Christian Opherk

Strategic Role of Frontal White Matter Tracts in Vascular Cognitive Impairment: A Voxel-Based Lesion-Symptom Mapping Study in CADASIL.

Cerebral small vessel disease is the most common cause of vascular cognitive impairment. It typically manifests with lacunar infarcts and ischaemic white matter lesions. However, little is known about how these lesions relate to the cognitive symptoms. Previous studies have found a poor correlation between the burden of ischaemic lesions and cognitive symptoms, thus leaving much of the variance in cognitive performance unexplained. The objective of the current study was to investigate the relationship between the location of subcortical ischaemic lesions and cognitive symptoms in small vessel disease. We applied a voxel-based lesion-symptom mapping approach to data from 215 patients with CADASIL, a genetically defined small vessel disease with mutations in the NOTCH3 gene. All patients were examined by magnetic resonance imaging and comprehensive neuropsychological testing. Lacunar lesions and white matter lesions were segmented on three-dimensional T(1) and fluid-attenuated inversion recovery sequences, respectively. One hundred and forty-five subjects had a total of 854 lacunar lesions (range 1-13 per individual). The normalized volume of white matter hyperintensities ranged from 0.0425% to 21.5% of the intracranial cavity. Significant clusters for cognitive performance were detected for both lacunar lesions and white matter hyperintensities. The most prominent results were obtained on a compound score for processing speed, the predominantly affected cognitive domain in this group of patients. Strategic locations included the anterior parts of the thalamus, the genu and anterior limb of the internal capsule, the anterior corona radiata and the genu of the corpus callosum. By combining the lesion-symptom mapping data with information from a probabilistic white matter atlas we found that the majority of the processing speed clusters projected on the anterior thalamic radiation and the forceps minor. In multivariate models that included demographic parameters, brain atrophy and the volume of ischaemic lesions, regional volumes of lacunar lesions and white matter hyperintensities in the anterior thalamic radiation predicted performance in processing speed tasks, whereas there was no independent contribution of the global volume of ischaemic lesions. These observations emphasize the importance of lesion location for both lacunar and ischaemic white matter lesions. Our findings further highlight the anterior thalamic radiation as a major anatomical structure impacting on processing speed. Together these findings provide strong support for a central role of frontal-subcortical circuits in cerebral small vessel disease and vascular cognitive impairment.

Cortical superficial siderosis: detection and clinical significance in cerebral amyloid angiopathy and related conditions

Cortical superficial siderosis describes a distinct pattern of blood-breakdown product deposition limited to cortical sulci over the convexities of the cerebral hemispheres, sparing the brainstem, cerebellum and spinal cord. Although cortical superficial siderosis has many possible causes, it is emerging as a key feature of cerebral amyloid angiopathy, a common and important age-related cerebral small vessel disorder leading to intracerebral haemorrhage and dementia. In cerebral amyloid angiopathy cohorts, cortical superficial siderosis is associated with characteristic clinical symptoms, including transient focal neurological episodes; preliminary data also suggest an association with a high risk of future intracerebral haemorrhage, with potential implications for antithrombotic treatment decisions. Thus, cortical superficial siderosis is of relevance to neurologists working in neurovascular, memory and epilepsy clinics, and neurovascular emergency services, emphasizing the need for appropriate blood-sensitive magnetic resonance sequences to be routinely acquired in these clinical settings. In this review we focus on recent developments in neuroimaging and detection, aetiology, prevalence, pathophysiology and clinical significance of cortical superficial siderosis, with a particular emphasis on cerebral amyloid angiopathy. We also highlight important areas for future investigation and propose standards for evaluating cortical superficial siderosis in research studies.

