Aging Effect, Reproducibility, and Test-Retest Reliability of a New Cerebral Amyloid Angiopathy MRI Severity Marker-Cerebrovascular Reactivity to Visual Stimulation.

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 (ß = -0.711) and prolonged time to baseline (ß = 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.

Distinct functional subnetworks of cognitive domains in older adults with minor cognitive deficits.

Although past research has established a relationship between functional connectivity and cognitive function, less is known about which cognitive domains are associated with which specific functional networks. This study investigated associations between functional connectivity and global cognitive function and performance in the domains of memory, executive function and psychomotor speed in 166 older adults aged 75-91 years (mean = 80.3 ± 3.8) with minor cognitive deficits (Mini-Mental State Examination scores between 21 and 27). Functional connectivity was assessed within 10 standard large-scale resting-state networks and on a finer spatial resolution between 300 nodes in a functional connectivity matrix. No domain-specific associations with mean functional connectivity within large-scale resting-state networks were found. Node-level analysis revealed that associations between functional connectivity and cognitive performance differed across cognitive functions in strength, location and direction. Specific subnetworks of functional connections were found for each cognitive domain in which higher connectivity between some nodes but lower connectivity between other nodes were related to better cognitive performance. Our findings add to a growing body of literature showing differential sensitivity of functional connections to specific cognitive functions and may be a valuable resource for hypothesis generation of future studies aiming to investigate specific cognitive dysfunction with resting-state functional connectivity in people with beginning cognitive deficits.

Functional connectivity in older adults-the effect of cerebral 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.

Neurovascular coupling in early stage dementia - A case-control study.

Cerebral amyloid angiopathy (CAA) is frequently found post mortem in Alzheimer's dementia, but often undetected during life especially since in vivo hallmarks of CAA and its vascular damage become overt relatively late in the disease process. Decreased neurovascular coupling to visual stimulation has been put forward as an early MRI marker for CAA disease severity. The current study investigates the role of neurovascular coupling in AD related dementia and its early stages. We included 25 subjective cognitive impairment, 33 mild cognitive impairment and 17 dementia patients and 44 controls. All participants underwent magnetic resonance imaging of the brain and neuropsychological assessment. Univariate general linear modeling analyses were used to assess neurovascular coupling between patient groups and controls. Moreover, linear regression analyses was used to assess the associations between neurovascular coupling and cognition. Our data show that BOLD amplitude is lower in dementia (mean 0.8 ± 0.2, p = 0.001) and MCI patients (mean 0.9 ± 0.3, p = 0.004) compared with controls (mean 1.1 ± 0.2). A low BOLD amplitude was associated with low scores in multiple cognitive domains. We conclude that cerebrovascular dysfunction, most likely due CAA, is an important comorbidity in early stages of dementia and has an independent effect on cognition.

Cerebral amyloid angiopathy is associated with decreased functional brain connectivity.

Cerebral amyloid angiopathy (CAA) is a major cause of intracerebral hemorrhage and neurological decline in the elderly. CAA results in focal brain lesions, but the influence on global brain functioning needs further investigation. Here we study functional brain connectivity in patients with Dutch type hereditary CAA using resting state functional MRI. Twenty-four DNA-proven Dutch CAA mutation carriers (11 presymptomatic, 13 symptomatic) and 29 age-matched control subjects were included. Using a set of standardized networks covering the entire cortex, we assessed both within- and between-network functional connectivity. We investigated group differences using general linear models corrected for age, sex and gray matter volume. First, all mutation carriers were contrasted against control subjects and subsequently presymptomatic- and symptomatic mutation carriers against control subjects separately, to assess in which stage of the disease differences could be found. All mutation carriers grouped together showed decreased connectivity in the medial and lateral visual networks, default mode network, executive control and bilateral frontoparietal networks. Symptomatic carriers showed diminished connectivity in all but one network, and between the left and right frontoparietal networks. Presymptomatic carriers also showed diminished connectivity, but only in the frontoparietal left network. In conclusion, global brain functioning is diminished in patients with CAA, predominantly in symptomatic CAA and can therefore be considered to be a late consequence of the disease.

Genetic and environmental influences on structure of the social brain in childhood.

Prosocial behavior and empathy are important aspects of developing social relations in childhood. Prior studies showed protracted structural development of social brain regions associated with prosocial behavior. However, it remains unknown how structure of the social brain is influenced by genetic or environmental factors, and whether overlapping heritability factors explain covariance in structure of the social brain and behavior. The current study examined this hypothesis in a twin sample (aged 7-9-year; N = 512). Bilateral measures of surface area and cortical thickness of the medial prefrontal cortex (mPFC), temporo-parietal junction (TPJ), posterior superior temporal sulcus (pSTS), and precuneus were analyzed. Results showed genetic contributions to surface area and cortical thickness for all brain regions. We found additional shared environmental influences for TPJ, suggesting that this region might be relatively more sensitive to social experiences. Genetic factors also influenced parent-reported prosocial behavior (A = 45%) and empathy (A = 59%). We provided initial evidence that the precuneus shares genetically determined variance with empathy, suggesting a possible small genetic overlap (9%) in brain structure and empathy. These findings show that structure of the social brain and empathy are driven by a combination of genetic and environmental factors, with some factors overlapping for brain structure and behavior.