Background/Objectives: Quantifying cerebrovascular reactivity (CVR) is essential for stroke risk assessment in patients with Moyamoya Angiopathy (MMA). Breath-hold functional MRI (bh-fMRI) is an easily implementable method to assess CVR. Determining the optimal time period of the BOLD signal for analyzing the best bh-fMRI data quality remains an open question. Methods: A retrospective analysis of 46 bh-fMRI data sets of MMA patients was conducted. The percentage BOLD signal changes were evaluated at different time periods (time point of the maximum cerebellar signal peak (TPcereb. max) ± 0 s, TPcereb. max ± 1 s, TPcereb. max ± 2 s, TPcereb. max ± 3 s, TPcereb. max ± 4 s, TPcereb. max ± 5 s). The agreement between the bh-fMRI maps and [15O]water PET maps was independently and consensually rated on a 4-point Likert scale (1 = poor, 2 = moderate, 3 = good, 4 = excellent) and compared with the Friedman test. The inter-rater agreement was calculated separately for each time period using quadratic weighted Cohen's kappa κw. Results: The selected time period had a significant impact on the agreement between bh-fMRI and [15O]water PET (χ2(5) = 79.448, p < 0.001, W = 0.345). Short time periods of TPcereb.max ± 0 s or TPcereb.max ±1 s demonstrated the highest level of concordance between bh-fMRI and [15O]water PET (median = 3.5 for TPcereb.max ± 0 s; median = 3 for TPcereb.max ± 1 s, modus = 4 in both cases). The agreement between bh-fMRI and [15O]water PET was significantly higher when evaluating time periods of TPcereb.max ± 0 s than when evaluating all time periods ≥ TPcereb. max ± 2 s. The inter-rater agreement was almost perfect for all time periods except one (TPcereb. max ± 1 s). Conclusions: Short time periods should be selected when evaluating CVR with bh-fMRI, as this study suggests a high level of validity in comparison to [15O]water PET.

Extracranial-intracranial (EC-IC) bypass surgery within the middle cerebral artery (MCA) territory is the gold standard for treating Moyamoya patients once hemodynamic insufficiency is confirmed. Although the anterior (ACA) and posterior cerebral arteries (PCA) are frequently involved, revascularization of these territories is not yet part of the standard treatment regimen; most centers focus exclusively on the MCA. Our approach, however, targets all hemodynamically compromised regions by providing tailored, multi-territorial revascularizations. Indications for additional ACA and/or PCA bypasses are determined by advanced imaging, such as PET-CT or CO2-triggered breath-hold MRI (bh-fMRI), to precisely evaluate cerebrovascular reserve. Here, we present the results of the first large case series focusing on non-MCA revascularization in adult Moyamoya patients. A total of 233 Moyamoya patients were analyzed, of whom 66 (28.3

BACKGROUND:Assessment of cerebrovascular reserve capacity (CVRC) is central to treatment planning in adult Moyamoya disease. [15O]-water-PET with acetazolamide challenge (PET-ACZ) serves as the reference standard but is resource-intensive and not universally available, whereas breathhold BOLD MRI (bh-fMRI) may offer a practical noninvasive alternative for screening and triage. METHODS:This retrospective diagnostic accuracy study compared bh-fMRI and PET-ACZ in 67 adult MMD patients (1072 ROIs across 402 supratentorial vascular territories) to determine correlation and clinically useful MRI thresholds for impaired cerebrovascular reserve. Data were analyzed using Pearson's correlation and ROC curves (STARD-compliant). Cerebellum-normalized percent signal change (CN-PSC) was referenced against PET-ACZ < 66% for pathological CVRC. RESULTS:Supratentorial territories showed strong correlation (r = 0.71, 95%CI 0.62-0.80). Optimal diagnostic threshold was <28.2% CN-PSC on bh-fMRI (Youden index; sensitivity 83.8%, specificity 80.9%, AUROC = 0.87); screening threshold < 60% CN-PSC yielded sensitivity 94.6% and NPV 91.1%. No patient factors (age, Suzuki stage, etc.) influenced agreement (univariate/multivariate analyses). CONCLUSIONS:Bh-fMRI supplements PET-ACZ as a screening and diagnostic tool for cerebrovascular reserve impairment in adult MMD. PET remains the reference standard for confirmation, especially in intermediate or discordant cases, and the proposed thresholds (<30% CN-PSC: impaired CVRC; 30-60%: confirm with PET-ACZ; >60%: monitor) require prospective validation before routine decision-making use.

