Sanneke van Rooden

Background: The mechanisms of early brain damage in cerebral amyloid angiopathy (CAA), a highly prevalent comorbid condition in Alzheimer's disease, are not completely understood. While current CAA diagnosis relies on late-stage MRI markers, impaired neurovascular coupling (NVC) has emerged as a promising early marker. Objective: To investigate whether early vascular changes in CAA are associated with functional brain consequences, we examined the association between NVC and various functional connectivity metrics. Methods: We analyzed MRI data from 93 older adults (71 ± 9 years old). A subgroup meeting Boston criteria v2.0 for possible or probable CAA ( n = 46) was analyzed separately to investigate associations in confirmed CAA-related pathology. NVC (time to peak, time to baseline, and BOLD amplitude) was assessed in the occipital cortex using a visual stimulation task. Functional connectivity was assessed at multiple scales using resting-state fMRI, including within ten standard networks, between individual brain regions (edgewise analysis), and across the whole brain (graph theory). Results: General linear models, adjusted for age, sex, and clinical diagnosis, showed no significant associations between NVC and global connectivity metrics (networks and graph theory). Edgewise analyses revealed limited significant localized functional connections for each NVC measure. Findings were consistent across the total sample and the CAA subgroup. Conclusions: Early CAA-related pathology is associated with localized rather than global functional connectivity. While large-scale connectivity remains preserved, edgewise analyses indicate subtle localized functional alterations. This suggests that functional connectivity disruption may originate as small-scale deficits that only progress into widespread, global impairment in advanced disease stages.

Background: Cognitive decline in Alzheimer's disease (AD) is increasingly linked to cerebrovascular dysfunction, including small vessel disease (SVD). Conventional SVD MRI markers primarily detect late-stage structural damage. Neurovascular coupling (NVC) has emerged as an early indicator of cerebrovascular function and is cross-sectionally associated with cognition, but its association with longitudinal decline remains unclear. Objective: To investigate whether baseline NVC is associated with cognitive decline over 3.5 years in individuals ranging from no cognitive complaints to memory clinic patients with subjective cognitive impairment (SCI) or mild cognitive impairment (MCI). Methods: Seventy-five participants underwent cognitive assessment and MRI, including BOLD fMRI during visual stimulation to assess NVC. Cognitive decline was analyzed as dichotomous outcome (stable versus decline; n = 75) using logistic regression and as continuous outcome for domain-specific change (z-score change; n = 69) using linear regression. Results: Lower baseline NVC was associated with global cognitive decline, both dichotomously (OR = 42.29, p = 0.017) and continuously (B = 0.45, p = 0.012). Baseline NVC was also associated with a decline in executive function (B = 0.47, p = 0.043), but not with other domain-specific decline. Among conventional SVD MRI markers, only lacunar infarcts were associated with decline (OR = 4.12, p = 0.037). Conclusions: Baseline NVC appears to be a predictor of global cognitive decline, outperforming most conventional SVD MRI markers. These findings support the potential utility of NVC as a prognostic marker of cognitive decline in early-stage AD, highlighting its promise for early intervention strategies targeting cerebrovascular dysfunction.

Background: Neurovascular coupling is a fundamental aspect of brain function by regulating cerebral blood flow in response to regional neuronal activity. Increasing evidence suggest neurovascular decoupling occurs early in the progression of Alzheimer disease (AD), potentially reflecting early vascular damage. Therefore, understanding the relationship between neurovascular coupling and established vascular risk factors for AD is essential to gain deeper insights into the vascular mechanisms underlying AD. Methods: This cross‐sectional observational study investigated the association between neurovascular coupling and vascular risk factors for AD, specifically small vessel disease magnetic resonance imaging markers, cardiovascular risk factors, and the apolipoprotein E genotype. The cohort included 119 participants diagnosed with subjective cognitive impairment, mild cognitive impairment, and AD‐related dementia, as well as individuals without cognitive complaints. Neurovascular coupling was measured by blood‐oxygen‐level‐dependent functional magnetic resonance imaging amplitude in response to visual stimulation. Results: Our findings revealed that decreased neurovascular coupling is linked to structural brain changes typically seen in small vessel disease; specifically we found an association between neurovascular coupling and white matter hyperintensities load ( β =−0.199, P =0.030) and presence of lobar intracerebral hemorrhage ( β =−0.228, P =0.011). Conclusions: This raises the suggestion that a decreased neurovascular coupling in the disease process of AD is related to comorbid small vessel disease.

Ageing is associated with functional reorganization that is mainly characterized by declining functional connectivity due to general neurodegeneration and increasing incidence of disease. Functional connectivity has been studied across the lifespan; however, there is a paucity of research within the older groups (≥75 years) where neurodegeneration and disease prevalence are at its highest. In this cross-sectional study, we investigated associations between age and functional connectivity and the influence of cerebral small vessel disease (CSVD)—a common age-related morbidity—in 167 community-dwelling older adults aged 75–91 years (mean = 80.3 ± 3.8). Resting-state functional MRI was used to determine functional connectivity within ten standard networks and calculate the whole-brain graph theoretical measures global efficiency and clustering coefficient. CSVD features included white matter hyperintensities, lacunar infarcts, cerebral microbleeds, and atrophy that were assessed in each individual and a composite score was calculated. Both main and interaction effects (age*CSVD features) on functional connectivity were studied. We found stable levels of functional connectivity across the age range. CSVD was not associated with functional connectivity measures. To conclude, our data show that the functional architecture of the brain is relatively unchanged after 75 years of age and not differentially affected by individual levels of vascular pathology.

