Abnormally reduced primary motor cortex output is related to impaired hand function in chronic stroke.

Stroke often involves primary motor cortex (M1) and its corticospinal projections (CST). As hand function is critically dependent on these structures, its recovery is often incomplete. The neuronal substrate supporting affected hand function is not well understood but likely involves reorganized M1 and CST of the lesioned hemisphere (M1IL and CSTIL). We hypothesized that affected hand function in chronic stroke is related to structural and functional reorganization of M1IL and CSTIL. We tested 18 patients with chronic ischemic stroke involving M1 or CST. Their hand function was compared with 18 age-matched healthy subjects. M1IL thickness and CSTIL fractional anisotropy (FA) were determined with MRI and compared with measures of the other hemisphere. Transcranial magnetic stimulation (TMS) was applied to M1IL to determine its input-output function [stimulus response curve (SRC)]. The plateau of the SRC (MEPmax), inflection point, and slope parameters of the curve were extracted. Results were compared with measures in 12 age-matched healthy controls. MEPmax of M1IL was significantly smaller ( P = 0.02) in the patients, indicating reduced CSTIL motor output, and was correlated with impaired hand function ( P = 0.02). M1IL thickness ( P < 0.01) and CSTIL-FA ( P < 0.01) were reduced but did not correlate with hand function. The results indicate that employed M1IL or CSTIL structural measures do not explain the extent of impairment in hand function once M1 and CST are sufficiently functional for TMS to evoke a motor potential. Instead, impairment of hand function is best explained by the abnormally low output from M1IL. NEW & NOTEWORTHY Hand function often remains impaired after stroke. While the critical role of the primary motor cortex (M1) and its corticospinal output (CST) for hand function has been described in the nonhuman primate stroke model, their structure and function have not been systematically evaluated for patients after stroke. We report that in chronic stroke patients with injury to M1 and/or CST an abnormally reduced M1 output is related to impaired hand function.

The Brain Thermal Response as a Potential Neuroimaging Biomarker of Cerebrovascular Impairment.

BACKGROUND AND PURPOSE: Brain temperature is critical for homeostasis, relating intimately to cerebral perfusion and metabolism. Cerebral thermometry is historically challenged by the cost and invasiveness of clinical and laboratory methodologies. We propose the use of noninvasive MR thermometry in patients with cerebrovascular disease, hypothesizing the presence of a measurable brain thermal response reflecting the tissue hemodynamic state. MATERIALS AND METHODS: Contemporaneous imaging and MR thermometry were performed in 10 patients (32-68 years of age) undergoing acetazolamide challenge for chronic, anterior circulation steno-occlusive disease. Cerebrovascular reactivity was calculated with blood oxygen level-dependent imaging and arterial spin-labeling methods. Brain temperature was calculated pre- and post-acetazolamide using previously established chemical shift thermometry. Mixed-effects models of the voxelwise relationships between the brain thermal response and cerebrovascular reactivity were computed, and the significance of model coefficients was determined with an F test (P < .05). RESULTS: We observed significant, voxelwise quadratic relationships between cerebrovascular reactivity from blood oxygen level-dependent imaging and the brain thermal response (x coefficient = 0.052, P < .001; x2coefficient = 0.0068, P < .001) and baseline brain temperatures (x coefficient = 0.59, P = .008; x2 coefficient = -0.13, P < .001). A significant linear relationship was observed for the brain thermal response with cerebrovascular reactivity from arterial spin-labeling (P = .001). CONCLUSIONS: The findings support the presence of a brain thermal response exhibiting complex but significant interactions with tissue hemodynamics, which we posit to reflect a relative balance of heat-producing versus heat-dissipating tissue states. The brain thermal response is a potential noninvasive biomarker for cerebrovascular impairment.

The Effects of Acetazolamide on the Evaluation of Cerebral Hemodynamics and Functional Connectivity Using Blood Oxygen Level-Dependent MR Imaging in Patients with Chronic Steno-Occlusive Disease of the Anterior Circulation.

BACKGROUND AND PURPOSE: Measuring cerebrovascular reactivity with the use of vasodilatory stimuli, such as acetazolamide, is useful for chronic cerebrovascular steno-occlusive disease. The purpose of this study was to evaluate the effects of acetazolamide on the assessment of hemodynamic impairment and functional connectivity by using noninvasive resting-state blood oxygen level-dependent MR imaging. MATERIALS AND METHODS: A 20-minute resting-state blood oxygen level-dependent MR imaging scan was acquired with infusion of acetazolamide starting at 5 minutes after scan initiation. A recently developed temporal-shift analysis technique was applied on blood oxygen level-dependent MR imaging data before and after acetazolamide infusion to identify regions with hemodynamic impairment, and the results were compared by using contrast agent-based DSC perfusion imaging as the reference standard. Functional connectivity was compared with and without correction on the signal by using information from temporal-shift analysis, before and after acetazolamide infusion. RESULTS: Visually, temporal-shift analysis of blood oxygen level-dependent MR imaging data identified regions with compromised hemodynamics as defined by DSC, though performance deteriorated in patients with bilateral disease. The Dice similarity coefficient between temporal-shift and DSC maps was higher before (0.487 ± 0.150 by using the superior sagittal sinus signal as a reference for temporal-shift analysis) compared with after acetazolamide administration (0.384 ± 0.107) (P = .006, repeated-measures ANOVA). Functional connectivity analysis with temporal-shift correction identified brain network nodes that were otherwise missed. The accuracy of functional connectivity assessment decreased after acetazolamide administration (P = .015 for default mode network, repeated-measures ANOVA). CONCLUSIONS: Temporal-shift analysis of blood oxygen level-dependent MR imaging can identify brain regions with hemodynamic compromise in relation to DSC among patients with chronic cerebrovascular disease. The use of acetazolamide reduces the accuracy of temporal-shift analysis and network connectivity evaluation.