Introduction: The posterior circulation is frequently overlooked when managing patients with moyamoya angiopathy, particularly the non-Asian population. This study aimed to identify the presence of angiopathy in the posterior cerebral artery (PCA), its patterns, and the consequences thereof in a paediatric cohort. METHODS:Retrospective clinical data, MRI scans, and cerebral angiograms of all patients referred to a single centre for cerebral revascularization were analysed for PCA involvement. Angiographic patterns of PCA involvement were defined. Associated stroke burden was evaluated using general estimation equation regression models adjusting for prespecified potential confounder age at onset, right or left laterality, and involvement of anterior circulation. RESULTS:PCA involvement was observed in 37% of 122 patients and was identified to be either proximal (proximal P1 segment, P1-posterior communicating artery [Pcomm] segment) or distal (Pcomm-P2 segment and distal P2 segment and beyond). Distal P2 (32%) and involvement of the entire PCA (26%) were most frequently observed. The odds of having any stroke (anterior distribution, i.e., anterior cerebral artery, middle cerebral artery, or posterior distribution, i.e., PCA) was five times higher (odds ratio [OR] 5.0, 95% CI [2.3, 10.9], p < 0.0001) when PCA was involved compared to without PCA involvement. Distal PCA involvement was observed in 59% of children <2 years of age. The OR of stroke in the PCA distribution with distal PCA involvement compared to proximal involvement was 4.1 (95% CI [0.9, 19.0], p = 0.07). The OR of anterior distribution stroke with Pcomm involvement versus no Pcomm involvement was 6.2 (95% CI [1.0, 37.2], p = 0.05). CONCLUSION:Involvement of the PCA in moyamoya children is highlighted. This may be proximal, distal, or along the entire course of the PCA and is strongly associated with overall stroke. The odds of PCA territory strokes is higher with distal PCA involvement, while involvement of the Pcomm plays a more important role in anterior stroke. Younger children are at higher risk of PCA stroke. .

Moyamoya disease (MMD) may lead to perfusion deficits, stroke and brain atrophy in the long-term. Our aim was to analyse whole-brain volumetry of a large cohort of Moyamoya disease patients compared to healthy controls. 3D T1w MRI sequences of adult Moyamoya disease patients treated at our centre between 2016 and 2022 without prior revascularization were analysed for whole-brain volumetry (AssemblyNet) and compared age-controlled to healthy controls. A total of 133 different regions of interest were examined retrospectively for each patient separately by localization, structure and tissue type. All segmentations were subjected to automated and manual quality control. After quality control, 149 hemispheres from 80 Moyamoya disease patients were compared to 258 hemispheres from 129 healthy controls. A significant brain volume loss was observed in Moyamoya disease patients with increasing age, with the greatest reduction seen in bilaterally affected patients with Suzuki grade >3. As direct signs of brain atrophy, significant differences were seen across all regions of interests, emphasized in cortical grey matter with a reduction of 4.4% (95% CI 2.7-6.1%; P < 0.001) in patients aged 30-45 years and 3.4% (95% CI 2.1-4.7%; P < 0.001) aged 46-60 years. As indirect sign for atrophy, external CSF spaces increased up to 26.4% (95% CI 17.0-35.9%; P < 0.001) for 30-45 years and 28.4% (95% CI 17.1-39.7%; P < 0.001) for 46-60 years compared to healthy controls. Infratentorial, significant volume loss was observed for patients aged 46-60 years with 11.6% for cerebellar white matter (95% CI 3.7-19.5%; P = 0.0025) and with 8.5% (95% CI 3.5-13.5%; P = 0.0006) for the brainstem, likely due to secondary neurodegeneration. Moyamoya disease patients >45 year without ischaemia also had significantly less grey matter and white matter volume, with accordingly enlarged CSF spaces. Moyamoya disease may lead to significant differences in brain volume of local and global regions of interest as a sign of brain atrophy, even in the absence of infarctions. These findings might be useful for the understanding of the disease burden and in decision-making for timely revascularization.