Background: Decreased cerebrovascular reactivity, measured as changes in blood‐oxygen‐level‐dependent (BOLD) signal, is a potential new cerebral amyloid angiopathy (CAA) severity marker. Before clinical application, the effect of aging on BOLD parameters, and reproducibility and test–retest reliability of these parameters should be assessed.Purpose: Assess the effect of healthy aging on cerebrovascular reactivity (BOLD amplitude, time to peak, and time to baseline). And determine reproducibility and test–retest reliability of these parameters.Study Type: Prospective‐observational.Population: Eighty‐six healthy adults (mean age 56 years, 55% female), 10 presymptomatic D‐CAA mutation carriers (mean age 34 years, 70% female), and 10 symptomatic D‐CAA mutation carriers (mean age 54 years, 70% female).Field Strength/Sequence: 3‐T, three‐dimensional (3D) T1‐weighted MRI and gradient echo BOLD fMRI.Assessment: To assess test–retest reliability of BOLD parameters, i.e. BOLD amplitude, time to peak, and time to baseline, BOLD fMRI scans were repeated three times immediately after each other, in both controls and mutation carriers. To assess reproducibility, BOLD fMRI scans were repeated with a 3‐week interval for each subject.Statistical Tests: Linear regression analyses and two‐way mixed absolute agreement intra‐class correlation approach.Results: Healthy aging was associated with decreased BOLD amplitude (β = −0.711) and prolonged time to baseline (β = 0.236) in the visual cortex after visual stimulation Reproducibility of BOLD amplitude was excellent (ICC 0.940) in the subgroup of healthy adults. Test–retest reliability for BOLD amplitude was excellent in healthy adults (ICC 0.856–0.910) and presymptomatic D‐CAA mutation carriers (ICC 0.959–0.981). In symptomatic D‐CAA mutation carriers, test–retest reliability was poor for all parameters (ICCs < 0.5).Data Conclusion: Healthy aging is associated with decreased cerebrovascular reactivity, measured by changes in BOLD response to visual stimulation. The BOLD amplitude appears to be a robust measurement in healthy adults and presymptomatic D‐CAA mutation carriers, but not in symptomatic D‐CAA mutation carriers.

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 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.

Background and Purpose—: The aim of the present study is to explore whether using 7 Tesla magnetic resonance imaging, additional brain changes can be observed in hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) patients as compared with the established magnetic resonance imaging features of sporadic cerebral amyloid angiopathy. Methods—: The local institutional review board approved this prospective cohort study. In all cases, informed consent was obtained. This prospective parallel cohort study was conducted between 2012 and 2014. We performed T ₂ *-weighted magnetic resonance imaging performed at 7 Tesla in presymptomatic mutation carriers (n=11, mean age 35±12 years), symptomatic HCHWA-D patients (n=15, mean age 45±14 years), and in control subjects (n=29, mean age 45±14 years). Images were analyzed for the presence of changes that have not been reported before in sporadic cerebral amyloid angiopathy and HCHWA-D. Innovative observations comprised intragyral hemorrhaging and cortical changes. The presence of these changes was systematically assessed in all participants of the study. Results—: Symptomatic HCHWA-D-patients had a higher incidence of intragyral hemorrhage (47% [7/15], controls 0% [0/29], P P <0.005). In presymptomatic HCHWA-D-mutation carriers, the prevalence of none of these markers was increased compared with control subjects. Conclusions—: The presence of cortical changes and intragyral hemorrhage are imaging features of HCHWA-D that may help recognizing sporadic cerebral amyloid angiopathy in living patients.

Studies have suggested that, in subjects with subjective cognitive impairment (SCI), Alzheimer's disease (AD)‐like changes may occur in the brain. Recently, an in vivo study has indicated the potential of ultra‐high‐field MRI to visualize amyloid‐beta (Aβ)‐associated changes in the cortex in patients with AD, manifested by a phase shift on T₂*‐weighted MRI scans. The main aim of this study was to investigate whether cortical phase shifts on T₂*‐weighted images at 7 T in subjects with SCI can be detected, possibly implicating the deposition of Aβ plaques and associated iron. Cognitive tests and T₂*‐weighted scans using a 7‐T MRI system were performed in 28 patients with AD, 18 subjects with SCI and 27 healthy controls (HCs). Cortical phase shifts were measured. Univariate general linear modeling and linear regression analysis were used to assess the association between diagnosis and cortical phase shift, and between cortical phase shift and the different neuropsychological tests, adjusted for age and gender. The phase shift (mean, 1.19; range, 1.00–1.35) of the entire cortex in AD was higher than in both SCI (mean, 0.85; range, 0.73–0.99; p < 0.001) and HC (mean, 0.94; range, 0.79–1.10; p < 0.001). No AD‐like changes, e.g. increased cortical phase shifts, were found in subjects with SCI compared with HCs. In SCI, a significant association was found between memory function (Wechsler Memory Scale, WMS) and cortical phase shift (β = –0.544, p = 0.007). The major finding of this study is that, in subjects with SCI, an increased cortical phase shift measured at high field is associated with a poorer memory performance, although, as a group, subjects with SCI do not show an increased phase shift compared with HCs. This increased cortical phase shift related to memory performance may contribute to the understanding of SCI as it is still unclear whether SCI is a sign of pre‐clinical AD. Copyright © 2014 John Wiley & Sons, Ltd.