Background:White matter hyperintensities (WMH) and cerebral microbleeds (CMB) are manifestations of cerebral small vessel disease (SVD). We investigated the racial differences in SVD among African American (AA) and white patients with stroke/TIA. Methods:Magnetic resonance imaging (MRI) of brain in consecutive patients were assessed in four years as part of a study. Deep and periventricular WMHs (DWMHs and PVWMHs, respectively) were rated visually on axial fluid-attenuated inversion recovery (FLAIR) sequence using the 3-point Fazekas scale and categorized into none/mild (grades 0 and 1) or moderate/severe (grades 2 and 3). Gradient echo imaging was used to categorize CMBs for number, location, and topography. Patient demographics were collected including vascular risk factors, periodontal disease (PD), and index event (TIA, stroke, and stroke subtype). Univariate (t-tests for continuous variables, and X2 test for categorical variables) and multivariable analyses (multiple logistic regression) were conducted to assess the association between race and SVD. Results:A total of 861 patients, 469 AA and 360 white, were compared for moderate/severe PVWMH, DWMH, and CMB ≥5. White patients were older (67±11 vs. 60±13, p <0.001) and more likely to be male (60% vs. 52%, p = 0.02). AA patients were more likely to be hypertensive (91% vs. 85%, p = 0.006), diabetic (49% vs. 40%, p = 0.009), and have moderately severe gum disease (55% vs. 36%, p <0.001). AA race was associated with PVWMH (Adjusted OR 1.83, 95% 1.32-2.55) adjusted for age, gender, hypertension, diabetes, and PD. AA race was associated with DWMH (Adjusted OR 1.5, 95% 1.08-2.1) adjusted for age, hypertension, diabetes, and PD. AA race was associated with CMB ≥5 (Adjusted OR 3.93, 95% 1.08-14.36) adjusted for age and hypertension. Conclusion:We report an independent association between AA race and various manifestations of SVD including moderate/severe DWMH, PVWMH, and CMB ≥5 in stroke/TIA patients.
Endothelial dysfunction causing impaired cerebrovascular vasodilatory capacity in response to reduced blood pressure has been proposed as a mechanism of white matter (WM) disease development. This study investigated autoregulation of CBF to blood pressure reduction in WM and gray matter (GM) in normal subjects recruited as controls for a study of cerebrovascular function in human immunodeficiency virus positive subjects. They underwent baseline CBF and oxygen extraction fraction measurement by MRI before and after mean arterial pressure (MAP) reduction. Autoregulatory Index (AI) was computed as CBF AI = -%CBF change/% MAP change. Thirty of 44 subjects achieved target MAP reduction. MAP was reduced -13.65 ± 2.35 (range 10 to 20) %. WM AI of -0.61 ± 1.23 was significantly more negative than GM AI of 0.02 ± 0.44 (paired t test, p= 0.016). WM CBF fell (paired Wilcoxon, p= 0.03) whereas GM CBF did not change (paired Wilcoxon, p=0.92). WM AI was different from 0 (p=0.011, one-sample t-test vs 0), whereas GM AI was not (p=0.913, one-sample t-test vs 0). These data demonstrate that maintenance of CBF to 10-20% reductions in MAP is less effective in WM than in GM. This may put WM at higher risk for ischemic damage.
OBJECTIVES:We investigated whether periodontal disease is associated with specific stroke subtype.MATERIALS AND METHODS:This is a single-center cross-sectional study. Periodontal disease was assessed in stroke and transient ischemic attack patients. Strokes caused by large-artery atherosclerosis were classified as intracranial atherosclerosis or extracranial atherosclerosis as well as anterior or posterior circulation disease.RESULTS:Consecutive patients (N=265) were enrolled (age 64 ± 12.8, 49% white, 46% black, and 56% male). A third (N=87) had moderately severe periodontal disease. Twenty percent (N=42) were strokes due to large-artery atherosclerosis. Large-artery strokes had a higher proportion of patients with periodontal disease than without periodontal disease (31% vs.16%, X2 p=0.01). There was also a higher proportion of patients with periodontal disease (12% vs. 5%) with stroke due to posterior circulation disease (crude odds ratio or OR 3.0, 95% CI 1.1-7.9, p=0.03), which persisted after adjustment for covariates (adjusted OR 3.1, 95% CI 1.04-9.1, p=0.004). Periodontal disease patients had a higher rate of large-artery stroke due to intracranial atherosclerosis compared to those without periodontal disease (20% vs. 8%; crude OR 2.6, 95% CI 1.3-5.6, p=0.01), and this association persisted after adjustment (adjusted OR 2.6, 95% CI 1.1-5.8, p=0.004).CONCLUSIONS:We report a higher proportion of stroke due to large-artery atherosclerosis in patients with periodontal disease compared to those without periodontal disease. We report an independent association between periodontal disease and intracranial atherosclerosis, as well as between periodontal disease and posterior circulation disease.
