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Background: Orthostatic hypotension (OH) is associated with an increased risk of dementia, potentially attributable to cerebral hypoperfusion. We investigated which patterns and characteristics of OH are related to cognition or to potentially underlying structural brain injury in hemodynamically impaired patients and healthy reference participants., Methods: Participants with carotid occlusive disease or heart failure, and reference participants from the Heart-Brain Connection Study underwent OH measurements, neuropsychological assessment and brain MRI. We analyzed the association between OH, global cognitive functioning, white matter hyperintensity (WMH) volume and brain parenchymal fraction with linear regression. We stratified by participant group, severity and duration of OH, chronotropic incompetence and presence of orthostatic symptoms., Results: Of 337 participants (mean age 67.3 ± 8.8 years, 118 (35.0%) women), 113 (33.5%) had OH. Overall, presence of OH was not associated with cognitive functioning (β: -0.12 [-0.24-0.00]), but we did observe worse cognitive functioning in those with severe OH (≥ 30/15 mmHg; β: -0.18 [-0.34 to -0.02]) and clinically manifest OH (β: -0.30 [-0.52 to -0.08]). These associations did not differ significantly by OH duration or chronotropic incompetence, and were similar between patient groups and reference participants. Similarly, both severe OH and clinically manifest OH were associated with a lower brain parenchymal fraction, and severe OH also with a somewhat higher WMH volume., Conclusions: Severe OH and clinically manifest OH are associated with worse cognitive functioning. This supports the notion that specific patterns and characteristics of OH determine its impact on brain health., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Arterial spin labeling (ASL) perfusion magnetic resonance imaging (MRI) may be used to determine brain regions at risk for ischemia in patients with moyamoya vasculopathy and to identify patients who may benefit from surgical revascularization. We aimed to investigate whether 1) the severity of moyamoya is related to the presence of leptomeningeal collaterals and cerebrovascular reactivity (CVR), 2) the presence of collaterals and ivy sign reflects disturbed CVR, and 3) arterial transit artefacts (ATAs) and ivy sign reflect the presence of collaterals., Methods: We determined severity of moyamoya on digital subtraction angiography (DSA) according to the modified Suzuki classification in 20 brain regions and scored regional tissue revascularization using a 4-point scale. Regional CVR and ATAs were assessed on ASL perfusion MRI, ivy sign on fluid attenuation inversion recovery MRI., Results: In 11 patients (median age 36 years; 91% female), we studied 203 regions. ATAs were associated with the presence of collaterals on DSA (P < 0.01). Of all regions with clearly visible collateral vessels on DSA, however, only 24% had ATAs. Ivy sign was not related to the presence or absence of collaterals nor to CVR. In 10% of regions with good vascularization on DSA, CVR was poor or showed steal., Conclusions: ATAs were associated with the presence of collaterals on DSA. Although DSA vascularization scores correlated with CVR, 10% of regions with good vascularization on DSA had absent CVR or steal on ASL-MRI. DSA and ivy sign did not provide adequate information on the hemodynamic status of brain tissue in patients with moyamoya vasculopathy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Knowledge of spatiotemporal patterns of language network changes may help in predicting outcome in aphasic stroke patients. Here we assessed language function and performed functional MRI four times during one year to measure language network activation and cerebrovascular reactivity (with breath-holding) in twelve left-hemispheric stroke patients, of whom two dropped out before the final measurement, and eight age-matched controls. Language outcome was related to increase of activation in left and right posterior inferior temporal gyrus over the first year, while activation increase in right inferior frontal gyrus was inversely correlated to language recovery. Outcome prediction improved by addition of early language-induced activation of the left posterior inferior temporal gyrus to a regression model with baseline language performance as first predictor. Variations in language-induced activation in right inferior frontal gyrus were primarily related to differences in vascular reactivity. Furthermore, several language-activation changes could not be linked to alterations in language proficiency nor vascular reactivity, and were assumed to be caused by unspecified intersession variability. In conclusion, early functional neuroimaging improves outcome prediction of aphasia after stroke. Controlling for cerebrovascular reactivity and unspecified intersession variability may result in more accurate assessment of the relationship between activation pattern shifts and function after stroke.

Background: Hemodynamic balance in the heart-brain axis is increasingly recognized as a crucial factor in maintaining functional and structural integrity of the brain and thereby cognitive functioning. Patients with heart failure (HF), carotid occlusive disease (COD), and vascular cognitive impairment (VCI) present themselves with complaints attributed to specific parts of the heart-brain axis, but hemodynamic changes often go beyond the part of the axis for which they primarily seek medical advice. The Heart-Brain Study hypothesizes that the hemodynamic status of the heart and the brain is an important but underestimated cause of VCI. We investigate this by studying to what extent hemodynamic changes contribute to VCI and what the mechanisms involved are. Here, we provide an overview of the design and protocol., Methods: The Heart-Brain Study is a multicenter cohort study with a follow-up measurement after 2 years among 645 participants (175 VCI, 175 COD, 175 HF, and 120 controls). Enrollment criteria are the following: 1 of the 3 diseases diagnosed according to current guidelines, age ≥50 years, no magnetic resonance contraindications, ability to undergo cognitive testing, and independence in daily life. A core clinical dataset is collected including sociodemographic factors, cardiovascular risk factors, detailed neurologic, cardiac, and medical history, medication, and a physical examination. In addition, we perform standardized neuropsychological testing, cardiac, vascular and brain MRI, and blood sampling. In subsets of participants we assess Alz-heimer biomarkers in cerebrospinal fluid, and assess echocardiography and 24-hour blood pressure monitoring. Follow-up measurements after 2 years include neuropsychological testing, brain MRI, and blood samples for all participants. We use centralized state-of-the-art storage platforms for clinical and imaging data. Imaging data are processed centrally with automated standardized pipelines., Results and Conclusions: The Heart-Brain Study investigates relationships between (cardio-)vascular factors, the hemodynamic status of the heart and the brain, and cognitive impairment. By studying the complete heart-brain axis in patient groups that represent components of this axis, we have the opportunity to assess a combination of clinical and subclinical manifestations of disorders of the heart, vascular system and brain, with hemodynamic status as a possible binding factor., (© 2017 The Author(s). Published by S. Karger AG, Basel.)

Background and Purpose: Accurate long-term outcome prognostication in basilar artery occlusion strokes may guide clinical management in the subacute stage. We determine the prognostic value of the follow-up neurological examination using the National Institutes of Health stroke scale (NIHSS) and identify 24- to 48-hour NIHSS risk categories in basilar artery occlusion patients., Methods: Participants of an observational registry of radiologically confirmed acute basilar artery occlusion (BASICS [Basilar Artery International Cooperation Study]) with prospectively collected 24- to 48-hour NIHSS and 1-month modified Rankin scale scores were included. Uni- and multivariable modeling were performed to identify independent predictors of poor outcome. Predictive powers of baseline and 24- to 48-hour NIHSS for poor outcome (modified Rankin scale, 4-6) and 1-month mortality were determined by receiver operating characteristic analyses. Classification and regression tree analysis was performed to identify risk groups., Results: Three hundred seventy-six of 619 BASICS participants were included, of whom 65.4% had poor outcome. In multivariable analyses, 24- to 48-hour NIHSS (odds ratio=1.28 [1.21-1.35]), history of minor stroke (odds ratio=2.64 [1.04-6.74], time to treatment >6 hours (odds ratio=3.07 [1.35-6.99]), and age (odds ratio=1.02 [0.99-1.04]) were retained in the final model as predictors of poor outcome. Prognostic power of 24- to 48-hour NIHSS was higher than baseline NIHSS for 1-month poor outcome (area under the curve, 0.92 versus 0.75) and mortality (area under the curve, 0.85 versus 0.72). Classification and regression tree analysis identified five 24- to 48-hour NIHSS risk categories with poor outcome rates of 9.4% (NIHSS 0-4), 36% (NIHSS 5-11), 84.3% (NIHSS 12-22), 96.1% (NIHSS 23-27), and 100% (NIHSS≥28)., Conclusions: Twenty-four- to 48-hour NIHSS accurately predicts 1-month poor outcome and mortality and represents a clinically valuable prognostic tool for the care of basilar artery occlusion patients., (© 2016 American Heart Association, Inc.)