Introduction: The middle meningeal artery (MMArt) is considered to be an important collateral in moyamoya angiopathy; however, an in-depth analysis of the underlying mechanisms directing this collateral formation is missing. The aim of this study was to analyze patterns of activation of MMArt in pediatric patients along with identifying factors influencing these collateral pathways. Methods: Retrospective clinical and angiographic data of a pediatric moyamoya cohort managed at a single center were analyzed. Angiographic staging, MMArt activation, and collateral supply via posterior cerebral artery (PCA) were evaluated on cerebral angiograms. Stroke burden was evaluated using cerebral MRI. Associations with angiographic staging, stroke burden, and PCA collateral supply were determined. Results: MMArt activation was observed in 49% of patients (n = 101). MMArt anterior division was activated more frequently (31% of all hemispheres). MMArt formed collaterals mostly to the frontal brain. Higher odds of activation of MMArt were observed in advanced anterior angiographic stages (stages 4-5) (OR 4.22, p < 0.001), higher posterior angiographic stages (stages 1-2) (OR 5.75, p < 0.001), longer duration of disease (OR 1.33, p = 0.014), and in cases showing collateral supply from the PCA (OR 3.39, p < 0.003). Age at symptom onset, stroke burden, and type of angiopathy (moyamoya disease/syndrome) were not associated with MMArt activation. Conclusion: The MMArt serves as a crucial collateral in pediatric moyamoya, particularly to the frontal lobes. Increased MMArt activation is seen in advanced angiopathy with prolonged disease duration and PCA-derived collaterals. Stroke burden and angiopathy subtype do not appear to influence MMArt activation.

Objective: In moyamoya disease (MMD), the internal carotid and proximal cerebral arteries narrow, potentially leading to stroke or hemorrhage from fragile collaterals. Disease activity and progression may be detected by contrast-enhanced (CE) high-resolution (HR) vessel wall imaging (CE-VWI) on T1-weighted MRI. However, this imaging approach needs standardization for the evaluation of signal intensity and longitudinal reproducibility. Methods: MMD patients with at least two separate CE-VWI examinations on the same and on different scanners were included. Signal intensity of the vessel wall, pituitary stalk, and temporal lobe white matter were measured and normalized using manually selected regions of interest. Intraindividual longitudinal reproducibility of MRI was analyzed and the clinical course was correlated with vessel wall enhancement data. Results: Eighty-seven patients were analyzed. Primary analysis included 60 patients with two or more CE-VWI measurements (n = 129) with median 14.8 months between examinations (range: 2–36 months) on the same scanner. Intraindividual variation in pituitary stalk enhancement (positive control) and temporal lobe white matter enhancement (negative control) showed median signal variability of 20.5% and 17.5%, respectively. The pituitary-to-temporal lobe signal intensity ratio remained stable over time (p = 0.843) with 9.4% median variability. Correlation analysis revealed a significant positive association between pituitary and temporal lobe signal changes (ρ = 0.717, p < 0.001). A total of 75% of patients showed vessel wall contrast enhancement with fluctuating signal intensity over approximately 15.9 months, likely depicting disease activity. Conclusions: CE-VWI is important for screening disease activity in moyamoya patients. Our findings demonstrate longitudinal intraindividual reproducibility when normalized to pituitary stalk, enabling quantified evaluation of disease progression through longitudinal vessel wall contrast-enhancement changes.

