Since the various contrast-weighted MR images of a given anatomy contain redundant information, one contrast can be used to guide the reconstruction of another undersampled contrast acquired subsequently in the same session. To solve this reconstruction problem leveraging multi-contrast side information, several end-to-end learning-based guided reconstruction methods have been proposed. However, a key challenge is the requirement for large paired training datasets comprising raw k-space data and aligned reference images. We propose a modular plug-and-play approach, which requires no k-space training data and relies solely on partially paired image-domain datasets. In this approach, a content/style model of two-contrast MR data is first learned from a purely image-domain dataset and subsequently applied as a plug-and-play operator in iterative reconstruction. The disentanglement of content and style allows explicit representation of contrast-independent and contrast-specific factors. Consequently, incorporating prior information into the reconstruction reduces to a simple replacement operation on the aliased content of the estimated image using high-quality content derived from the reference scan. Combining this so-called content consistency operation with an MR data consistency step, followed by a corrective procedure for the content estimate, yields an iterative scheme. We name this novel approach PnP-CoSMo. This approach, by design, offers cross-contrast generalizability and provides an explanatory framework based on the shared and non-shared generative factors underlying the two given contrasts. We explore various aspects of PnP-CoSMo, including interpretability and convergence, via simulations. Furthermore, its practicality is demonstrated on the public NYU fastMRI DICOM dataset, showing equivalent or superior quality and greater generalizability compared to end-to-end methods. On two in-house multi-coil datasets, PnP-CoSMo enabled up to 32.6% greater acceleration over non-guided plug-and-play reconstruction at given SSIM.

Enlarged perivascular spaces (PVS) in the centrum semiovale are an important marker of Cerebral Amyloid Angiopathy (CAA) and are thought to reflect brain clearance dysfunction. However, the current golden standard for assessing PVS is limited to a unilateral, single slice, qualitative analysis, which has the disadvantage of a strong ceiling effect. We aim to introduce a whole-brain PVS volume fraction (PVSvf) measurement to assess cross-sectional and longitudinal PVSvf differences between pre-symptomatic and symptomatic Dutch-type CAA (D-CAA) mutation carriers and similar-age controls. PVSvf was assessed with a Frangi-vesselness filter-based, segmentation tool developed in-house and was compared cross-sectionally in 70 participants (28 symptomatic D-CAA, 17 pre-symptomatic D-CAA, 10 controls > 50 years, 17 controls ≤ 50 years) and longitudinally in 40 participants (16 symptomatic D-CAA, 13 pre-symptomatic D-CAA, 11 controls combined from both age groups). We found a higher baseline PVSvf in symptomatic D-CAA compared to controls ≤ 50 years (p < 0.0001, 95% CI [-0.051, -0.025]) and controls > 50 years (p < 0.0001, 95% CI [-0.042, -0.016]), in pre-symptomatic D-CAA compared to controls ≤ 50 years (p = 0.023, 95% CI [-0.035, -0.002]), and in controls > 50 years compared to controls ≤ 50 years (p < 0.001, 95% CI [0.004, 0.014]). We found no group differences in PVSvf change over time. The introduction of this quantitative measure of PVS volume in D-CAA showed cross-sectional differences already in pre-symptomatic D-CAA, indicating increased PVSvf in the early stages of D-CAA. We did not observe longitudinal differences over a four-year follow-up when analyzed at group level.

WMH shape is associated with long-term risk for dementia after 10 years in community-dwelling older adults. The current study aimed to investigate the association of WMH shape and decline in three cognitive domains over five years' time in community-dwelling older adults. The association of baseline WMH shape (solidity, convexity, concavity index, fractal dimension, and eccentricity) and cognitive decline over 5.2 ± 0.3 years (domains: memory, executive function, and processing speed) was investigated using linear regression models in the Age, Gene/Environment Susceptibility-Reykjavik (AGES) study (n = 2493). A more irregular shape of periventricular/confluent WMH was related to cognitive decline in the memory domain, the executive function domain, and the processing speed domain over five years (p < 0.05). No associations were found between deep WMH shape and decline in the cognitive domains. These findings show that WMH shape patterns may be indicative of relatively short-term cognitive decline in community-dwelling older adults. This supports the evidence of WMH shape being a valuable marker that may be used to assess and predict cognitive outcome related to cerebrovascular disease progression.