Cerebral perivascular spaces (PVS) are small physiological structures around blood vessels in the brain. MRI visible PVS are associated with ageing and cerebral small vessel disease (SVD). 7 Tesla (7T) MRI improves PVS detection. We investigated the association of age, vascular risk factors, and imaging markers of SVD with PVS counts on 7 T MRI, in 50 persons aged ≥ 40. The average PVS count ± SD in the right hemisphere was 17 ± 6 in the basal ganglia and 71 ± 28 in the semioval centre. We observed no relation between age or vascular risk factors and PVS counts. The presence of microbleeds was related to more PVS in the basal ganglia (standardized beta 0.32; p = 0.04) and semioval centre (standardized beta 0.39; p = 0.01), and white matter hyperintensity volume to more PVS in the basal ganglia (standardized beta 0.41; p = 0.02). We conclude that PVS counts on 7T MRI are high and are related SVD markers, but not to age and vascular risk factors. This latter finding may indicate that due to the high sensitivity of 7T MRI, the correlation of PVS counts with age or vascular risk factors may be attenuated by the detection of "normal", non-pathological PVS., (© The Author(s) 2016.)

Purpose: Cerebral perfusion territories are known to vary widely among individuals. This may lead to misinterpretation of the symptomatic artery in patients with ischaemic stroke to a wrong assumption of the underlying aetiology being thromboembolic or hypoperfusion. The aim of the present study was to investigate such potential misinterpretation with territorial arterial spin labelling (T-ASL) by correlating infarct location with imaging of the perfusion territory of the carotid arteries or basilar artery., Materials and Methods: 223 patients with subacute stroke underwent MRI including structural imaging scans to determine infarct location, time-of-flight MR angiography (MRA) to determine the morphology of the circle of Willis and T-ASL to identify the perfusion territories of the internal carotid arteries, and basilar artery. Infarct location and the perfusion territory of its feeding artery were classified with standard MRI and MRA according to a perfusion atlas, and were compared to the classification made according to T-ASL., Results: A total of 149 infarctions were detected in 87 of 223 patients. 15 out of 149 (10%) infarcts were erroneously attributed to a single perfusion territory; these infarcts were partly located in the originally determined perfusion territory but proved to be localised in the border zone with the adjacent perfusion territory instead. 12 out of 149 (8%) infarcts were misclassified with standard assessments and were not located in the original perfusion territory., Conclusions: T-ASL with territorial perfusion imaging may provide important additional information for classifying the symptomatic brain-feeding artery when compared to expert evaluation with MRI and MRA., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objective: To investigate the role of large vessel atherosclerosis, blood clot extent, and penumbra volume in relation to headache in ischemic stroke patients., Methods: In this cross-sectional study, we performed noncontrast CT, CT angiography (CTA), and CT perfusion (CTP) in 284 participants from the Dutch Acute Stroke Study and Leiden Stroke Cohort within 9 hours after ischemic stroke onset. We collected headache characteristics prospectively using a semi-structured questionnaire. Atherosclerosis was assessed by evaluating presence of plaques in extracranial and intracranial vessels and by quantifying intracranial carotid artery calcifications. Clot extent was estimated by the clot burden score on CTA and penumbra volume by CTP. We calculated risk ratios (RRs) with adjustments (aRR) for possible confounders using multivariable Poisson regression., Results: Headache during stroke was reported in 109/284 (38%) participants. Headache was less prevalent in patients with than in patients without atherosclerosis in the extracranial anterior circulation (35% vs 48%; RR 0.72; 95% confidence interval [CI] 0.54-0.97). Atherosclerosis in the intracranial arteries was also associated with less headache, but this association was not statistically significant. Penumbra volume (aRR 1.08; 95% CI 0.63-1.85) and clot extent (aRR 1.02; 95% CI 0.86-1.20) were not related with headache., Conclusions: Headache in the early phase of ischemic stroke tends to occur less often in patients with atherosclerosis than in patients without atherosclerosis in the large cerebral arteries. This finding lends support to the hypothesis that vessel wall elasticity is a necessary contributing factor in the occurrence of headache during acute ischemic stroke., (© 2016 American Academy of Neurology.)

Background and Purpose: Preclinical studies showed that thrombus permeability improves recombinant tissue-type plasminogen activator (r-tPA) efficacy. We hypothesize that thrombus permeability estimated from radiological imaging is associated with improved recanalization after treatment with intravenously administered r-tPA (r-tPA) and with better functional outcome., Methods: We assessed thrombus attenuation increase (TAI) in patients from the Dutch Acute Stroke Study with an occlusion of an intracranial artery on computed tomographic angiography. Patients were included within 9 hours after the stroke onset. After dichotomization of TAI as pervious or impervious, logistic regressions analyses were performed to estimate associations of intravenous r-tPA therapy with complete recanalization and with favorable functional outcome (modified Rankin Scale score of ≤2)., Results: Three hundred eight patients matched the inclusion criteria. The median TAI was 20.1 (interquartile range, 8.5-37.8) Hounsfield unit (HU). We found a significant increase in the odds of complete recanalization with increasing TAI for patients treated with intravenous r-tPA (P=0.030). One hundred thirty-one (42%) thrombi were classified as pervious with TAI of ≥23 HU. In patients with a pervious thrombus, complete recanalization was more frequent after treatment with intravenous r-tPA than after conservative treatment (odds ratio, 6.26; 95% confidence interval, 2.4-16.8; P<0.001). In patients with an impervious thrombus, the effect of intravenous r-tPA was not significant (odds ratio, 1.4; 95% confidence interval, 0.5-4.1; P=0.47). Favorable outcome was more common in patients with a pervious thrombi than without (odds ratio, 2.1; 95% confidence interval, 1.3-3.4; P=0.001)., Conclusions: Thrombus perviousness, as measured on computed tomography in the acute stage of ischemic stroke, is strongly associated with recanalization after intravenous r-tPA treatment and with favorable functional outcome., (© 2016 American Heart Association, Inc.)

Recognition memory, that is, the ability to judge whether an item has been previously encountered in a particular context, depends on two factors: discriminability and criterion setting. Discriminability draws on memory processes while criterion setting (i.e., the application of a threshold resulting in a yes/no response) is regarded as a process of cognitive control. Discriminability and criterion setting are assumed to draw on distinct anatomical structures, but definite evidence for this assumption is lacking. We applied voxel-based and region of interest-based lesion-symptom mapping to 83 patients in the acute phase of ischemic stroke to determine the anatomical correlates of discriminability and criterion setting in verbal recognition memory. Recognition memory was measured with the Rey Auditory Verbal Learning Test. Signal-detection theory was used to calculate measures for discriminability and criterion setting. Lesion-symptom mapping revealed that discriminability draws on left medial temporal and temporo-occipital structures, both thalami and the right hippocampus, while criterion setting draws on the right inferior frontal gyrus. Lesions in the right inferior frontal gyrus were associated with liberal response bias. These findings indicate that discriminability and criterion setting indeed depend on distinct anatomical structures and provide new insights in the anatomical correlates of these cognitive processes that underlie verbal recognition memory., (© 2014 Wiley Periodicals, Inc.)

Type 2 diabetes mellitus (T2DM) is associated with cognitive dysfunction and dementia. Brain imaging may provide important clues about underlying processes. This review focuses on the relationship between T2DM and brain abnormalities assessed with different imaging techniques: both structural and functional magnetic resonance imaging (MRI), including diffusion tensor imaging and magnetic resonance spectroscopy, as well as positron emission tomography and single-photon emission computed tomography. Compared to people without diabetes, people with T2DM show slightly more global brain atrophy, which increases gradually over time compared with normal aging. Moreover, vascular lesions are seen more often, particularly lacunar infarcts. The association between T2DM and white matter hyperintensities and microbleeds is less clear. T2DM has been related to diminished cerebral blood flow and cerebrovascular reactivity, particularly in more advanced disease. Diffusion tensor imaging is a promising technique with respect to subtle white matter involvement. Thus, brain imaging studies show that T2DM is associated with both degenerative and vascular brain damage, which develops slowly over the course of many years. The challenge for future studies will be to further unravel the etiology of brain damage in T2DM, and to identify subgroups of patients that will develop distinct progressive brain damage and cognitive decline., (Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.)