t-PA has a widespread neuroendocrine distribution including prominent expression in chromaffin cells of the sympathoadrenal system. Chromaffin cell t-PA is sorted into catecholamine storage vesicles and co-released with catecholamines in response to sympathoadrenal activation, suggesting that catecholamine storage vesicles may serve as a reservoir for the rapid release of t-PA. Chromogranin A (CgA), a major core protein in secretory vesicles throughout the neuroendocrine system, may play a crucial role in targeting proteins into the regulated secretory pathway, by forming aggregated "granin" complexes to which other proteins destined for the regulated secretory vesicle bind and become separated from constitutively secreted proteins in the trans-Golgi network (TGN). Formation of such complexes is facilitated by conditions of the TGN (low pH, high Ca+2). We tested the hypothesis that t-PA interacts specifically with CgA and that this interaction is enhanced under conditions of the TGN. Immobilized t-PA was incubated with 125I-CgA. t-PA interacted specifically and saturably with CgA and the interaction was domain-specific, mediated by the EGF/finger and kringle 1 domains of t-PA and by a specific internal hydrophilic domain within CgA (KERTHQQKKHSSYEDELSEVL) as assessed by antibody and peptide competition studies. The interaction of t-PA with aggregated CgA complexes may play a role in the targeting of t-PA and its release from neurosecretory cells. These results may have broad implications for the regulation of local neurosecretory cell plasminogen activation under both normal physiological conditions and pathological conditions including cerebral ischemia.
Endoplasmic reticulum stress is activated following both stroke and traumatic brain injury producing reactive oxgygen species, increasing intracellular calcium levels, and inducing inflammation; however, the timing and duration of activation varies between injuries. Preventing the immediate effects of ischemic/reperfusion injury or traumatic brain injury is challenging due to short onset of injury, but mitigating the secondary effects is a therapeutically targetable option. Preventative therapies using pharmacological agents have been utilized in pre-clinical models of neural injury to ameliorate secondary effects such as apoptosis and neurodegeneration. The connection between ER stress activation, apoptosis, and subsequent neurodegeneration has been proposed, but not yet causally linked. Researchers are now pursuing effective treatment strategies to suppress the secondary effects of neural injury in order to mitigate the development of chronic deficits. Secondary effects such as endoplasimic reticulum stress and neuroinflammation can be prevented in pre-clinical models, but the results have yet to translate to meaningful treatment options for patients. Evidence suggests that targeting the right transcription factors, at the right time, will aid in the prevention of apoptosis and neurodegenerative disease development following neural injury. In this review, we examine therapeutic approaches that target secondary injury and how these may correlate to better treatment options for patients.
BACKGROUNDElevated factor VIII (FVIII) has been linked with higher risk of vascular events. We aimed to determine the relationship between FVIII and hypertension in patients with acute ischemic stroke.METHODSFVIII levels and transthoracic echocardiogram reports were reviewed in patients with acute ischemic stroke who presented to our stroke center between July 2008 and September 2011. Presenting systolic and diastolic blood pressure, history of hypertention, left ventricular hypertrophy, diastolic dysfunction, and depressed left ventricular function (ejection fraction <50%) were compared in patients with normal and elevated FVIII levels.RESULTSNo differences in presenting blood pressure or frequency of hypertension history were found based on FVIII level. Patients with elevated FVIII had demonstrated a statistically significant higher frequency of diastolic dysfunction (64.8 vs. 43.6%, p=0.042) and a trend towards higher frequency of left ventricular hypertrophy (18.5 vs 5.1%, p=0.073). Median FVIII was significantly higher in patients with left ventricular hypertrophy (194.4 vs 152.9%, p=0.042) and diastolic dysfunction (180.5 vs 149.3%, p=0.031) than patients without these findings.CONCLUSIONSAmong patients with acute ischemic stroke, FVIII levels were higher when there was evidence of hypertensive heart disease. Synthesis of FVIII may be augmented by the ongoing presence of shear stress and could contribute to the higher risk of vaso-occlusive events in patients with elevated FVIII.