Many neurological diseases are characterized by the accumulation of toxic proteins in the brain. This accumulation has been associated with improper clearance from the parenchyma. Recent discoveries highlighted perivascular spaces, which are cerebrospinal fluid (CSF)-filled spaces, as the channels of brain clearance. The forces driving CSF mobility within perivascular spaces are still debated. Here we present a noninvasive, CSF-specific magnetic resonance imaging technique (CSF-Selective T2-prepared REadout with Acceleration and Mobility-encoding) that enables detailed in vivo measurement of CSF mobility in humans, down to the level of perivascular spaces located around penetrating vessels, which is close to protein production sites. We find region-specific drivers of CSF mobility and demonstrate that CSF mobility can be increased by entraining vasomotion. Furthermore, we find region-specific CSF mobility alterations in patients with cerebral amyloid angiopathy, a brain disorder associated with clearance impairment. The availability of this technique opens up avenues to investigate the impact of CSF-mediated clearance in neurodegeneration and sleep.

BACKGROUND AND PURPOSE: Delayed postcontrast FLAIR MRI can be used to visualize endolymphatic hydrops (EH) and their herniation into the semicircular canals (SCCs), which has been linked to impaired caloric function. However, the prevalence and anatomic distribution of EH herniation and its clinical relevance remains unclear. The purpose of this study is to investigate the frequency and localization of EH herniation into the SCCs in patients with primary hydropic ear disease (HED) and to correlate these findings with clinical parameters.MATERIALS AND METHODS: This was a retrospective study evaluating 409 patients with MRI-confirmed primary HED for the presence and anatomic location of EH herniation into the SCCs. Findings were correlated with the severity of cochleovestibular EH, vertiginous symptoms, audiometric data, and caloric test results.RESULTS: EH herniation into the SCCs was identified in 172 (42%) of patients with primary HED. The most frequent site of herniation was the nonampullated limb of the horizontal SCC (hSCC) (n=174), followed by the common limb of the posterior and superior SCCs (pSCC and sSCC, respectively) (n=114). EH herniation was significantly associated with a prolonged disease duration and a higher grade of vestibular and cochlear EH (P < .001 for all 3 analyses). Caloric testing revealed that EH herniation into the hSCC (hSCC-herniation) was associated with a higher incidence of vestibular hypofunction (P = .002) and a reduced maximum slow phase velocity (SPVmax) of the evoked nystagmus, compared with patients without hSCC-herniation (P < .001).CONCLUSIONS: EH herniation predominantly occurs in the nonampullated limb of the hSCC and is associated with prolonged disease duration, greater severity of EH, and a more pronounced impairment of caloric function.

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.

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 β, 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.

White matter hyperintensity (WMH) shape is associated with long-term dementia risk in community-dwelling older adults, however, the underlying structural correlates of this association are unknown. We therefore aimed to investigate the association between baseline WMH shape and cerebrovascular disease progression over time in community-dwelling older adults. The association of WMH shape and cerebrovascular disease markers was investigated using linear and logistic regression models in the Age, Gene/Environment Susceptibility-Reykjavik (AGES) study (n = 2297; average time to follow-up: 5.2 years). A more irregular shape of periventricular/confluent WMH at baseline was associated with a larger increase in WMH volume, and with occurrence of new subcortical infarcts, new microbleeds, new enlarged perivascular spaces, and new cerebellar infarcts at the 5.2-year follow-up (all p < 0.05). Furthermore, less elongated and more irregularly shaped deep WMHs were associated with a larger increase in WMH volume, and new cortical infarcts at follow-up (p < 0.05). A less elongated shape of deep WMH was associated with new microbleeds at follow-up (p < 0.05). Our findings show that WMH shape may be indicative of the type of cerebrovascular disease marker progression. This underlines the significance of WMH shape to aid in the assessment of cerebrovascular disease progression.