Cerebral small vessel disease, including microvascular lesions, is considered to play an important role in the development of type 2 diabetes mellitus (T2DM)-associated cognitive deficits. With ultra-high field MRI, microvascular lesions (e.g., microinfarcts and microbleeds) can now be visualized in vivo. For the current study, 48 nondemented older individuals with T2DM (mean age 70.3 ± 4.1 years) and 49 age-, sex-, and education-matched control subjects underwent a 7-Tesla brain MRI scan and a detailed cognitive assessment. The occurrence of cortical microinfarcts and cerebral microbleeds was assessed on fluid-attenuated inversion recovery and T1-weighted and T2*-weighted images, respectively, compared between the groups, and related to cognitive performance. Microinfarcts were found in 38% of control subjects and 48% of patients with T2DM. Microbleeds were present in 41% of control subjects and 33% of patients (all P > 0.05). The presence and number of microinfarcts or microbleeds were unrelated to cognitive performance. This study showed that microvascular brain lesions on ultra-high field MRI are not significantly more common in well-controlled patients with T2DM than in control subjects., (© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Aims: It has been suggested that in patients with type 2 diabetes mellitus (T2DM), brain atrophy is most pronounced in the hippocampus, but this has not been investigated systematically. The present pooled analysis of three studies examined if hippocampal atrophy is more prominent than global brain atrophy in patients with T2DM relative to controls., Methods: Data were derived from a cohort study of patients with vascular disease (SMART-Medea (T2DM=120; no T2DM=502)), and from two case-control studies (UDES1 (T2DM=61; controls=30) and UDES2 (T2DM=54; controls=53)). In SMART-Medea and UDES1, hippocampal volume was obtained by manual tracing on 1.5 Tesla (T) MRI scans. Total brain and intracranial volume (ICV) were determined by an automated segmentation method. In UDES2, hippocampal and total brain volume were determined by FreeSurfer and ICV by manual segmentation on 3 T MRI scans., Results: The pooled analyses, adjusted for age and sex, showed a significant negative relation between T2DM and total brain-to-ICV ratio (standardized mean difference=-1.24%, 95% CI: -1.63; -0.86), but not between T2DM and hippocampal-to-ICV ratio (0.00%, 95% CI: -0.01; 0.00) or between T2DM and hippocampal-to-total brain volume ratio (0.01%, 95% CI: -0.01; 0.02). In patients with T2DM no associations were found between brain volume measures and HbA1c or memory., Conclusion: Patients with T2DM had greater brain atrophy but not hippocampal atrophy, compared to controls. These findings do not support specific vulnerability of the hippocampus in patients with T2DM., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Visuospatial construction is a complex cognitive operation that is composed of a purely constructional component (visuoconstruction proper), and visuoperceptive, attentional, and decision-making components. The anatomical correlates of visuospatial construction and its cognitive subcomponents are poorly understood. The purpose of the present study was to determine the anatomical correlates of visuospatial construction by applying lesion-symptom mapping in a cohort of 111 patients with first-ever ischemic stroke. We employed the Rey-Osterrieth Complex Figure (ROCF) copy test and the Judgment of Line Orientation (JLO); both tests measure visuoperception, while only the ROCF has a constructional component. We first performed assumption-free voxel-based lesion-symptom mapping, which revealed large shared right hemispheric correlates for the ROCF and JLO in the frontal lobe, superior temporal lobe, and supramarginal gyrus. These shared anatomical correlates reflect the visuoperceptive component of the ROCF and JLO. Anatomical correlates were discordant in the right superior parietal lobule, and angular and middle occipital gyri: lesions in these regions were associated with poor performance on the ROCF, but not the JLO. Secondly, these findings were reproduced with a region of interest-based analysis that yielded a statistically significant correlation between infarct volume in the right inferior and superior parietal, angular and middle occipital cortices, and poor performance on the ROCF, but not the JLO. This discordance in anatomical correlates of the ROCF and JLO reflects the visuoconstructive component of the ROCF. These findings provide new insights in the anatomical correlates of the visuoperceptive and visuoconstructive components of the ROCF and provide evidence for a crucial role of the right inferior and superior parietal, angular and middle occipital gyri in visuoconstruction proper., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objectives: The objectives of this study were to explore the possibilities of 7 T brain magnetic resonance imaging to visualize perivascular spaces (PVS) and to depict their related blood vessels., Materials and Methods: Five subjects aged 19 to 27 years and 5 subjects aged 51 to 72 years were scanned. High-resolution 3-dimensional T1-, T2-, as well as T2*-weighted sequences and time-of-flight angiography were used for the visualization of PVS, veins, and perforating arteries. Three extra subjects were scanned with a 2-dimensional time-of-flight sequence tailored to visualize small arteries and veins in the semioval center. The anatomy of PVS and their spatial relation with blood vessels were examined. The number and size of PVS in the semioval center were compared between the 2 groups., Results: In the basal ganglia, PVS were connected to the basal cisterns. Prominent dilations were observed in these PVS around the lower end of the putamen. From here, they ran upward and frequently showed caliber changes along their track. In the semioval center, smoothly shaped PVS started a few millimeters below the cortex, converged and tapered toward the ventricles, and ended 1 to 2 cm before the ventricle wall. Perivascular spaces correlated spatially with lenticulostriate arteries and with perforating arteries in the semioval center, but not with veins. The mean (SD) number of PVS was larger in the older subjects (55 [14]) than in the younger subjects (22 [11]), (P = 0.004). No difference in PVS diameter was observed., Conclusions: Seven-tesla magnetic resonance imaging offers detailed 3-dimensional visualization of PVS, their morphological features, and their related perforating arteries. This may offer new opportunities to study the role of PVS in ageing and cerebral small vessel disease.

Objectives: Extracellular vesicles (EVs) and their protein levels have been identified as a potential risk marker for the development of vascular disease. In the present study, we assessed whether levels of four previously identified EV proteins (cystatin C, serpin G1, serpin F2 and CD14) are associated with cerebral white matter lesions (WMLs) and brain atrophy., Design: Cohort study; cross-sectional and prospective., Setting: Single centre, secondary and tertiary setting., Participants: 1309 patients with manifest vascular disease from the Second Manifestations of ARTerial disease-MR (SMART-MR) study, of which 994 had successful brain MRI and EV protein level measurements., Outcomes: WML and brain parenchymal fraction (BPF), as parameter for brain atrophy, at baseline and follow-up., Statistical Methods: The relationship between EV protein levels and WML volume (expressed as log transformed percentage of intracranial volume) and BPF (expressed percentage of intracranial volume) on 1.5 T brain MRI was assessed with multivariable linear regression modelling. Subsequently, the relationship between baseline EV protein levels and progression of atrophy and WML was analysed in 534 patients, in whom a follow-up MRI was obtained after 4 years., Results: Higher EV-cystatin C and EV-CD14 were significantly associated with larger WML volume (linear regression coefficient (95% CI) 0.10 log %/SD (0.04 to 0.17) and 0.14 log %/SD (0.07 to 0.20), respectively. Higher EV-CD14 was associated with more brain atrophy (-0.14%/SD; -0.27 to -0.01). Baseline EV-CD14 was significantly associated with increase of WMLs (0.11 log %/SD (0.04 to 0.18)). No relationship with EV-serpins was observed at baseline or at follow-up., Conclusions: EV proteins cystatin C and CD14 are related to cerebral WMLs and the progression of brain atrophy in patients with manifest vascular disease, potentially identifying EVs in the aetiology of structural brain changes.