Before revascularization, moyamoya patients require hemodynamic evaluation. In this study, we evaluated the scoring system Prior Infarcts, Reactivity and Angiography in Moyamoya Disease (PIRAMID). We also devised a new scoring system, MRI-Based Assessment of Risk for Stroke in Moyamoya Angiopathy (MARS-MMA), and compared the scoring systems with respect to the capability to predict impaired [15O]water PET cerebral perfusion reserve capacity (CPR). We evaluated 69 MRI, 69 DSA and 38 [15O]water PET data sets. The PIRAMID system was validated by ROC curve analysis with neurological symptomatology as a dependent variable. The components of the MARS-MMA system and their weightings were determined by binary logistic regression analysis. The comparison of PIRAMID and MARS-MMA was performed by ROC curve analysis. The PIRAMID score correlated well with the symptomatology (AUC = 0.784). The MARS-MMA system, including impaired breath-hold-fMRI, the presence of the Ivy sign and arterial wall contrast enhancement, correlated slightly better with CPR impairment than the PIRAMID system (AUC = 0.859 vs. 0.827, Akaike information criterion 140 vs. 146). For simplified clinical use, we determined three MARS-MMA grades without loss of diagnostic performance (AUC = 0.855). The entirely MRI-based MARS-MMA scoring system might be a promising tool to predict the risk of stroke.

BACKGROUND:Concentric vessel-wall contrast enhancement (VW-CE) of the terminal carotid artery and its proximal branches may be linked to ischemic strokes, disease activity and progression in Moyamoya disease (MMD). The objective of this retrospective cohort study is to analyze the association between VW-CE and perioperative acute ischemic stroke (PAIS) occurring within 24 h after revascularization. METHODS:All previously untreated MMD patients who required revascularization and who had undergone preoperative MRI with VW-CE-sequences were included. PAIS was detected by CT and/or diffusion-weighted MRI sequences within 24 h postoperatively. RESULTS:Of the 110 patients included (female-to-male ratio: 2.7:1, median age: 45.1 (16.6-69.2); n = 247 revascularizations), a priori VW-CE was present in 67.3% (mean time from MRI to first surgery: 86 days ± 82 days). PAIS occurred in five patients undergoing primary revascularization (PAIS rate per revascularization: 2.1%), all of whom had a preoperative pathological VW-CE in the vascular segment corresponding to the stroke area. Two (40%) incidents of PAIS occurred in revascularized territory, while three (60%) occurred in non-revascularized vascular territory. In each case, the supplying artery exhibited VW-CE, indicating disease activity. No additional PAIS occurred during subsequent revascularizations in cases of multistage procedures (n = 38), such as ACA or PCA revascularization as a second step. CONCLUSIONS:Preoperative VW-CE in one or more vascular segments may be a marker for postoperative stroke in the respective vascular territory at the time of revascularization. VW-CE imaging should be routinely performed when planning revascularization in MMD. If VW-CE is found, strict perioperative monitoring of these high-risk patients should be performed to achieve the best results possible.

Moyamoya disease (MMD) is a rare stenoocclusive cerebral vasculopathy often treated by neurosurgical revascularization using extracranial-intracranial bypasses to prevent ischemic or hemorrhagic events. Little is known about the vascular risk profile of adult MMD patients compared to the general population. We therefore analyzed 133 adult MMD patients and compared them with data from more than 22,000 patients from the German Health Update database. Patients with MMD showed an age- and sex-adjusted increased prevalence of arterial hypertension, especially in women between 30 and 44 years and in patients of both sexes between 45 and 64 years. Diabetes mellitus was diagnosed significantly more frequently in MMD patients with increasing age, whereas the vascular risk profile in terms of obesity, nicotine and alcohol consumption was similar to that of the general population. Antihypertensive medication was changed one year after surgical revascularization in 67.5% of patients with a tendency towards dose reduction in 43.2% of all patients. After revascularization, physicians need to be aware of a high likelihood of changes in arterial hypertension and should adjust all other modifiable systemic vascular risk factors to achieve the best treatment possible.