Peak width of skeletonized mean diffusivity (PSMD) is an emerging diffusion-MRI based marker to study subtle early alterations to white matter microstructure. We assessed PSMD over the clinical continuum in Dutch-type hereditary CAA (D-CAA) and its association with other CAA-related MRI-markers and cognitive symptoms. We included (pre)symptomatic D-CAA mutation-carriers and calculated PSMD from diffusion-MRI data. Associations between PSMD-levels, cognitive performance and CAA-related MRI-markers were assessed with linear regression models. We included 59 participants (25/34 presymptomatic/symptomatic; mean age 39/58 y). PSMD-levels increased with disease severity and were higher in symptomatic D-CAA mutation-carriers (median [range] 4.90 [2.77–9.50]mm2/s × 10−4) compared with presymptomatic mutation-carriers (2.62 [1.96–3.43]mm2/s × 10−4) p = <0.001. PSMD was positively correlated with age, CAA-SVD burden on MRI (adj.B [confidence interval] = 0.42 [0.16–0.67], p = 0.002), with number of cerebral microbleeds (adj.B = 0.30 [0.08–0.53], p = 0.009), and with both deep (adj.B = 0.46 [0.22–0.69], p = <0.001) and periventricular (adj.B = 0.38 [0.13–0.62], p = 0.004) white matter hyperintensities. Increasing PSMD was associated with decreasing Trail Making Test (TMT)-A performance (B = −0.42 [−0.69–0.14], p = 0.04. In D-CAA mutation-carriers microstructural white matter damage is associated with disease phase, CAA burden on MRI and cognitive impairment as reflected by a decrease in information processing speed. PSMD, as a global measure of alterations to the white matter microstructure, may be a useful tool to monitor disease progression in CAA.

Highlights CSF-mobility can be measured in humans down to the level of perivascular spaces surrounding penetrating vessels using CSF-STREAM In perivascular spaces surrounding penetrating vessels, the cardiac and respiratory cycles have similar effects on CSF-mobility Entraining vasomotion at 0.1 Hz can drive CSF-mobility in humans CSF-mobility is altered in patients with cerebral amyloid angiopathy Abstract Many neurological diseases are characterized by the accumulation of toxic proteins in the brain. This accumulation has been associated with improper clearance from the parenchyma. Recent discoveries highlighted perivascular spaces, which are cerebrospinal fluid (CSF)-filled spaces, as the channels of brain clearance. The forces driving CSF-mobility within perivascular spaces are still debated. Here, we present a new, non-invasive, CSF-specific magnetic resonance imaging technique (CSF-STREAM), that enables detailed in vivo measurement of CSF-mobility in humans, for the first time down to the level of perivascular spaces located around penetrating vessels, i.e. close to protein production sites. We find region-specific drivers for CSF-mobility and demonstrate that CSF-mobility can be increased by entraining vasomotion. Furthermore, we found region-specific CSF-mobility alterations in patients with cerebral amyloid angiopathy, a brain disorder associated with clearance impairment. The availability of this new technique opens up avenues to investigate the impact of CSF-mediated clearance in neurodegeneration and sleep.