While both cardiac dysfunction and progressive loss of cognitive functioning are prominent features of an aging population, surprisingly few studies have addressed the link between heart and brain function. This is probably due to the monodisciplinary approach to these problems by cardiologists, neurologists, and geriatricians. Recent data indicate that autoregulation of cerebral flow cannot always protect the brain from hypoperfusion when cardiac output is reduced or atherosclerosis is prominent. This suggests a close link between cardiac function and large vessel atherosclerosis on the one hand and brain perfusion and cognitive functioning on the other. In a national research program, we will test the hypothesis that impaired hemodynamic status of both heart and brain is an important and potentially reversible cause of vascular cognitive impairment (VCI) offering promising opportunities for treatment. Using a multidisciplinary approach, we will address the following questions: 1) To what extent do hemodynamic changes contribute to VCI? 2) What are the mechanisms involved? 3) Does improvement of the hemodynamic status lead to improvement of cognitive dysfunction? To this end we will perform clinical studies in elderly patients with clinically manifest VCI, carotid occlusive disease, or heart failure and evaluate their cardiac and large vascular function, atherosclerotic load, and cerebral perfusion with a comprehensive magnetic resonance imaging protocol and thoroughly test their cognitive function. We will also analyze epidemiological data from the Rotterdam Study.

We examined the association between brain atrophy and vascular brain lesions (i.e., white matter lesions [WMLs] or brain infarcts), alone or in combination, with decline in memory and executive functioning over 4 years of follow-up in 448 patients (57 ± 9.5 years) with symptomatic atherosclerotic disease from the Second Manifestations of ARTerial disease--Magnetic Resonance SMART-MR study. Automated brain segmentation was used to quantify volumes of total brain, ventricles, cortical gray matter, and WMLs on 1.5-T magnetic resonance imaging (MRI). Brain infarcts were rated visually. WML volume was associated with significant decline in z score of executive functioning. No independent associations between MRI measures and memory decline were found. Significant declines in z scores of memory performance and of executive functioning were observed in patients with a combination of severe atrophy (upper quartile) and most vascular brain lesions (upper quartile) compared with those with minimal atrophy (lowest quartile) and fewest vascular brain lesions (lowest quartile). Our findings suggest that in patients with symptomatic atherosclerotic disease, the combination of brain atrophy and WMLs or brain infarcts accelerates cognitive decline over 4 years., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background and Purpose: Good reliability of methods to assess the extent of ischemia in acute stroke is important for implementation in clinical practice, especially between observers with varying experience. Our aim was to determine inter- and intra-observer reliability of the 1/3 middle cerebral artery (MCA) rule and the Alberta Stroke Program Early CT Score (ASPECTS) for different CT modalities in patients suspected of acute ischemic stroke., Methods: We prospectively included 105 patients with acute neurological deficit due to suspected acute ischemic stroke within 9 hours after symptom onset. All patients underwent non-contrast CT, CT perfusion and CT angiography on admission. All images were evaluated twice for presence of ischemia, ischemia with >1/3 MCA involvement, and ASPECTS. Four observers evaluated twenty scans twice for intra-observer agreement. We used kappa statistics and intraclass correlation coefficient to calculate agreement., Results: Inter-observer agreement for the 1/3 MCA rule and ASPECTS was fair to good for non-contrast CT, poor to good for CT angiography source images, but excellent for all CT perfusion maps (cerebral blood volume, mean transit time, and predicted penumbra and infarct maps). Intra-observer agreement for the 1/3 MCA rule and ASPECTS was poor to good for non-contrast CT, fair to moderate for CT angiography source images, and good to excellent for all CT perfusion maps., Conclusion: Between observers with a different level of experience, agreement on the radiological diagnosis of cerebral ischemia is much better for CT perfusion than for non-contrast CT and CT angiography source images, and therefore CT perfusion is a very reliable addition to standard stroke imaging.

Background and Purpose: Although collateral vessels have been shown to be an important prognostic factor in acute ischemic stroke, patients with lack of collaterals on standard imaging techniques may still have good clinical outcome. We postulate that in these cases collateral vessels are present though not visible on standard imaging techniques that are based on a single time frame., Methods: This study included 40 consecutive patients with acute ischemic stroke with a large-vessel occlusion. Standard computed tomography angiography (CTA, single time frame) and CT perfusion (multiple time frames) were obtained at admission and timing-invariant (TI)-CTA was created from the CT perfusion data. Clinical outcome data (modified Rankin Scale) were assessed at 3-month follow-up. Four experienced observers independently assessed collateral status twice on both standard CTA and TI-CTA in an independent, blinded, randomized manner. Collateral status was rated as good if ≥50% and poor if <50% of collaterals were present compared with the contralateral hemisphere., Results: Collateral status was rated higher on TI-CTA (good in 84%) compared with standard CTA (good in 49%; P<0.001). Thirty-one percent of patients with poor collateral status on standard CTA still had good clinical outcome. All of those patients, however, showed good collaterals on TI-CTA. All cases with poor collateral status rated on TI-CTA had poor clinical outcome., Conclusions: Collateral vessels may not always be visible on standard single time-frame CTA because of delayed contrast arrival. Future prognostic studies in acute stroke should consider delay-insensitive techniques, such as TI-CTA, instead of standard single time-frame imaging, such as standard CTA.

Retinal microvascular changes can be visualized noninvasively and have been associated with cognitive decline and brain changes in relation to aging and vascular disease. We systematically reviewed studies, published between 1990 and November 2012, on the association between retinal microvascular changes and dementia, cognitive functioning, and brain imaging abnormalities, in the context of aging and vascular risk factors. In cross-sectional studies (k=26), retinal microvascular changes were associated with the presence of dementia (range of odds ratios (ORs) 1.17;5.57), with modest decrements in cognitive functioning in nondemented people (effect sizes -0.25;0.03), and with brain imaging abnormalities, including atrophy and vascular lesions (ORs 0.94;2.95). Longitudinal studies were more sparse (k=9) and showed no consistent associations between retinal microvascular changes and dementia or cognitive dysfunctioning 3 to 15 years later (ORs and hazard ratios 0.77;1.55). However, there were indications of prospective associations with brain imaging abnormalities ((ORs) 0.81;3.19). In conclusion, particularly in cross-sectional studies there is a correlation between retinal microvascular changes and dementia, cognitive impairment, and brain imaging abnormalities. Associations are strongest for more severe retinal microvascular abnormalities. Retinal microvascular abnormalities may offer an important window on the brain for etiological studies.

Patients with type 2 diabetes often show slowing of information processing. Disruptions in the brain white matter network, possibly secondary to vascular damage, may underlie these cognitive disturbances. The current study reconstructed the white matter network of 55 nondemented individuals with type 2 diabetes (mean age, 71 ± 4 years) and 50 age-, sex-, and education-matched controls using diffusion magnetic resonance imaging-based fiber tractography. Graph theoretical analysis was then applied to quantify the efficiency of these networks. Patients with type 2 diabetes showed alterations in local and global network properties compared with controls (P < 0.05). These structural network abnormalities were related to slowing of information processing speed in patients. This relation was partly independent of cerebrovascular lesion load. This study shows that the approach of characterizing the brain as a network using diffusion magnetic resonance imaging and graph theory can provide new insights into how abnormalities in the white matter affect cognitive function in patients with diabetes.