BACKGROUND:In 2008, the European Cooperative Acute Stroke Study-3 (ECASS-3) demonstrated that intravenous-tissue plasminogen activator could be safely administered for acute stroke patients presenting between 3 and 4.5 hours from symptom onset. Recently, the Food and Drug Administration rejected expansion of this time window in the United States. We sought to determine how many fewer patients would be treated by maintaining this restricted time window. METHODS:We reviewed charts from patients who received intravenous thrombolysis at the University of Alabama at Birmingham between January 2009 and December 2011. Patients were divided into two groups (treated within 3 hours of onset, treated between 3 and 4.5 hours from onset). Demographics, stroke severity and protocol deviations according to the ECASS-3 trial were collected. Our safety measures were any hemorrhagic transformation, symptomatic intracerebral hemorrhage and systemic hemorrhage. RESULTS:Two hundred and twelve patients were identified, of whom 192 were included in our analysis. A total of 36 patients (19%) were treated between 3 and 4.5 hours. No statistical differences were seen between age (p=0.633), gender (p=0.677), race (p=0.207) or admission stroke severity (p=0.737). Protocol deviations from the ECASS-3 criteria were found in 20 patients (56%). These were primarily age > 80 and aggressive blood pressure management. Despite these deviations, we did not see significant increases in the rates of adverse events in patients treated in the extended time window. CONCLUSIONS:Our data are consistent with previously reported international data that IV thrombolysis can safely be used up to 4.5 hours from symptom onset. Restricting the time window to 3 hours would have resulted in almost one-fifth fewer patients treated at our center.
BACKGROUND Neuroprotective agents have the potential to reduce ischemia to penumbra of the cortex, but are time-sensitive. To quickly determine whether a cortical stroke is present without imaging, we created a scoring system based on the NIH stroke scale (NIHSS) that can accurately predict cortical damage in an acute ischemic stroke (AIS). METHODS Patients treated with tPA for AIS were retrospectively assessed through prospectively acquired databases at two stroke centers. Stroke was classified as cortical vs. non-cortical stroke. The total NIHSS score, cortical components (gaze, visual fields, language, and neglect) and cortical score (sum of cortical components) were analyzed for site 1 and then validated for site 2 for sensitivity and positive predictive value (PPV) for a cortical stroke. RESULTS An acute infarct was detected in 194/239 (81%) patients at site 1 and 122/174 (70%) at site 2 on diffusion-weighted MRI. Cortical involvement was found in 71% (site 1) and 75% (site 2). The median cortical score was 25% of the total NIHSS score at both sites. NIHSS ≥ 4 had the highest sensitivity; PPV was 90% for any cortical sign with ≥ 2 points. The best combination of sensitivity and PPV was cortical score/NIHSS score ≥10%. DISCUSSION If a trial targeting cortical stroke required that the cortical score represent at least 10% of the total NIHSS score with no imaging, less than 10% of patients with cortical stroke would be missed and less than 18% of patients would be misclassified as having a cortical stroke.