Objective Despite the widespread recognition of the importance of artificial intelligence (AI) in healthcare, its implementation is often limited. This article aims to address this implementation gap by presenting insights from an in-depth case study of an organisation that approached AI implementation with a holistic approach. Materials and methods We conducted a longitudinal, qualitative case study of the implementation of AI in radiology at a large academic medical centre in the Netherlands for three years. Collected data consists of 43 days of work observations, 30 meeting observations, 18 interviews and 41 relevant documents. Abductive reasoning was used for systematic data analysis, which revealed three change initiative themes responding to specific AI implementation challenges. Results This study identifies challenges of implementing AI in radiology at different levels and proposes a holistic approach to tackle those challenges. At the technology level, there is the issue of multiple narrow AI applications with no standard use interface; at the workflow level, AI results allow limited interaction with radiologists; at the people and organisational level, there are divergent expectations and limited experience with AI. The case of Southern illustrates that organisations can reap more benefits from AI implementation by investing in long-term initiatives that holistically align both social and technological aspects of clinical practice. Conclusion This study highlights the importance of a holistic approach to AI implementation that addresses challenges spanning technology, workflow, and organisational levels. Aligning change initiatives between these different levels has proven to be important to facilitate wide-scale implementation of AI in clinical practice. Critical relevance statement Adoption of artificial intelligence is crucial for future-ready radiological care. This case study highlights the importance of a holistic approach that addresses technological, workflow, and organisational aspects, offering practical insights and solutions to facilitate successful AI adoption in clinical practice. Key points 1. Practical and actionable insights into successful AI implementation in radiology are lacking. 2. Aligning technology, workflow, organisational aspects is crucial for a successful AI implementation 3. Holistic approach aids organisations to create sustainable value through AI implementation. Graphical Abstract

INTRODUCTION:We aimed to investigate the association between white matter hyperintensity (WMH) shape and volume and the long-term dementia risk in community-dwelling older adults. METHODS:Three thousand seventy-seven participants (mean age: 75.6 ± 5.2 years) of the Age Gene/Environment Susceptibility (AGES)-Reykjavik study underwent baseline 1.5T brain magnetic resonance imaging and were followed up for dementia (mean follow-up: 9.9 ± 2.6 years). RESULTS:More irregular shape of periventricular/confluent WMH (lower solidity (hazard ratio (95% confidence interval) 1.34 (1.17 to 1.52), p < .001) and convexity 1.38 (1.28 to 1.49), p < .001); higher concavity index 1.43 (1.32 to 1.54), p < .001) and fractal dimension 1.45 (1.32 to 1.58), p < .001)), higher total WMH volume (1.68 (1.54 to 1.87), p < .001), higher periventricular/confluent WMH volume (1.71 (1.55 to 1.89), p < .001), and higher deep WMH volume (1.17 (1.08 to 1.27), p < .001) were associated with an increased long-term dementia risk. DISCUSSION:WMH shape markers may in the future be useful in determining patient prognosis and may aid in patient selection for future preventive treatments in community-dwelling older adults.

White matter hyperintensity (WMH) shape was recently introduced as a novel small vessel disease (SVD) marker that may provide a more detailed characterization of WMH than volume alone. We aimed to investigate the association between baseline WMH shape and cerebrovascular disease progression over 5 years. A more irregular shape of periventricular/confluent and deep WMH at baseline is associated with increased progression of WMH volume. Moreover, a more irregular shape of periventricular/confluent WMH was associated with occurrence of new microbleeds and new subcortical infarcts at follow-up. Our findings indicate that a more irregular WMH shape is associated with SVD progression.

