Ed Gronenschild

Increased Aortic Pulse Wave Velocity Is Associated With Silent Cerebral Small-Vessel Disease in Hypertensive Patients

Aortic stiffness predicts an excess risk of stroke, supposedly via cerebral small-vessel disease. White matter hyperintensities, silent lacunar infarcts, and brain microbleeds, manifestations of cerebral small-vessel disease on neuroimaging, may precede overt cerebrovascular disease. Therefore, we assessed whether aortic stiffness is also related to such lesions. In 167 hypertensive patients (85 men) without a history of cardiovascular or cerebrovascular disease, a mean age of 51.8±13.1 years, and untreated office blood pressure levels of 169±25/104±12 mm Hg, we determined aortic pulse wave velocity and office and ambulatory 24-hour pulse pressure (off medication), as well as the volume of white matter hyperintensities and the presence of lacunar infarcts and microbleeds using brain MRI. Linear and logistic regression analyses were performed to assess the relationships between the arterial stiffness measures and brain lesions. Aortic stiffness and pulse pressure were significantly related to each of the brain lesions in univariate analyses (P<0.05). Multivariate analyses, adjusted for age, sex, brain volume, mean arterial pressure, and heart rate, showed that a higher pulse wave velocity was significantly associated with a greater volume of white matter hyperintensities (unstandardized regression coefficient: 0.041; 95% CI: 0.005 to 0.078; P<0.05) and the presence of lacunar infarcts (odds ratio [per SD increase in pulse wave velocity]: 1.78; 95% CI: 1.06 to 2.99; P<0.05) but not with microbleeds. The models for pulse pressure failed to reach statistical significance in multivariate analyses. In conclusion, aortic stiffness is independently associated with manifestations of cerebral small-vessel disease in hypertensive patients, linking systemic large- to cerebral small-artery disease.

The effects of FreeSurfer Version, workstation type, and Macintosh Operating System Version on anatomical volume and cortical thickness measurements.

FreeSurfer is a popular software package to measure cortical thickness and volume of neuroanatomical structures. However, little if any is known about measurement reliability across various data processing conditions. Using a set of 30 anatomical T1-weighted 3T MRI scans, we investigated the effects of data processing variables such as FreeSurfer version (v4.3.1, v4.5.0, and v5.0.0), workstation (Macintosh and Hewlett-Packard), and Macintosh operating system version (OSX 10.5 and OSX 10.6). Significant differences were revealed between FreeSurfer version v5.0.0 and the two earlier versions. These differences were on average 8.8±6.6% (range 1.3–64.0%) (volume) and 2.8±1.3% (1.1–7.7%) (cortical thickness). About a factor two smaller differences were detected between Macintosh and Hewlett-Packard workstations and between OSX 10.5 and OSX 10.6. The observed differences are similar in magnitude as effect sizes reported in accuracy evaluations and neurodegenerative studies. The main conclusion is that in the context of an ongoing study, users are discouraged to update to a new major release of either FreeSurfer or operating system or to switch to a different type of workstation without repeating the analysis; results thus give a quantitative support to successive recommendations stated by FreeSurfer developers over the years. Moreover, in view of the large and significant cross-version differences, it is concluded that formal assessment of the accuracy of FreeSurfer is desirable.

The accuracy and reproducibility of a global method to correct for geometric image distortion in the x-ray imaging chain

A method to correct for geometric image distortion in the x-ray imaging chain, so-called dewarping, has been developed. A global two-dimensional polynomial model of which the degree is optimized is used. The performance of the method has been tested in a number of experiments using images of a plate with a 1 cm spaced wire grid put against the input screen of the x-ray image intensifier (14/17/27 cm). Both offline cine film and online video images were analyzed. The accuracy of the dewarp method was derived from the acquired images and from computer-simulated distorted images. The robustness and reproducibility of the dewarp method was evaluated by means of imaging the grid in various random orientations. Three parameters describing the behavior of the algorithm were considered. One is the reproducibility of the location of a dewarped position. The second parameter is the reproducibility of the distance between two adjacent dewarped positions as a measure of the reproducibility of the size of an object under investigation. The third parameter is the reproducibility of the pixel size in the plane of the calibration plate. The major results are: the reproducibility of the location of a dewarped position was 0.01-0.04 mm for cine film and 0.04-0.07 mm for video images. The coefficient of variation of the distance between two dewarped positions was 0.04%-0.11% for cine film and 0.15%-0.18% for video images. The dewarp algorithm turned out to be fast and accurate and the distortion was removed over the whole image field down to a low random residual level. It was found that a random orientation of the grid did not affect the assessment of the distortion nor its correction. The dewarp method proved to be intrinsically robust and highly reliable. Time instability of the imaging chain was the main source of variability in the dewarp results.