In 2001, we described six patients with cerebellar ataxia and severe deficiency of coenzyme Q10 (CoQ10, ubiquinone) in skeletal muscle [1]. Within one year, we described 13 additional patients [2]; therefore, we suspected this was not a very rare syndrome. Twelve years after our original report, cerebellar ataxia and atrophy has emerged as the most common clinical presentation of CoQ10 deficiency, and now we know that it can be primary (associated with mutations in genes coding proteins involved in the biosynthesis of CoQ10 or its regulation), or secondary to other causes. In fact, 3 of the first patients reported by Musumeci et al. have a homozygous mutation in APTX, encoding aprataxin [3], a protein involved in DNA break repair, and one of the patients reported by Lamperti et al. carried heterozygous mutations in ADCK3/CABC1, which encodes a kinase required for CoQ10 biosynthesis [4]. To date, mutations in ADCK3/CABC1 have been identified in 21 patients (14 families), some of them presenting with cerebellar ataxia and atrophy, plus exercise intolerance, dystonia and mild cognitive impairment [4–9]. Secondary CoQ10 deficiency has been confirmed in additional patients carrying APTX mutations [3,10–12]. The clinical picture is characterized by cerebellar ataxia and atrophy variably associated with peripheral neuropathy, seizures, mental retardation, migraine, psychiatric manifestations, muscle weakness, exercise intolerance, upper motor neuron signs, ptosis and ophthalmoplegia, retinitis pigmentosa, optic atrophy, hearing impairment, lipomas, Dandy-Walker syndrome, agenesis of the corpus callosum, hypogonadism, and other endocrinological problems [13]. CoQ10 levels are low in muscle, and frequently fibroblasts and lymphoblasts. Complex I+II and II+III activities are reduced in severely affected patients, but have been reported normal in muscle from less severely affected patients. Although muscle biopsies showed only non-specific myopathic changes in the first report, subsequent publications noted that skeletal muscle of some patients revealed mitochondrial proliferation and lipid accumulation, and COX-deficient fibers, but no typical ragged red fibers (RRF). The condition usually begins in childhood or adolescence; however, patients with adult-onset, very mild phenotype, have been described [13,9]. Interestingly, functionally impaired variants of COQ2 were recently associated with an increased risk of multiple-system atrophy, a neurodegenerative disease characterized by autonomic failure in addition to various combinations of cerebellar ataxia, parkinsonism, and pyramidal dysfunction [14]. Supplementation with CoQ10 was associated with increased strength and disappearance of seizures in the affected individuals with aprataxin mutations we described [1,3], and with mild clinical improvement in patients with cerebellar ataxia associated with mutations in ADCK3/CABC1 [4,5]. In a recent study, Pineda et al. assessed the clinical outcome in 14 patients with cerebellar ataxia with and without documented CoQ10 deficiency in muscle and/or fibroblasts and unknown molecular defect and observed that all patients with CoQ10 deficiency responded to therapy [6]. Therefore, muscle CoQ10 levels should be investigated in patients with autosomal recessive cerebellar ataxia, to diagnose and treat patients with this condition and to increase our understanding of this expanding group of disorders.
BACKGROUND Functional MRI (fMRI) basic cognitive paradigms such as the n-back have been shown to detect cognitive impairment (CI) in Multiple Sclerosis (MS). The immediate memory task/delayed memory task (IMT/DMT) detects varying degrees of working memory (WM) by alternating three levels of complexity and two levels of WM delay. This paradigm has not been evaluated in MS nor validated against standard neuropsychological (NP) testing. OBJECTIVE To evaluate the correlation between WM function and blood oxygen level dependent (BOLD) activation on fMRI in MS patients undergoing the IMT/DMT. To compare IMT/DMT behavioral scores to NP scores. METHODS 10 MS patients with no history of CI underwent the Minimal Assessment of Cognitive Function in MS (MACFIMS) and an fMRI session where they performed the IMT/DMT. Working-memory ("wmem") activation was defined as the BOLD signal during DMT blocks for a particular condition (3, 5, or 7 digits per stimuli) minus the BOLD signal during IMT blocks for that condition. Areas of statistically significant Family Wise Error (FWE) -corrected cluster-level BOLD activation were identified using SPM8 Random Effects t-test. IMT/DMT behavioral data and MACFIMS scores were compared. RESULTS The 3-digit as well as the 5-digit wmem showed significant fMRI BOLD activation. The 3-digit wmem, activation was found in portions of the bilateral superior and mid frontal cortex, supplementary motor area, pre and post central gyrus, bilateral superior and inferior parietal lobule, inferolateral pre-frontal cortex, cuneus, insula and cingulate regions. The 5 digit wmen activation was seen in the inferior medial frontal and medial orbitofrontal cortex. IMT/DMT behavioral scores were within normal range and consistent with MACFIMS. CONCLUSION IMT/DMT, a novel fMRI working memory paradigm, is associated with BOLD activation in areas of the brain related to cognitive function in patients with MS. Both MACFIMS and IMT/DMT scores were in agreement and supported intact cognitive function.