Background:Ménière's disease (MD) is a chronic inner ear disorder with a multifactorial etiology. Decreased visualization of the endolymphatic duct (ED) and sac (ES) is thought to be associated with MD, although controversy exists about whether this finding is specific to MD. Recent literature has revealed that two distinct ES pathologies, developmental hypoplasia and epithelial degeneration, can be distinguished in MD using the angular trajectory of the vestibular aqueduct (ATVA) or ED-ES system as a radiographic surrogate marker. It has been suggested that these two subtypes are associated with distinct phenotypical features. However, the clinical differences between the ATVA subtypes require further validation.Research objective:The objective of this study is to investigate whether (1) non-visualization of the ED-ES system is a discriminative radiological feature for MD in a cohort of vertigo-associated pathologies (VAPs) and whether (2) different angular trajectories of the ED-ES system in MD are associated with distinguishable clinical features.Setting:The study was conducted in the Vertigo Referral Center (Haga Teaching Hospital, The Hague, the Netherlands).Methods:We retrospectively assessed 301 patients (187 definite MD and 114 other VAPs) that underwent 4h-delayed 3D FLAIR MRI. We evaluated (1) the visibility of the ED-ES system between MD and other VAP patients and (2) measured the angular trajectory of the ED-ES system. MD patients were stratified based on the angular measurements into αexit ≤ 120° (MD-120), αexit 120°-140° (MD-intermediate), or αexit ≥ 140° (MD-140). Correlations between ATVA subgroups and clinical parameters were evaluated.Results:Non-visualization of the ED-ES system was more common in definite MD patients compared with other VAPs (P < 0.001). Among definite MD patients, the MD-140 subtype demonstrated a longer history of vertigo (P = 0.006), a higher prevalence of bilateral clinical disease (P = 0.005), and a trend toward a male preponderance (p = 0.053). No significant differences were found between ATVA subgroups regarding the presence or severity of auditory symptoms, or the frequency of vertigo attacks.Conclusion:Non-visualization of the ED-ES system is significantly associated with MD. Among MD patients with a visible ED-ES system, we demonstrated that the MD-140 subtype is associated with a longer disease duration, a higher prevalence of bilateral MD, and a trend toward a male preponderance.

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 combined hierarchical clustering analysis based on neurodegenerative and neurovascular brain MRI markers in community-dwelling individuals. Within each of these brain MRI phenotype subgroups, we determined the long-term dementia risk. A hierarchical clustering analysis based on combined brain MRI markers in community-dwelling individuals of the Age-Gene/Environment Susceptibility (AGES) Reykjavik Study (n = 3056) was applied to identify different brain MRI phenotypes. Brain MRI markers used in the hierarchical clustering analysis were brain volumes for the estimation of brain atrophy, WMH markers (volume and shape), brain infarcts, microbleeds, and enlarged perivascular spaces. We identified 14 distinct subgroups of individuals with different brain MRI phenotypes (figure 1 and figure 2). The brain MRI phenotypes of the subgroups ranged from limited burden (subgroup (S) 12), mostly atrophy and infarcts (S14), mostly irregularly shaped WMH and atrophy (S3) to a multi-burden subgroup (S2). These subgroups had a different long-term risk for dementia (mean time to follow-up: 9.9 ± 2.6 years; hazard ratio ranging from 4.1 (95%-CI: 3.19-13.40) to 13.8 (95%-CI: 4.28-44.37); see figure 3); especially the multi-burden brain MRI phenotype showed an increased risk compared to the reference group (HR: 13.8 (95%-CI: 4.28-44.37)). Our results indicate that distinct brain MRI phenotypes are related to different long-term risks of developing dementia. Brain MRI phenotypes may assist in an improved understanding of the structural correlates of dementia predisposition. These findings may in the future be useful to determine patient prognosis and may aid in patient selection for future treatment studies.