Background: Type 2 diabetes mellitus (T2DM) is associated with cognitive impairment and brain abnormalities on MRI. The underlying mechanisms are unclear. We examined the relationship between cerebral haemodynamics (cerebral blood flow (CBF) and cerebrovascular reactivity (CVR)) and cognitive performance and brain volumes in patients with T2DM, at baseline and after four years., Methods: 114 patients with T2DM, aged 56-80 years, underwent a detailed cognitive assessment and MRI scan. In 68 patients the evaluation was repeated after four years. CBF (two-dimensional flow-encoded phase-contrast MRI) and CVR (carbogen breathing response middle cerebral artery; transcranial Doppler) were measured at baseline. Cognitive performance was expressed as composite z-score and regression based index score. Brain volumes were measured on MRI by automated segmentation. The relationship of haemodynamics with cognition and brain volumes was examined with linear regression analyses adjusted for age, sex and IQ., Results: Mean CVR was 51.8% ± 18.0% and mean rCBF 53.3 ± 11.3 ml/min/100 ml brain tissue. CBF was associated with baseline cognitive performance (standardized regression coefficient β (95% CI): 0.17 (0.00; 0.32) and total brain volume (0.23 (0.05; 0.41)). No correlation was found between CVR and baseline cognitive performance. Neither CBF nor CVR predicted change in cognition (CBF 0.11 (-0.21; 0.44); CVR 0.07 (-0.21; 0.36)) or total brain volume (CBF 0.09 (-0.22; 0.39); CVR 0.13 (-0.13; 0.40)) over four years., Conclusions: CBF was associated with impaired cognition and total brain volume in cross-sectional analyses, but did not predict changes in cognition or brain volumes over time. Apparently, alterations in cerebral haemodynamics play no major etiological role in cognitive decline or change in brain volumes in non-demented individuals with T2DM., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Vascular cognitive impairment is an umbrella term for cognitive dysfunction associated with and presumed to be caused by vascular brain damage. Autopsy studies have identified microinfarcts as an important neuropathological correlate of vascular cognitive impairment that escapes detection by conventional magnetic resonance imaging (MRI). As a frame of reference for future high-resolution MRI studies, we systematically reviewed the literature on neuropathological studies on cerebral microinfarcts in the context of vascular disease, vascular risk factors, cognitive decline and dementia. We identified 32 original patient studies involving 10,515 people. The overall picture is that microinfarcts are common, particularly in patients with vascular dementia (weighted average 62%), Alzheimer's disease (43%), and demented patients with both Alzheimer-type and cerebrovascular pathology (33%) compared with nondemented older individuals (24%). In many patients, multiple microinfarcts were detected. Microinfarcts are described as minute foci with neuronal loss, gliosis, pallor, or more cystic lesions. They are found in all brain regions, possibly more so in the cerebral cortex, particularly in watershed areas. Reported sizes vary from 50 μm to a few mm, which is within the detection limit of current high-resolution MRI. Detection of these lesions in vivo would have a high potential for future pathophysiological studies in vascular cognitive impairment.

Purpose: We assessed test-retest variability of cerebral blood flow (CBF), cerebral blood volume (CBV), cerebral metabolic rate of oxygen (CMRO(2)), and oxygen extraction fraction (OEF) measurements derived from dynamic (15)O positron emission tomography (PET) scans., Procedures: In seven healthy volunteers, complete test-retest (15)O PET studies were obtained; test-retest variability and left-to-right ratios of CBF, CBV, OEF, and CMRO(2) in arterial flow territories were calculated., Results: Whole-brain test-retest coefficients of variation for CBF, CBV, CMRO(2), and OEF were 8.8%, 13.8%, 5.3%, and 9.3%, respectively. Test-retest variability of CBV left-to-right ratios was <7.4% across all territories. Corresponding values for CBF, CMRO(2), and OEF were better, i.e., <4.5%, <4.0%, and <1.4%, respectively., Conclusions: The test-retest variability of CMRO(2) measurements derived from dynamic (15)O PET scans is comparable to within-session test-retest variability derived from steady-state (15)O PET scans. Excellent regional test-retest variability was observed for CBF, CMRO(2), and OEF. Variability of absolute CBF and OEF measurements is probably affected by physiological day-to-day variability of CBF.

Background: Type 2 diabetes mellitus is associated with an increased risk of cognitive decline and dementia. We examined brain imaging correlates and vascular and metabolic risk factors of accelerated cognitive decline in patients with type 2 diabetes., Methods: Cognitive functioning and brain volume as well as metabolic and vascular risk factors were assessed twice in 68 patients with no dementia with type 2 diabetes with a 4-year interval. Thirty-eight control participants served as a reference group. Volumetric measurements of the total brain, lateral ventricles and white-matter hyperintensities were performed on 1.5T magnetic resonance imaging scans. A regression-based index score was calculated on the basis of the reference group to assess changes in cognitive performance over time, adjusted for age, sex and estimated intelligence quotient. Brain volumes were compared between patients with and without accelerated cognitive decline. Logistic regression analyses were used to identify baseline risk factors for accelerated cognitive decline within the diabetes group., Results: Accelerated cognitive decline was found in 17 (25%) patients with type 2 diabetes and was associated with a greater increase in ventricular volume [mean difference (95% confidence interval): 0.23% (0.08-0.38); p = 0.003] and white-matter hyperintensities volume [0.16% (0.05-0.27); p = 0.006] over the 4-year period. There were no specific vascular or metabolic risk factors associated with accelerated cognitive decline., Conclusions: Accelerated cognitive decline in patients with type 2 diabetes was associated with progressive changes on brain magnetic resonance imaging, comprising both vascular damage and global atrophy. Exploration of vascular and metabolic risk factors revealed no specific determinants of accelerated cognitive decline., (Copyright © 2011 John Wiley & Sons, Ltd.)

Automated brain segmentation methods with a good precision and accuracy are required to detect subtle changes in brain volumes over time in clinical applications. However, the ability of established methods such as SIENA, US and kNN to estimate brain volume change have not been compared on the same data, nor been evaluated with ground-truth manual segmentations. We compared measurements of brain volume change between SIENA, US and kNN in terms of precision (repeatability) and accuracy (ground-truth) using one baseline and two repeated follow-up 1.5 T MRI scans after 4 years of 10 subjects. The coefficient of repeatability (brain volume/volume change) was larger for US (29.6 cc/2.84%) than for kNN (4.9 cc/0.31%) and SIENA (-/0.92%). In terms of absolute brain volume measurements US and kNN showed good correlation with the manual segmentations and with each other (all Spearman's correlation coefficients ρ≥0.96; all p<0.001). Concerning brain volume changes, SIENA showed a good (ρ=0.82; p=0.004), kNN a moderate (ρ=0.60; p=0.067) and US a weak (ρ=0.50; p=0.138) correlation with the manual segmentations. For measurements of volume change, SIENA-US (mean correlation coefficient and p-value: ρ=0.28; p=0.442) and US-kNN (ρ=0.17; p=0.641) showed a weak correlation, but correlation was fairly good for kNN-SIENA (ρ=0.65; p=0.048). In conclusion, US and kNN showed a good precision, accuracy and comparability for brain volume measurements. For measurements of volume change, SIENA showed the best performance. kNN is a good alternative if volume change measurements of other brain structures are required., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Object: Clinical signs and symptoms of hydrocephalus can be clear and specific, but also subtle, nonspecific, or even absent. It may be difficult to decide whether shunt placement is indicated, especially in infants. Therefore, there is a need for the development of better noninvasive detection methods to distinguish between compensated and (slowly) progressive hydrocephalus. Early interference can reverse the cerebral damage, whereas the detection of a nonpathological state in infants with compensated hydrocephalus avoids the complications of unnecessary shunt procedures. Using MR imaging, the authors investigated cerebral blood flow (CBF) and apparent diffusion coefficients (ADCs) measured in infants with clinically compensated hydrocephalus., Methods: The diagnosis of compensated hydrocephalus was made on the basis of clinical criteria, consisting of no signs or symptoms of increased intracranial pressure (ICP), measurement of a normal ICP, and standard MR imaging showing enlarged ventricles. Flow measurements through both internal carotid arteries and the basilar artery were considered to represent the total CBF. In addition, ADC values were assessed in 5 different regions of interest in the brain parenchyma using diffusion weighted imaging. Brain volumetric measurement was performed to express CBF in ml/100 cm(3) brain/min, thus compensating for physiological CBF growth over time. Mean arterial blood pressure was manually measured to exclude this factor as a cause of a possible change in CBF. Intracranial pressure measurement was performed noninvasively using the Rotterdam Teletransducer., Results: Eighteen infants with clinically compensated hydrocephalus were included. The mean CBF was 53.5 ml/100 cm(3) of brain/min. The individual CBF values were graphically compared with age-related normal CBF values and fell in the normal range. Mean ADC value was 890.0 x10(-6) mm(2)/sec. Apparent diffusion coefficient values per region of interest were graphically compared with normal ADC values per region of interest and fell within the normal range., Conclusions: In infants with hydrocephalus, normal CBF and low ADC values, as measured using MR imaging, are associated with compensated hydrocephalus and may support a conservative approach with respect to the decision on whether to place a shunt.