A Two-Year Clinical Follow-Up Study in 80 CADASIL Subjects Progression Patterns and Implications for Clinical Trials

Background and Purpose— Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease causing stroke and dementia. The aim of this study was to explore the patterns of clinical progression in CADASIL, to check for prognostic variables, and to provide sample size estimates for future therapeutic trials. Methods— Eighty CADASIL subjects (aged 45.7±9.9 years [mean±SD]) were followed prospectively during a mean period of 26.3±1.1 months. Standardized scales on disability (Rankin), activities of daily living (Barthel index), neurological outcome (National Institutes of Health Stroke Scale [NIHSS]), and cognition (structural interview for diagnosis of Alzheimer dementia and multi-infarct dementia [SIDAM] and Mattis dementia rating scale [MDRS]) were assessed at baseline and at follow-up. Results— All but 1 individual completed the protocol. At follow-up, the cohort had deteriorated with respect to all clinical scales: Rankin scores (0.3±0.7 [mean change±SD]; P =0.001), Barthel index (−5.4±15.9; P <0.001), NIHSS scores (1.0±2.6; P <0.001), SIDAM scores (−2.1±6.4; P =0.004), and MDRS scores (−4.3±18.5; P =0.09). The spectrum ranged from marked worsening to some degree of improvement. Seventeen patients experienced a new stroke. Overall, there were 18 strokes within 173 person-years, giving an average incidence rate of stroke of 10.4 per 100 person-years (95% CI, 5.6 to 15.2). Age at baseline was found to be a predictor of clinical progression. Sample size estimates show that the number of individuals needed to include in an interventional trial (assumed duration 2 years, assumed treatment effect 40%) is 602 when using stroke occurrence as an outcome measure. Conclusions— The clinical course of CADASIL includes periods of acute worsening, chronic progression, stabilization, and improvement. Sample size calculations emphasize the need for surrogate markers of disease progression for future interventional trials.

Staged Escalation Therapy in Acute Basilar Artery Occlusion Intravenous Thrombolysis and On-Demand Consecutive Endovascular Mechanical Thrombectomy: Preliminary Experience in 16 Patients

Background and Purpose— The prognosis of acute basilar artery occlusion (BAO) is poor if early recanalization is not achieved. Recanalization strategies include intravenous thrombolysis (IVT) and intra-arterial thrombolysis, as well as endovascular mechanical thrombectomy (EMT). The combination of IVT with consecutive on-demand EMT may allow for early treatment initiation with high recanalization rates but has never been systematically tested in patients with BAO. Methods— Starting in January 2006, we treated all eligible patients with acute BAO admitted to our academic stroke center or one of our cooperating community hospitals after a standardized protocol combining IVT with consecutive on-demand EMT. Inclusion criteria were: (1) presence of predefined symptoms clearly suggestive of BAO; (2) exclusion of intracerebral hemorrhage on CT scan; (3) evidence of BAO on CT angiography; (4) start of therapy within 6 hours after symptom onset; and (5) no contraindications for IVT. If CT angiography showed persistent BAO after IVT, EMT was performed. Results— Since January 2006, 16 patients have been treated. All patients received IVT; in 7 of them, EMT became necessary because of persistent BAO. Final recanalization was achieved in 15 patients. Three months after therapy, 12 of 16 patients were still alive; 7 of them had a good outcome (modified Rankin score ≤2). Conclusions— Our data suggest that the combination of IVT with on-demand consecutive EMT in BAO is feasible, allows for early treatment, and provides excellent recanalization rates.

Prevalence of cortical superficial siderosis in patients with cognitive impairment

Cortical superficial siderosis (cSS) is a magnetic resonance imaging marker of cerebral amyloid angiopathy (CAA) and can be its sole imaging sign. cSS has further been identified as a risk marker for future intracranial hemorrhage. Although uncommon in the general population, cSS may be much more prevalent in high risk populations for amyloid pathology. We aimed to determine the frequency of cSS in patients with cognitive impairment presenting to a memory clinic. We prospectively evaluated consecutive patients presenting to our memory clinic between April 2011 and April 2013. Subjects received neuropsychological testing using the Consortium to Establish a Registry for Alzheimer’s Disease battery (CERAD-NP). Two hundred and twelve patients with documented cognitive impairment further underwent a standardized 3T-MR-imaging protocol with T2*-weighted gradient-echo sequences for detection of cSS. Thirteen of 212 patients (6.1xa0%) displayed cSS. In seven of them (54xa0%) cSS was the only imaging sign of CAA. Patients with cSS did not differ from patients without cSS with regard to medical history, age or cardiovascular risk profile. Subjects with cSS performed worse in the mini-mental state examination (pxa0=xa00.001), showed more white matter hyperintensities (pxa0=xa00.005) and more often had microbleeds (pxa0=xa00.001) compared to those without cSS. cSS is common in patients with cognitive impairment. It is associated with lower cognitive scores, white matter hyperintensities and microbleeds and can be the only imaging sign for CAA in this patient group.