Cerebral amyloid angiopathy (CAA) is a disease caused by the accumulation of the amyloid-beta protein and is a major cause of intracerebral hemorrhage (ICH) and vascular dementia in the elderly. The presence of the amyloid-beta protein in the vessel wall may induce a chronic state of cerebral inflammation by activating astrocytes, microglia, and pro-inflammatory substances. Minocycline, an antibiotic of the tetracycline family, is known to modulate inflammation, gelatinase activity, and angiogenesis. These processes are suggested to be key mechanisms in CAA pathology. Our aim is to show the target engagement of minocycline and investigate in a double-blind placebo-controlled randomized clinical trial whether treatment with minocycline for 3 months can decrease markers of neuroinflammation and of the gelatinase pathway in cerebrospinal fluid (CSF) in CAA patients. The BATMAN study population consists of 60 persons: 30 persons with hereditary Dutch type CAA (D-CAA) and 30 persons with sporadic CAA. They will be randomized for either placebo or minocycline (15 sporadic CAA/15 D-CAA minocycline, 15 sporadic CAA/15 D-CAA placebo). At t = 0 and t = 3 months, we will collect CSF and blood samples, perform a 7-T MRI, and collect demographic characteristics. The results of this proof-of-principle study will be used to assess the potential of target engagement of minocycline for CAA. Therefore, our primary outcome measures are markers of neuroinflammation (IL-6, MCP-1, and IBA-1) and of the gelatinase pathway (MMP2/9 and VEGF) in CSF. Secondly, we will look at the progression of hemorrhagic markers on 7-T MRI before and after treatment and investigate serum biomarkers. ClinicalTrials.gov NCT05680389. Registered on January 11, 2023

The underlying mechanisms of the association between cardiovascular risk factors and a higher white matter hyperintensity (WMH) burden are unknown. We investigated the association between cardiovascular risk factors and advanced WMH markers in 155 non-demented older adults (mean age: 71 +/- 5 years). The association between cardiovascular risk factors and quantitative MRI-based WMH shape and volume markers were examined using linear regression analysis. Presence of hypertension was associated with a more irregular shape of periventricular/confluent WMH (convexity (B (95 % CI)): -0.12 (-0.22--0.03); concavity index: 0.06 (0.02-0.11)), but not with total WMH volume (0.22 (-0.15-0.59)). Presence of diabetes was associated with deep WMH volume (0.89 (0.15-1.63)). Body mass index or hyperlipidemia showed no association with WMH markers. In conclusion, different cardiovascular risk factors seem to be related to a distinct pattern of WMH shape markers in non-demented older adults. These findings may suggest that different underlying cardiovascular pathological mechanisms lead to different WMH MRI phenotypes, which may be valuable for early detection of individuals at risk for stroke and dementia.

Background: Hemorrhagic and ischemic magnetic resonance imaging lesions as well as the more recently described decrease in vasomotor reactivity have been suggested as possible biomarkers for cerebral amyloid angiopathy (CAA). Analyses of these markers have been primarily cross-sectional during the symptomatic phase of the disease, with little data on their longitudinal progression, particularly in the presymptomatic phase of the disease when it may be most responsive to treatment. We used the unique opportunity provided by studying Dutch-type hereditary cerebral amyloid angiopathy (D-CAA) to determine longitudinal progression of CAA biomarkers during the presymptomatic as well as the symptomatic phase of the disease. Methods: In this longitudinal case-control study, magnetic resonance imaging markers and cognitive performance were assessed at baseline and after ≈4 years in 10 presymptomatic and 6 symptomatic D-CAA mutation carriers and 20 control subjects. These magnetic resonance imaging markers included hemorrhagic and ischemic manifestations, measurements of cerebral blood flow, and vasomotor reactivity to visual stimulation. Results: In presymptomatic D-CAA mutations carriers, vasomotor reactivity showed a decline over time for blood-oxygen-level–dependent amplitude (P=0.011) and prolongation of time to peak (P<0.001). In contrast, no significant changes in hemorrhagic markers, ischemic markers, cerebral blood flow, and cognition were found. In symptomatic D-CAA mutation carriers, the number of intracerebral hemorrhages increased over the 4-year period (P=0.007). Conclusions: Our findings indicate that in the presymptomatic phase of D-CAA, cerebrovascular reactivity measured by the blood-oxygen-level–dependent amplitude and time to peak to visual stimulation progressively worsens and can thus be regarded as a disease progression marker. In the symptomatic phase, the most salient marker of progression appears to be recurrent intracerebral hemorrhage.