BACKGROUND AND OBJECTIVES:The underlying pathophysiological cause of moyamoya angiopathy (MMA) is still unclear. High-resolution vessel wall imaging has become a useful tool. The aim was to study vessel wall contrast-enhancement (VW-CE) as an imaging marker to predict disease progression in MMA. METHODS:Patients with MMA, who had undergone serial contrast-enhanced high-resolution MRI with concomitant and follow-up digital subtraction angiography, were analyzed retrospectively. VW-CE was semiquantified by measurement of the signal intensity of the vessel wall in in contrast-enhanced high-resolution MRI. A comparative quotient with the contrast-intensity of the pituitary stalk was calculated and graded accordingly from grade 1 to 5. VW-CE status was correlated with disease status, stroke, cerebrovascular reactivity in CO2-triggered blood-oxygen level-dependent MRI, angiographic disease progression, revascularization surgery, and follow-up imaging. RESULTS:Forty eight patients met the inclusion criteria. N = 56 MRI and digital subtraction angiography time-intervals were evaluated for 12 vessel sections per hemisphere each (N = 1344). N = 38 (79%) patients showed VW-CE and N = 10 (21%) did not. VW-CE was only observed in the terminal internal carotid artery and the proximal circle of Willis (N = 96/1344). Notably, patients with VW-CE significantly more often presented with acute infarction in the concomitant MRI. The incidence of angiographically proven disease progression was significantly associated with the incidence of VW-CE, and time to disease progression was earlier in higher grades of VW-CE compared with lower grades. CONCLUSION:VW-CE is a semiquantifiable marker for disease activity in patients with MMA and associated with disease progression and increased risk of stroke. VW-CE analysis can be routinely performed in patients with MMA to estimate the risk for disease progression and stroke.

BACKGROUND AND OBJECTIVES: Patients with Moyamoya disease (MMD) have an above-average incidence of neuropsychological impairment and psychiatric comorbidities such as depression. Prevalence and correlation with preoperative imaging findings were identified in previous studies, and a reduced health-related quality of life (HRQOL) has been shown. This study investigates changes in neuropsychological performance and HRQOL after revascularization. METHODS: Thirty-two adult patients with MMD (23 female, 9 male; mean age 39.1 year ±14.7) with revascularization were included in this retrospective cohort study, and their results of structured neuropsychological testing were analyzed preoperatively and 1 year postoperatively. Sensorimotor deficits assessed with the National Institutes of Health Stroke Scale were considered to be possible confounders. RESULTS: Patients with preoperatively poor test results showed improvement in various items such as psychological well-being (95% CI [0.55-2.25], P = .002), vitality (95% CI [0.23-1.68], P = .007), general health perception (95% CI [0.09-1.44], P = .014), psychoticism (95% CI [−12.24 to −4.85], P < .001), and psychomotor processing speed (95% CI [0.10-1.14], P = .010), whereas the intensity of depression fell by a mean of 6.9 points (95% CI [−10.14 to −3.61], P < .001). For patients without preoperative neuropsychological or HRQOL deterioration, preservation of these functions without relevant worsening after revascularization was observed. Significant improvement in vitality, psychological well-being, psychoticism, psychomotor processing speed, and depression were also seen in patients with unchanged National Institutes of Health Stroke Scale. CONCLUSION: Chronic steno-occlusive cerebral hypoperfusion in patients with MMD not only may lead to neurological deficits but is also associated with neuropsychological impairment, reduced HRQOL, and increased depression. The results of this study show that patients with preoperative neuropsychological deterioration might benefit from revascularization surgery, whereas patients without preoperative impairment continue to remain stable postoperatively. Neuropsychological assessment should be routinely evaluated and considered a relevant variable when determining treatment for patients with MMD.