Reduced Cortical Thickness as an Outcome of Differential Sensitivity to Environmental Risks in Schizophrenia

BACKGROUND The etiology of schizophrenia is thought to involve differential-likely genetically mediated-sensitivity to environmental exposures. However, examination of differential sensitivity in models of psychopathologic constructs is subject to bias because psychopathology itself may distort exposure assessment. The use of neuroimaging phenotypes, conversely, may provide unbiased evidence for differential sensitivity to environmental exposures. This study examined the impact of two environmental exposures associated with both schizophrenia and magnetic resonance imaging (MRI) cerebral alterations in models of cerebral cortical thickness. METHODS T1-weighted MRI scans were acquired from 88 patients with schizophrenia, 98 healthy siblings at higher than average genetic risk for schizophrenia, and 87 control subjects. Freesurfer software was used to measure cortical thickness for 68 brain regions. Associations between 1) cortical thickness and 2) cannabis use and developmental trauma were examined. RESULTS A significant group × developmental trauma interaction (χ(2) = 9.65, p = .01), as well as a significant group × cannabis interaction (χ(2) = 6.04, p = .05) was apparent, indicating differential sensitivity of the patient group, which displayed stronger reductions of cortical thickness for both exposures. A similar pattern was found in the sibling-control comparison for cannabis. For developmental trauma, siblings did not differ from control subjects, displaying an increase in cortical thickness with higher levels of trauma. CONCLUSIONS The findings suggest that schizophrenia and its genetic liability are associated with differential cerebral cortical sensitivity to developmental environmental exposures such as cannabis. Gene-environment interactions may underlie some of the brain alterations observed in patients with schizophrenia and their relatives.

Ambulatory blood pressure, asymptomatic cerebrovascular damage and cognitive function in essential hypertension

Prolonged exposure to elevated blood pressure (BP) can lead to both structural (white matter lesions (WML) or infarctions) and functional changes in the brain. We studied in previously diagnosed essential hypertensive individuals if diurnal BP variation and ambulatory BP (ABP) profile (daytime, night time and 24-h BP averages) were related to evidence of WML, the presence of ‘silent’ infarcts, and cognitive performance. A group of 86 patients (mean age 57.4±10 years, range 40–80) were first screened for hypertension-related organ damage and underwent 24-h ABP monitoring, magnetic resonance imaging (MRI) of the brain, and a comprehensive neurocognitive assessment. Age and ABP profile were related to more periventricular, but not subcortical, WML and to presence of lacunar infarctions on MRI. After correction for demographical group differences, no association was found between night time dipping of BP on the one hand and both WML load and cognitive parameters (verbal memory, sensorimotor speed, cognitive flexibility) on the other. The presence of lacunar infarctions, however, predicted lower performance on verbal memory. Furthermore, daytime and 24-h pulse pressure averages were associated with pWML, whereas systolic BP and mean arterial pressure (MAP) for daytime, night-time and 24-h periods were higher in patients with lacunar infarctions. Notwithstanding the large variability of WML in this sample, the evidence of a connection between diurnal BP variation and early target organ damage in the brain was not convincing. However, the ABP profile may be predictive of cerebral lesion type.

Multiple Indicators of Age-related Differences in Cerebral White Matter and the Modifying Effects of Hypertension

We investigated differences associated with age and hypertension, a common risk factor for vascular disease, in three aspects of white matter integrity--gross regional volumes of the white matter, volume of the white matter hyperintensities (WMH) and diffusion properties. We acquired MRI scans on 93 adult volunteers (age 50-77 years; 36 with diagnosis of hypertension or elevated blood pressure), and obtained all measures in seven brain regions: frontal, temporal, parietal and occipital white matter, and the genu, body and splenium of the corpus callosum. The results demonstrated robust age-related differences in diffusion-based indices of cerebral white matter integrity and age-related increase in the WMH volume, but no age differences in the gross regional volumes of the white matter. Hypertension was associated with decline in fractional anisotropy, and exacerbated age differences in fractional anisotropy more than those in the volume of WMH. These findings indicate that of all examined measures, diffusion-based indices of white matter integrity may be the most sensitive indicators of global and regional declines and vascular damage in the aging brain.

Correction for geometric image distortion in the x‐ray imaging chain: Local technique versus global technique