Objective: Type 2 diabetes is associated with a moderate degree of cerebral atrophy and a higher white matter hyperintensity (WMH) volume. How these brain-imaging abnormalities evolve over time is unknown. The present study aims to quantify cerebral atrophy and WMH progression over 4 years in type 2 diabetes., Research Design and Methods: A total of 55 patients with type 2 diabetes and 28 age-, sex-, and IQ-matched control participants had two 1.5T magnetic resonance imaging scans with a 4-year interval. Volumetric measurements of total brain, peripheral cerebrospinal fluid (CSF), lateral ventricles, and WMH were performed with k-nearest neighbor-based probabilistic segmentation. All volumes were expressed as percentage of intracranial volume. Linear regression analyses, adjusted for age and sex, were performed to compare brain volumes between the groups and to identify determinants of volumetric change within the type 2 diabetic group., Results: At baseline, patients with type 2 diabetes had a significantly smaller total brain volume and larger peripheral CSF volume than control participants. In both groups, all volumes showed a significant change over time. Patients with type 2 diabetes had a greater increase in lateral ventricular volume than control participants (mean adjusted between-group difference in change over time [95% CI]: 0.11% in 4 years [0.00 to 0.22], P = 0.047)., Conclusions: The greater increase in lateral ventricular volume over time in patients with type 2 diabetes compared with control participants shows that type 2 diabetes is associated with a slow increase of cerebral atrophy over the course of years.

Background: The International Carotid Stenting Study (ICSS) of stenting and endarterectomy for symptomatic carotid stenosis found a higher incidence of stroke within 30 days of stenting compared with endarterectomy. We aimed to compare the rate of ischaemic brain injury detectable on MRI between the two groups., Methods: Patients with recently symptomatic carotid artery stenosis enrolled in ICSS were randomly assigned in a 1:1 ratio to receive carotid artery stenting or endarterectomy. Of 50 centres in ICSS, seven took part in the MRI substudy. The protocol specified that MRI was done 1-7 days before treatment, 1-3 days after treatment (post-treatment scan), and 27-33 days after treatment. Scans were analysed by two or three investigators who were masked to treatment. The primary endpoint was the presence of at least one new ischaemic brain lesion on diffusion-weighted imaging (DWI) on the post-treatment scan. Analysis was per protocol. This is a substudy of a registered trial, ISRCTN 25337470., Findings: 231 patients (124 in the stenting group and 107 in the endarterectomy group) had MRI before and after treatment. 62 (50%) of 124 patients in the stenting group and 18 (17%) of 107 patients in the endarterectomy group had at least one new DWI lesion detected on post-treatment scans done a median of 1 day after treatment (adjusted odds ratio [OR] 5.21, 95% CI 2.78-9.79; p<0.0001). At 1 month, there were changes on fluid-attenuated inversion recovery sequences in 28 (33%) of 86 patients in the stenting group and six (8%) of 75 in the endarterectomy group (adjusted OR 5.93, 95% CI 2.25-15.62; p=0.0003). In patients treated at a centre with a policy of using cerebral protection devices, 37 (73%) of 51 in the stenting group and eight (17%) of 46 in the endarterectomy group had at least one new DWI lesion on post-treatment scans (adjusted OR 12.20, 95% CI 4.53-32.84), whereas in those treated at a centre with a policy of unprotected stenting, 25 (34%) of 73 patients in the stenting group and ten (16%) of 61 in the endarterectomy group had new lesions on DWI (adjusted OR 2.70, 1.16-6.24; interaction p=0.019)., Interpretation: About three times more patients in the stenting group than in the endarterectomy group had new ischaemic lesions on DWI on post-treatment scans. The difference in clinical stroke risk in ICSS is therefore unlikely to have been caused by ascertainment bias. Protection devices did not seem to be effective in preventing cerebral ischaemia during stenting. DWI might serve as a surrogate outcome measure in future trials of carotid interventions., Funding: UK Medical Research Council, the Stroke Association, Sanofi-Synthélabo, European Union, Netherlands Heart Foundation, and Mach-Gaensslen Foundation., (2010 Elsevier Ltd. All rights reserved.)

Background/aims: The present study examined the relationship between microvascular complications and cognitive decline and the development of structural brain abnormalities over a period of 4 years in patients with type 2 diabetes mellitus (T2DM)., Methods: Sixty-eight elderly patients with T2DM had 2 cognitive assessments with a 4-year interval. Two MRI scans, performed at the same time as the cognitive assessments, were available from 55 patients. Changes in cognitive performance over time were expressed as a regression-based index (RBI). Automated volumetric measurements of total brain, lateral ventricles and white matter hyperintensities were performed. The relationship between baseline microvascular complications [diabetic retinopathy, peripheral neuropathy or albuminuria (micro- or macroalbuminuria)] and cognition and brain volumes was examined with linear regression analyses adjusted for age and sex (for cognition also for IQ)., Results: At baseline, diabetic retinopathy was present in 18% of patients, peripheral neuropathy in 36%, albuminuria in 15%. Retinopathy or neuropathy were not significantly associated with baseline cognition or brain volumes, or changes in these measures over time. Albuminuria was associated with a lower composite RBI score, indicating accelerated cognitive decline (adjusted mean difference between patients with or without albuminuria: -0.58, 95% CI -0.85 to -0.31, p < 0.001)., Conclusion: Albuminuria predicted accelerated cognitive decline in patients with T2DM, but other microvascular complications were unrelated to accelerated cognitive decline or brain MRI abnormalities., (Copyright © 2010 S. Karger AG, Basel.)

Object-location memory is an important form of spatial memory, comprising different subcomponents that each process specific types of information within memory, i.e. remembering objects, remembering positions and binding these features in memory. In the current study we investigated the neural correlates of binding categorical (relative) or coordinate (exact) position information with objects in memory. Therefore, an object-location memory battery was used, including different task conditions assessing object-location memory, i.e. memory for position information per se, and binding object information with coordinate and categorical position information. Sixty-one stroke patients with focal brain lesions were examined and compared with 77 healthy matched controls. The lesion subtraction method was used to define the area of overlap. Results indicate an important role of the left posterior parietal cortex in the binding of both categorical and coordinate positions with object information. Additionally, the hippocampus seems important for categorical object-location memory. This suggests that categorical and coordinate object-location memory depend on similar cognitive and neural systems.

Background: Cerebral atrophy on brain magnetic resonance imaging (MRI) has been associated with vascular risk factors including hypertension. Progression of cerebral atrophy and its risk factors have not been studied in vascular disease patients. This study aimed to assess the progression of cerebral atrophy and to evaluate possible associations with blood pressure (BP) in patients with pre-existing vascular disease., Methods: A total of 331 patients with manifest vascular disease from the Second Manifestations of ARTerial Disease (SMART) Study underwent baseline and follow-up MRI scanning (mean follow-up 4.1 +/- 0.3 years). The annual change in brain and ventricular volume was calculated with an automated quantitative volumetric method. Associations between BP and change in brain and ventricular volumes and between BP and the occurrence of lacunar infarcts were analyzed., Results: At baseline mean age was 58 +/- 9 years and mean BP was 138/80 mm Hg. Mean annual decrease in brain tissue volume was 6.5 +/- 3.8 ml and mean annual increase in ventricular volume was 1.0 +/- 1.0 ml. There was no association observed between BP and annual change in brain or ventricular volume, but a clear association was found between BP and incident lacunar infarcts (odds ratio 1.57; 1.11-2.22 per s.d. increase in systolic BP (SBP))., Conclusions: The magnitude of changes in brain tissue and ventricular volume in patients with vascular disease was comparable to the physiological changes described in normal people at a much higher age. Progression of cerebral atrophy in this population may be associated with advanced physiological aging, but is probably not caused by elevated BP.