Moyamoya angiopathy (MMA) is a rare steno-occlusive condition resulting in transient ischemic attacks and strokes in children and adults. Previous studies, mainly in adult patients, suggested RNF213 as the most prevalent susceptibility gene due to an Asian founder variant. Nevertheless, the genetic landscape in early-onset European MMA patients requires further elucidation. Exome-sequencing was performed in 104 pediatric MMA patients, including three with Down syndrome, and 520 healthy controls. Rare-variant enrichment testing was performed using the R-package SKAT on the whole cohort as well as in a 100% European subset, revealing a total of 28 enriched genes. Both tests showed the most common known MMA genes (RNF213 and NF1) among the top three enriched genes, underlining the validity of our approach. Seven of the concordantly enriched genes are novel MMA candidates (ATAD2, COL18A1, NAV1, ALOX12B, KRTAP4-7, KCNJ12, and KBTBD13). De novo variants were found in NF1, RNF213, COL18A1, ECI1, and YIPF1. In summary, our study confirms RNF213 and NF1 as major susceptibility genes and suggests seven novel early-onset MMA susceptibility genes. Of special interest is the novel candidate gene COL18A1, which is involved in angiogenesis and endothelial cell proliferation, due to its potential additional role as a modifier of MMA in trisomy 21.

PURPOSE:Vessel-encoded arterial spin labeling (VE-ASL) is able to provide noninvasive information about the contribution of individual arteries to the cerebral perfusion. The aim of this study was to compare VE-ASL to the diagnostic standard digital subtraction angiography (DSA) with respect to its ability to visualize vascular territories.METHODS:In total, 20 VE-ASL and DSA data sets of 17 patients with Moyamoya angiopathy with and without revascularization surgery were retrospectively analyzed. Two neuroradiologists independently assessed the agreement between VE-ASL and DSA using a 4-point Likert scale (no- very high agreement). Additionally, grading of the vascular supply of subterritories (A1-A2, M1-M6) on the VE-ASL images and angiograms was performed. The intermodal agreement was calculated for all subterritories in total and for the subdivision into without and after revascularization (direct or indirect bypass).RESULTS:There was a very high agreement between the VE-ASL and the DSA data sets (median = 1, modus = 1) with a substantial inter-rater agreement (kw = 0.762 (95% CI 0.561-0.963)). The inter-modality agreement between VE-ASL and DSA in vascular subterritories was almost perfect for all subterritories (k = 0.899 (0.865-0.945)), in the subgroup of direct revascularized subterritories (k = 0.827 (0.738-0.915)), in the subgroup of indirect revascularized subterritories (k = 0.843 (0.683-1.003)), and in the subgroup of never revascularized subterritories (k = 0.958 (0.899-1.017)).CONCLUSION:Vessel-encoded ASL seems to be a promising non-invasive method to depict the contributions of individual arteries to the cerebral perfusion before and after revascularization surgery.

Pediatric Moyamoya Angiopathy (MMA) is a progressive intracranial occlusive arteriopathy that represents a leading cause of transient ischemic attacks and strokes in childhood. Despite this, up to now no large, exclusively pediatric MMA cohort has been subjected to systematic genetic investigation. In this study, we performed molecular karyotyping, exome sequencing and automated structural assessment of missense variants on a series of 88 pediatric MMA patients and correlated genetic, angiographic and clinical (stroke burden) findings. The two largest subgroups in our cohort consisted of RNF213 and neurofibromatosis type 1 (NF1) patients. While deleterious RNF213 variants were associated with a severe MMA clinical course with early symptom onset, frequent posterior cerebral artery involvement and higher stroke rates in multiple territories, NF1 patients had a similar infarct burden compared to non-NF1 individuals and were often diagnosed incidentally during routine MRIs. Additionally, we found that MMA-associated RNF213 variants have lower predicted functional impact compared to those associated with aortic disease. We also raise the question of MMA as a feature of recurrent as well as rare chromosomal imbalances and further support the possible association of MMA with STAT3 deficiency. In conclusion, we provide a comprehensive characterization at the genetic and clinical level of a large exclusively pediatric MMA population. Due to the clinical differences found across genetic subgroups, we propose genetic testing for risk stratification as part of the routine assessment of pediatric MMA patients.