnormal in CAA, followed by MRI biomarkers for cerebrovascular reactivity and nonhemorrhagic injury and lastly hemorrhagic injury. This temporal ordering probably reflects the pathological stages of CAA and should be taken into account when future therapeutic trials targeting specific stages are designed.

Identification of Distinct Brain MRI Phenotypes and Their Association With Long-Term Dementia Risk in Community-Dwelling Older Adults.

BACKGROUND AND OBJECTIVES: Individual brain MRI markers only show at best a modest association with long-term occurrence of dementia. Therefore, it is challenging to accurately identify individuals at increased risk for dementia. We aimed to identify different brain MRI phenotypes by hierarchical clustering analysis based on combined neurovascular and neurodegenerative brain MRI markers and to determine the long-term dementia risk within the brain MRI phenotype subgroups. METHODS: Hierarchical clustering analysis based on 32 combined neurovascular and neurodegenerative brain MRI markers in community-dwelling individuals of the Age-Gene/Environment Susceptibility Reykjavik Study was applied to identify brain MRI phenotypes. A Cox proportional hazards regression model was used to determine the long-term risk for dementia per subgroup. RESULTS: We included 3,056 participants and identified 15 subgroups with distinct brain MRI phenotypes. The phenotypes ranged from limited burden, mostly irregular white matter hyperintensity (WMH) shape and cerebral atrophy, mostly irregularly WMHs and microbleeds, mostly cortical infarcts and atrophy, mostly irregularly shaped WMH and cerebral atrophy to multiburden subgroups. Each subgroup showed different long-term risks for dementia (min-max range hazard ratios [HRs] 1.01-6.18; mean time to follow-up 9.9 ± 2.6 years); especially the brain MRI phenotype with mainly WMHs and atrophy showed a large increased risk (HR 6.18, 95% CI 3.37-11.32). DISCUSSION: Distinct brain MRI phenotypes can be identified in community-dwelling older adults. Our results indicate that distinct brain MRI phenotypes are related to varying long-term risks of developing dementia. Brain MRI phenotypes may in the future assist in an improved understanding of the structural correlates of dementia predisposition.

Fluid biomarkers in cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) is a type of cerebrovascular disorder characterised by the accumulation of amyloid within the leptomeninges and small/medium-sized cerebral blood vessels. Typically, cerebral haemorrhages are one of the first clinical manifestations of CAA, posing a considerable challenge to the timely diagnosis of CAA as the bleedings only occur during the later disease stages. Fluid biomarkers may change prior to imaging biomarkers, and therefore, they could be the future of CAA diagnosis. Additionally, they can be used as primary outcome markers in prospective clinical trials. Among fluid biomarkers, blood-based biomarkers offer a distinct advantage over cerebrospinal fluid biomarkers as they do not require a procedure as invasive as a lumbar puncture. This article aimed to provide an overview of the present clinical data concerning fluid biomarkers associated with CAA and point out the direction of future studies. Among all the biomarkers discussed, amyloid ß, neurofilament light chain, matrix metalloproteinases, complement 3, uric acid, and lactadherin demonstrated the most promising evidence. However, the field of fluid biomarkers for CAA is an under-researched area, and in most cases, there are only one or two studies on each of the biomarkers mentioned in this review. Additionally, a small sample size is a common limitation of the discussed studies. Hence, it is hard to reach a solid conclusion on the clinical significance of each biomarker at different stages of the disease or in various subpopulations of CAA. In order to overcome this issue, larger longitudinal and multicentered studies are needed.