Object: Progressive hydrocephalus may lead to edema of the periventricular white matter and to damage of the brain parenchyma because of compression, stretching, and ischemia. The aim of the present study was to investigate whether cerebral edema can be quantified using diffusion-weighted imaging in infants with hydrocephalus and whether CSF diversion could decrease cerebral edema., Methods: Diffusion-weighted MR imaging was performed in 24 infants with progressive hydrocephalus before and after CSF diversion. Parametric images of the trace apparent diffusion coefficients (ADCs) were obtained. The ADCs of 5 different cortical and subcortical regions of interest were calculated pre- and postoperatively in each patient. The ADC values were compared with age-related normal values. Mean arterial blood pressure and anterior fontanel pressure were measured immediately after each MR imaging study., Results: After CSF diversion, the mean ADC decreased from a preoperative value of 1209 +/- 116 x 10(-6) mm(2)/second to a postoperative value of 928 +/- 64 x 10(-6) mm(2)/second (p < 0.005). Differences between pre- and postoperative ADC values were most prominent in the periventricular white matter, supporting the existence of preoperative periventricular edema. Compared with age-related normal values, the preoperative ADC values were higher and the postoperative ADC values were lower, although within normal range. The decrease in ADC after CSF drainage was more rapid than the more gradual physiological decrease that is related to age. The preoperative ICP was elevated in all patients. After CSF diversion the ICP decreased significantly to within the normal range. A linear correlation between ADC values and ICP was found (correlation coefficient 0.496, p < 0.001). In all patients the mean arterial blood pressure was within physiological limits both pre- and postoperatively., Conclusions: This study shows a rapid and more extensive decrease in ADC values after CSF diversion than is to be expected from physiological ADC decrease solely due to increasing patient age. The preoperative ADC increase can be explained by interstitial edema caused by transependymal CSF leakage or by vasogenic edema caused by capillary compression and stretching of the brain parenchyma. This study population of infants with (early recognized) hydrocephalus did not suffer from cytotoxic edema. These findings may help to detect patients at risk for cerebral damage by differentiating between progressive and compensated hydrocephalus.

Several neuropsychological studies have suggested parallel processing of somatosensory input when localising a tactile stimulus on one's own by pointing towards it (body schema) and when localising this touched location by pointing to it on a map of a hand (body image). Usually these reports describe patients with impaired detection, but intact sensorimotor localisation. This study examined three patients with a lesion of the angular gyrus with intact somatosensory processing, but with selectively disturbed finger identification (finger agnosia). These patients performed normally when pointing towards the touched finger on their own hand but failed to indicate this finger on a drawing of a hand or to name it. Similar defects in the perception of other body parts were not observed. The findings provide converging evidence for the dissociation between body image and body schema and, more importantly, reveal for the first time that this distinction is also present in higher-order cognitive processes selectively for the fingers.

Object: Raised intracranial pressure (ICP) that is associated with hydrocephalus may lead to alterations in cerebral hemodynamics and ischemic changes in the brain. In infants with hydrocephalus, defining the right moment for surgical intervention based on clinical signs alone can sometimes be a difficult task. Clinical signs of raised ICP are known to be unreliable and sometimes even misleading. Furthermore, when sutures are closed, ICP does not always correlate with the size of the ventricles or with the clinical signs or symptoms. In this study the authors investigated whether cerebral blood flow (CBF) can be measured by using quantitative MR angiography in infants with progressive hydrocephalus. In addition, the authors investigated the relationship between CBF and ICP, before and after cerebrospinal fluid (CSF) diversion., Methods: Fifteen infants with progressive hydrocephalus (age range 1 day-7 months) were examined. All patients underwent anterior fontanel pressure measurement, MR angiography, and mean arterial blood pressure measurements before and after CSF diversion. Brain volume was measured to compensate for the physiological increase in CBF during brain maturation in infants., Results: The mean preoperative ICP was 19.1 +/- 8.4 cm H(2)O (+/- standard deviation). The mean postoperative ICP was 6.7 +/- 4.0 cm H(2)O (p < 0.005). The mean preoperative CBF was 25.7 +/- 11.3 ml/100 cm(3) brain/min. After CSF diversion, CBF increased to 50.1 +/- 12.1 ml/100 cm(3) brain/min (p < 0.005). The mean arterial blood pressure did not change after surgical intervention., Conclusions: Magnetic resonance imaging can be used to measure CBF in infants with hydrocephalus. Raised ICP was related to a decrease in CBF. After CSF diversion, CBF and ICP improved to values within the normal range.

Background/aims: Diabetes mellitus (DM) may affect the central nervous system, resulting in cognitive impairments. It has been suggested that cognitive impairments are more pronounced in DM2 than in DM1, but studies that directly compare the effects of these 2 types of DM on cognition are lacking., Methods: Forty patients with DM1 (mean duration: 34 years) were compared with 40 age- and education-matched patients who were known to have DM2 (mean duration: 7 years). Extensive neuropsychological assessment focussed on abstract reasoning, memory, attention and executive function, visuoconstruction and information processing speed. Psychological well-being was measured and brain MRIs were obtained., Results: No systematic between-group differences were observed in neuropsychological measures or levels of psychological well-being. DM2 patients showed significantly more deep white matter lesions and cortical atrophy on MRI (p < 0.01)., Conclusion: DM1 patients with more than 30 years of DM have a similar cognitive profile and better MRI ratings than age- and education-matched DM2 patients with only 7 years of DM., (Copyright 2007 S. Karger AG, Basel.)

Background and Purpose: In this study we compared risk factors, clinical features, and stroke recurrence in a large series of patients with large subcortical, cortical, or small deep infarcts., Methods: Patients with a transient or minor ischemic attack (modified Rankin Scale grade of < or =3) who had a single relevant supratentorial infarct of presumed noncardioembolic origin on CT were classified as suffering from a large subcortical (n=120), small deep (n=324), or cortical (n=211) infarct. Mean follow-up was 8 years. Rates of recurrent stroke were compared with Cox regression., Results: The clinical deficits caused by large subcortical infarcts resembled either those of a cortical or those of a small deep infarct. Risk factor profiles were similar in the 3 groups. The rate of recurrent stroke in patients with a large subcortical infarct (25/120; 21%) did not differ from that of patients with a cortical infarct (46/211; 22%) or with a small deep infarct (60/324; 19%). After adjustment for age, sex, and vascular risk factors, hazard ratios for recurrent stroke of large subcortical and cortical infarcts were 1.05 (95% CI, 0.65 to 1.70) and 1.17 (95% CI, 0.79 to 1.73), respectively, compared with small deep infarcts., Conclusions: Clinical features, risk factor profiles, and stroke recurrence rate in patients with a large subcortical infarct only differ slightly from those in patients with small deep or cortical infarcts.

Modest cognitive impairment has been reported in young-adult patients with type 1 diabetes. In older patients with type 2 diabetes, cognitive impairments are more pronounced, which might be due to age but also to differential effects of type 1 diabetes and type 2 diabetes on the brain. This study therefore assessed cognitive performance and magnetic resonance imaging (MRI) of the brain in older type 1 diabetic patients. Forty type 1 diabetic patients (age >50 years) and 40 age-matched control subjects were included. Neuropsychological assessment included all major cognitive domains, and psychological well-being was assessed with questionnaires. Atrophy, white-matter abnormalities, and infarcts were rated on MRI scans. Type 1 diabetic patients performed slightly (effect sizes <0.4) worse on cognitive tasks, but only "speed of information processing" reached statistical significance. No significant between-group differences were found on any of the MRI parameters. Type 1 diabetic patients tended to report more cognitive and depressive problems than control subjects, but this did not correlate with the performance on cognitive tests. We conclude that cognition in older type 1 diabetic patients is only mildly disturbed. Chronic exposure to hyperglycemia is in itself, even at older age, apparently not sufficient to have considerable impact on the brain.