Identification of a strategic brain network underlying processing speed deficits in vascular cognitive impairment

Patients with vascular cognitive impairment (VCI) commonly exhibit deficits in processing speed. This has been attributed to a disruption of frontal-subcortical neuronal circuits by ischemic lesions, but the exact mechanisms and underlying anatomical structures are poorly understood. We set out to identify a strategic brain network for processing speed by applying graph-based data-mining techniques to MRI lesion maps from patients with small vessel disease. We studied 235 patients with CADASIL, a genetic small vessel disease causing pure VCI. Using a probabilistic atlas in standard space we first determined the regional volumes of white matter hyperintensities (WMH) and lacunar lesions (LL) within major white matter tracts. Conditional dependencies between the regional lesion volumes and processing speed were then examined using Bayesian network analysis. Exploratory analysis identified a network of five imaging variables as the best determinant of processing speed. The network included LL in the left anterior thalamic radiation and the left cingulum as well as WMH in the left forceps minor, the left parahippocampal white matter and the left corticospinal tract. Together these variables explained 34% of the total variance in the processing speed score. Structural equation modeling confirmed the findings obtained from the Bayesian models. In summary, using graph-based models we identified a strategic brain network having the highest predictive value for processing speed in our cohort of patients with pure small vessel disease. Our findings confirm and extend previous results showing a role of frontal-subcortical neuronal circuits, in particular dorsolateral prefrontal and cingulate circuits, in VCI.

Enhanced L-arginine-induced vasoreactivity suggests endothelial dysfunction in CADASIL

BackgroundMutations in the Notch3 gene are the cause of CADASIL, a hereditary small vessel disease leading to stroke and vascular dementia. The disease is characterized by ultrastructural granular deposits within small arterial vessels and degeneration of vascular smooth muscle cells. Yet, little is known about endothelial function in CADASIL. Vasoreactivity induced by L-arginine, which is the substrate for endothelial nitric oxide synthase, is a parameter of endothelial function and has been shown to be altered in patients with cerebrovascular disease.MethodsTo assess endothelial function in CADASIL, L-arginine-induced vasoreactivity was studied in 25 CADASIL subjects and 24 non-CADASIL control subjects without previous history of cerebrovascular disease by transcranial Doppler sonography of the middle cerebral artery.ResultsResting mean flow velocity was significantly reduced in patients (43.7 ± 14.5 cm/s) compared to controls (57.0 ± 10.4 cm/s) [p < 0.001]. Patients exhibited a significantly higher pulsatility index (PI = 0.94 ± 0.19) than control subjects (PI = 0.79 ± 0.11) [p < 0.01]. L-arginine-induced vasoreactivity was significantly increased in patients (36.1 ± 15.5 % ) versus controls (27.9 ± 8.5 %) [p < 0.05]. In patients, there was a significant reduction of the PI following L-arginine application (PI = 0.86 ± 0.13) compared to resting PI [p < 0.01].ConclusionsOur results may indicate a pathogenic role of impaired cerebral hemodynamics and endothelial dysfunction in CADASIL. Our finding of enhanced L-arginine vasoreactivity might have therapeutic implications for CADASIL and sporadic small vessel disease.