The local technique to correct for geometric image distortion in the x-ray imaging chain has been implemented and compared with the global correction technique reported previously. Three local correction models were considered, all applied locally within each quadrilateral cell bounded by four adjacent points on a distorted 1.0 cm spaced rectilinear calibration grid. Model 1 uses bilinear interpolation between the correction vectors derived at the four vertices. In Models 2 and 3 a polynomial mapping from distorted to undistorted positions is applied, with Model 2 representing a linear six-parameter correction and Model 3 a nonlinear eight-parameter correction. Both techniques have been analyzed in depth concerning their accuracy. To this end, experimental (35 mm cine film and online video) and computer simulated distorted images of the calibration grid were used. Both radial and sigmoidal distortions were considered in the simulations. The main results are summarized as follows. The accuracy of the local technique depends upon the position within each quadrilateral cell and upon the local direction of the distortion gradient, contrary to the global technique. The accuracy of the local technique decreases with increasing radial as well as sigmoidal distortion. For the global technique only the latter dependency applies. The relationship of the accuracy with the pixel size is different for all models. Finally, the local technique is more sensitive to noise than the global technique. The reproducibility of the correction methods has been evaluated by means of imaging the calibration grid in various orientations with respect to the input screen of the image intensifier. The local technique turns out to reproduce a factor of 4-10 worse than the global technique. In summary, Model 1 is the worst method in all respects, whereas Model 3 is slightly better than Model 2. However, the global technique is to be preferred because it outperforms the local technique on all relevant issues.

Associations of ambulatory blood pressure levels with white matter hyperintensity volumes in hypertensive patients

Objective High daytime and nighttime blood pressure (BP) levels, and apparently also an abnormal nocturnal BP dip, coincide with a greater extent of cerebral white matter hyperintensities (WMHs). We assessed the relationship between ambulatory BP and volumes of WMH, and distinguished between periventricular and deep WMH because of their supposedly different cause. Methods A total of 210 hypertensive patients (106 men) without cardiovascular and cerebrovascular disease, with a mean age of 52.5 ± 12.5 years, and untreated office BP levels of 170 ± 24/104 ± 12 mmHg underwent duplicate 24-h ambulatory blood pressure monitoring (off medication) and brain MRI to quantify the WMHs (total, periventricular, and deep) and brain volumes. We performed linear regression analyses to relate the mean 24-h, awake, and asleep BPs, and the relative nocturnal BP dip to the different volumes of WMHs, while adjusting for age, sex, brain volume, and vascular risk factors. Results Higher 24-h, awake, and asleep BP levels were continuously, without distinct thresholds, and independently associated with a greater volume of total (all P < 0.001), periventricular (P < 0.001), and, to a lesser extent, deep (P < 0.05) WMHs. Nocturnal BP dipping was not related to the volume of WMHs. Conclusion Higher 24-h, daytime, and nighttime BP levels are independently associated with WMH volumes.

Functional integration of parietal lobe activity in early Alzheimer disease.

Objectives: Parietal lobe dysfunction is an important characteristic of early Alzheimer disease (AD). Functional studies have shown conflicting parietal activation patterns indicative of either compensatory or dysfunctional mechanisms. This study aimed at examining activation differences in early AD using a visuospatial task. We focused on functional characteristics of the parietal lobe and examined compensation or disconnection mechanisms by combining a fMRI task with effective connectivity measures from Granger causality mapping (GCM). Methods: Eighteen male patients with amnestic mild cognitive impairment (aMCI) and 18 male cognitively healthy older individuals were given a mental rotation task with different rotation angles. Results: There were no behavioral group differences on the fMRI task. Separate measurements at each angle revealed widespread activation group differences. More temporal and parietal activation in the higher angle condition was observed in patients with aMCI. The parametric modulation, which identifies regions associated with increasing angle, confirmed these results. The GCM showed increased connectivity within the parietal lobe and between parietal and temporal regions in patients with aMCI. Decreased connectivity was found between the inferior parietal lobule and posterior cingulate gyrus. Connectivity patterns correlated with memory performance scores in patients with aMCI. Conclusions: Our results demonstrate increased effective temporoparietal connectivity in patients with aMCI, while maintaining intact behavioral performance. This might be a compensational mechanism to counteract a parietal-posterior cingulate gyrus disconnection. These findings highlight the importance of connectivity changes in the pathophysiology of AD. In addition, effective connectivity may be a promising method for evaluating interventions aimed at the promotion of compensatory mechanisms.

Age differences in speed of processing are partially mediated by differences in axonal integrity

Advanced age is associated with declines in brain structure and in cognitive performance, but it is unclear which aspects of brain aging mediate cognitive declines. We inquired if individual differences in white matter integrity contribute to age differences in two cognitive domains with established vulnerability to aging: executive functioning and speed of processing. The participants were healthy volunteers aged 50-81, some of whom had elevated blood pressure, a known vascular risk factor. Using latent variable analyses, we examined whether age differences in regional white matter integrity mediated age-related differences in executive functions and speed of processing. Although diffusion-related latent variables showed stronger age differences than white matter volumes and white matter hyperintensity volumes, only one of them was significantly associated with cognitive performance. Smaller linear anisotropy partially mediated age-related reduction in speed of processing. The effect was significant in posterior (temporal-parietal-occipital) but not anterior (frontal) region, and appeared stronger for cognitive rather than reaction time measures of processing speed. The presence of hypertensive participants did not affect the results. We conclude that in healthy adults, deterioration of axonal integrity and ensuing breech of connectivity may underpin age-related slowing of information processing.