The structural correlates of impaired cognition in type 2 diabetes are unclear. The present study compared cognition and brain magnetic resonance imaging (MRI) between type 2 diabetic patients and nondiabetic control subjects and assessed the relationship between cognition and MRI findings and blood pressure and metabolic control. The study included 113 patients and 51 control subjects. Brain MRI scans were rated for white matter lesions (WMLs), cortical and subcortical atrophy, and infarcts. Neuropsychological test scores were divided into five cognitive domains and expressed as standardized Z values. Type 2 diabetes was associated with deep WMLs (P = 0.02), cortical (P < 0.001) and subcortical (P < 0.05) atrophy, (silent) infarcts (P = 0.06), and impaired cognitive performance (attention and executive function, information-processing speed, and memory, all P < 0.05). Adjustment for hypertension did not affect the results. Within the type 2 diabetic group, cognitive function was inversely related with WMLs, atrophy, and the presence of infarcts (adjusted for age, sex, and estimated IQ), and there was a modest association with HbA1c and diabetes duration. This association was strongest for age, even more so than in control subjects. We conclude that cognitive impairments in patients with type 2 diabetes are not only associated with subcortical ischemic changes in the brain, but also with increased brain atrophy.

Wayfinding is a complex cognitive function involving different types of information, such as knowledge about landmarks and direction information. This variety of processes suggest that multiple neural mechanisms are involved, e.g., the hippocampal system, the posterior parietal and temporal cortical areas. Although patient studies and imaging studies have given important insights in the exact neural circuitry underlying wayfinding, many controversies remain. Therefore, the current study sets out to further examine the neuroanatomical correlates of wayfinding in a sample of 31 stroke patients with unilateral lesions, tested with a series of different wayfinding tasks, including landmark recognition, landmark ordering, route reversal and route drawing. For all patients, the exact location of their lesion was determined using CT or MRI scans. Based on existing literature, a number of relevant brain areas were demarcated, after which the extent of damage to these areas was determined for each patient separately. Performance on the landmark recognition task was impaired by damage to the right hippocampal formation, whereas a weak correlation was found between damage to the dorsolateral prefrontal cortex and processing the order of the landmarks. Several brain areas were found to be involved in retracing a route from the end to the beginning, including the right hippocampal formation, the right posterior parietal cortex, the right dorsolateral prefrontal cortex and the right temporal lobe. Finally, damage to the right temporal lobe impaired the ability to draw the route.

Spatial working memory entails the ability to keep spatial information active in working memory over a short period of time. To study the areas of the brain that are involved in spatial working memory, a group of stroke patients was tested with a spatial search task. Patients and healthy controls were asked to search through a number of boxes shown at different locations on a touch-sensitive computer screen in order to find a target object. In subsequent trials, new target objects were hidden in boxes that were previously empty. Within-search errors were made if a participant returned to an already searched box; between-search errors occurred if a participant returned to a box that was already known to contain a target item. The use of a strategy to remember the locations of the target objects was calculated as well. Damage to the right posterior parietal and right dorsolateral prefrontal cortex impaired the ability to keep spatial information 'on-line', as was indicated by performance on the Corsi Block-Tapping task and the within-search errors. Moreover, patients with damage to the right posterior parietal cortex, the right dorsolateral prefrontal cortex and the hippocampal formation bilaterally made more between-search errors, indicating the importance of these areas in maintaining spatial information in working memory over an extended time period.

Type 1 diabetes can lead to several well-described complications such as retinopathy, nephropathy and peripheral neuropathy. Evidence is accumulating that it is also associated with gradually developing end-organ damage in the central nervous system. This relatively unknown complication can be referred to as "diabetic encephalopathy" and is characterised by electrophysiological and neuroradiological changes, such as delayed latencies of evoked potentials, modest cerebral atrophy and (periventricular) white matter lesions. Furthermore, individuals with type 1 diabetes may show performance deficits in a wide range of cognitive domains. The exact mechanisms underlying this diabetic encephalopathy are only partially known. Chronic metabolic and vascular changes appear to play an important role. Interestingly, the differences in the "cognitive profile" between type 1 and type 2 diabetes also suggest a critical role for disturbances of insulin action in the central nervous system.

The inflammatory response that exacerbates cerebral injury after ischemia is an attractive therapeutic target: it progresses over days and strongly contributes to worsening of the neurologic outcome. The authors show that, after transient ischemic injury to the rat brain, systemic application of interferon-beta (IFN-beta), a cytokine with antiinflammatory properties, attenuated the development of brain infarction. Serial magnetic resonance imaging (MRI) showed that IFN-beta treatment reduced lesion volume on diffusion-weighted MRI by 70% (P < 0.01) at 1 day after stroke. IFN-beta attenuated the leakage of contrast agent through the blood-brain barrier (P < 0.005), indicating a better-preserved blood-brain barrier integrity. Both control and IFN-beta-treated animals showed a similar degree of relative hyperperfusion of the lesioned hemisphere, indicating that neuroprotection by IFN-beta was not mediated by improved cerebral perfusion as assessed 24 hours after stroke onset. IFN-beta treatment resulted in an 85% reduction (P < 0.0001) in infarct volume 3 weeks later, as determined from T2-weighted MRI and confirmed by histology. This effect was achieved even when treatment was started 6 hours after stroke onset. Quantitative immunohistochemistry at 24 hours after stroke onset showed that IFN-beta almost completely prevented the infiltration of neutrophils and monocytes into the brain. Gelatinase zymography showed that this effect was associated with a decrease in matrix metalloproteinase-9 expression. In conclusion, treatment with the antiinflammatory cytokine IFN-beta affords significant neuroprotection against ischemia/reperfusion injury, and within a relatively long treatment window. Because IFN-beta has been approved for clinical use, it may be rapidly tested in a clinical trial for its efficacy against human stroke.

Background: The precise etiology of border zone infarcts is controversial. Hemodynamic impairment due to obstructive disease of the internal carotid artery (ICA) is suggested as a cause of border zone infarcts., Objective: To investigate changes in prevalence and volume of ischemic border zone lesions over time in patients with occlusive disease of the ICA after 1 year of follow-up., Design: Follow-up study., Setting: Referral center., Patients: Fifty-eight patients with an occlusion of the ICA were included. At baseline, ischemic lesions were classified on magnetic resonance imaging, and vasomotor reactivity was assessed with transcranial Doppler ultrasonography with carbon dioxide challenge., Main Outcome Measures: Changes in prevalence and volume of ischemic lesions were monitored and were correlated with carbon dioxide reactivity at baseline., Results: No significant changes in the prevalence of any infarct types were observed after 1 year of follow-up in the hemispheres ipsilateral or contralateral to the ICA occlusion. However, in hemispheres ipsilateral to an occluded ICA, we found an increase in mean volume of internal border zone infarcts (P =.002). In hemispheres with a low carbon dioxide reactivity, we found an increase in mean volume of internal border zone lesions after 1 year (carbon dioxide reactivity,

Background and Purpose: Patients with carotid artery occlusion (CAO) and ipsilateral transient ischemic attack (TIA) can have lasting cognitive impairment, despite the recovery of focal neurological deficits. We sought to assess whether cognitive impairment in these patients is associated with hemodynamic compromise and/or impaired cerebral metabolism., Methods: In 39 consecutive patients with a TIA associated with an angiographically proven occlusion of the carotid artery, we examined (1) cognitive functioning, (2) cerebrovascular reserve capacity of the middle cerebral artery ipsilateral to the CAO as measured by transcranial Doppler ultrasound, and (3) metabolic ratios as measured by 1H-MR spectroscopy in the centrum semiovale ipsilateral to the symptomatic CAO. Findings were compared with those in healthy control subjects., Results: As a group, patients were cognitively impaired. Mean CO2 reactivity and the mean ratio of N-acetyl aspartate to creatine were decreased. In approximately one third of patients, lactate was present in noninfarcted regions. The presence of lactate proved to be a stronger correlate of cognitive impairment than MRI-detected lesions (beta=0.41 versus beta=0.15). Cognitive impairment did not correlate with CO2 reactivity or the ratio of N-acetyl aspartate to creatine., Conclusions: This exploratory study in patients with CAO and ipsilateral TIA showed that 1H-MR spectroscopy-detected lactate in noninfarcted regions is a better indicator of cognitive impairment than MRI-detected lesions. Cognitive impairment did not correlate with CO2 reactivity.