Vertebral Artery Hypoplasia Frequency and Effect on Cerebellar Blood Flow Characteristics

Background and Purpose— Vertebral artery hypoplasia (VAH) is supposed to be a risk factor for posterior circulation ischemia (PCI), particularly in the territory of the posterior inferior cerebellar artery (PICA). The aim of our study was to determine whether VAH impedes perfusion in the dependent PICA territory even in the absence of manifest PCI. Methods— VA diameter was retrospectively measured in 934 consecutive patients who underwent whole-brain multimodal computed tomography because of suspected stroke. VAH was defined by a diameter of ⩽2 mm and an asymmetry ratio of ⩽1:1.7 of both VAs. We performed blinded computed tomography perfusion reading in patients with VAH without PCI (MRI-confirmed) and in control patients (ratio 1:2) with normal VAs. Four different perfusion maps were evaluated for a relative hypoperfusion in the PICA territory. Results— VAH was found in 146 of 934 patients (15.6%). It was more frequent on the right side (66.1%). Of 146 patients, 59 without PCI qualified for computed tomography perfusion analysis. Depending on the perfusion map, ⩽42.4% (25/59) of patients with VAH, but only 7.6% (9/118) without VAH, showed an ipsilateral PICA hypoperfusion (P<0.001). Sensitivities in patients with VAH were as follows: time to drain 42.4% (25/59)>mean transit time 39.0% (23/59)>cerebral blood flow 25.4% (15/59). Cerebral blood volume was never affected. Conclusions— VAH is a frequent vascular variant that can lead to a relative regional hypoperfusion in the PICA territory. Additional research should clarify the pathophysiological role of VAH in PCI.

Education modifies the relation of vascular pathology to cognitive function: cognitive reserve in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

A clinical impact of cognitive reserve (CR) has been demonstrated in Alzheimers disease, whereas its role in vascular cognitive impairment (VCI) is largely unknown. In this study, we investigated the impact of CR in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a genetic variant of pure VCI. A total of 247 NOTCH3 mutation carriers from a two-center study were investigated using detailed neuropsychological and neuroimaging protocols. CR was operationalized as years of formal education. Brain pathology was assessed by MRI using normalized brain volume and lacunar lesion volume as proxies. Multivariate analyses were done for each structural measure with scores of processing speed, executive function, and memory as dependent variables. Additional linear regression models were conducted with interaction terms for education × brain volume and education × lacunar lesion volume. Education had an independent impact on cognitive performance in subjects with mild and moderate degrees of brain pathology, whereas there was no significant influence of education on cognition in patients with severe MRI changes. This interaction was found for processing speed, the cognitive domain most impaired in our patients. Our findings demonstrate an interaction of education and brain pathology in regard to cognitive impairment: the effect of education seems most pronounced in early disease stages but may ultimately be overwhelmed by the pathological changes. The results extend the concept of CR to VCI.

Age determination of vessel wall hematoma in spontaneous cervical artery dissection: A multi-sequence 3T Cardiovascular Magnetic resonance study

BackgroundPreviously proposed classifications for carotid plaque and cerebral parenchymal hemorrhages are used to estimate the age of hematoma according to its signal intensities on T1w and T2w MR images. Using these classifications, we systematically investigated the value of cardiovascular magnetic resonance (CMR) in determining the age of vessel wall hematoma (VWH) in patients with spontaneous cervical artery dissection (sCAD).Methods35 consecutive patients (mean age 43.6 ± 9.8 years) with sCAD received a cervical multi-sequence 3T CMR with fat-saturated black-blood T1w-, T2w- and TOF images. Age of sCAD was defined as time between onset of symptoms (stroke, TIA or Horners syndrome) and the CMR scan. VWH were categorized into hyperacute, acute, early subacute, late subacute and chronic based on their signal intensities on T1w- and T2w images.ResultsThe mean age of sCAD was 2.0, 5.8, 15.7 and 58.7 days in patients with acute, early subacute, late subacute and chronic VWH as classified by CMR (p < 0.001 for trend). Agreement was moderate between VWH types in our study and the previously proposed time scheme of signal evolution for cerebral hemorrhage, Cohens kappa 0.43 (p < 0.001). There was a strong agreement of CMR VWH classification compared to the time scheme which was proposed for carotid intraplaque hematomas with Cohens kappa of 0.74 (p < 0.001).ConclusionsSignal intensities of VWH in sCAD vary over time and multi-sequence CMR can help to determine the age of an arterial dissection. Furthermore, findings of this study suggest that the time course of carotid hematomas differs from that of cerebral hematomas.