Performance of CT ASPECTS and Collateral Score in Risk Stratification: Can Target Perfusion Profiles Be Predicted without Perfusion Imaging?

BACKGROUND AND PURPOSE: Endovascular trials suggest that revascularization benefits a subset of acute ischemic stroke patients with large-artery occlusion and small-core infarct volumes. The objective of our study was to identify thresholds of noncontrast CT-ASPECTS and collateral scores on CT angiography that best predict ischemic core volume thresholds quantified by CT perfusion among patients with acute ischemic stroke. MATERIALS AND METHODS: Fifty-four patients with acute ischemic stroke (<12 hours) and MCA/intracranial ICA occlusion underwent NCCT/CTP during their initial evaluation. CTP analysis was performed on a user-independent platform (RApid processing of PerfusIon and Diffusion), computing core infarct (defined as CBF of <30% normal). A target mismatch profile consisting of infarction core of ≤50 mL was selected to define candidates with acute ischemic stroke likely to benefit from revascularization. RESULTS: NCCT-ASPECTS of ≥9 with a CTA collateral score of 3 had 100% specificity for identifying patients with a CBF core volume of ≤50 mL. NCCT-ASPECTS of ≤6 had 100% specificity for identifying patients with a CBF core volume of >50 mL. In our cohort, 44 (81%) patients had an NCCT-ASPECTS of ≥9, a CTA collateral score of 3, or an NCCT-ASPECTS of ≤6. CONCLUSIONS: Using an NCCT-ASPECTS of ≥9 or a CTA collateral score of 3 best predicts CBF core volume infarct of ≤50 mL, while an NCCT-ASPECTS of ≤6 best predicts a CBF core volume infarct of >50 mL. Together these thresholds suggest that a specific population of patients with acute ischemic stroke not meeting such profiles may benefit most from CTP imaging to determine candidacy for revascularization.

Performance and Predictive Value of a User-Independent Platform for CT Perfusion Analysis: Threshold-Derived Automated Systems Outperform Examiner-Driven Approaches in Outcome Prediction of Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Treatment strategies in acute ischemic stroke aim to curtail ischemic progression. Emerging paradigms propose patient subselection using imaging biomarkers derived from CT, CTA, and CT perfusion. We evaluated the performance of a fully-automated computational tool, hypothesizing enhancements compared with qualitative approaches. The correlation between imaging variables and clinical outcomes in a cohort of patients with acute ischemic stroke is reported. MATERIALS AND METHODS: Sixty-two patients with acute ischemic stroke and MCA or ICA occlusion undergoing multidetector CT, CTA, and CTP were retrospectively evaluated. CTP was processed on a fully operator-independent platform (RApid processing of PerfusIon and Diffusion [RAPID]) computing automated core estimates based on relative cerebral blood flow and relative cerebral blood volume and hypoperfused tissue volumes at varying thresholds of time-to-maximum. Qualitative analysis was assigned by 2 independent reviewers for each variable, including CT-ASPECTS, CBV-ASPECTS, CBF-ASPECTS, CTA collateral score, and CTA clot burden score. Performance as predictors of favorable clinical outcome and final infarct volume was established for each variable. RESULTS: Both RAPID core estimates, CT-ASPECTS, CBV-ASPECTS, and clot burden score correlated with favorable clinical outcome (P < .05); CBF-ASPECTS and collateral score were not significantly associated with favorable outcome, while hypoperfusion estimates were variably associated, depending on the selected time-to-maximum thresholds. Receiver operating characteristic analysis demonstrated disparities among tested variables, with RAPID core and hypoperfusion estimates outperforming all qualitative approaches (area under the curve, relative CBV = 0.86, relative CBF = 0.81; P < .001). CONCLUSIONS: Qualitative approaches to acute ischemic stroke imaging are subject to limitations due to their subjective nature and lack of physiologic information. These findings support the benefits of high-speed automated analysis, outperforming conventional methodologies while limiting delays in clinical management.

Sleep-related falling out of bed in Parkinson's disease.

BACKGROUND AND PURPOSE: Sleep-related falling out of bed (SFOB), with its potential for significant injury, has not been a strong focus of investigation in Parkinson's disease (PD) to date. We describe the demographic and clinical characteristics of PD patients with and without SFOB. METHODS: We performed a retrospective analysis of 50 consecutive PD patients, who completed an REM sleep behavior disorder screening questionnaire (RBDSQ), questionnaires to assess for RBD clinical mimickers and questions about SFOB and resulting injuries. Determination of high risk for RBD was based on an RBDSQ score of 5 or greater. RESULTS: Thirteen patients reported history of SFOB (26%). Visual hallucinations, sleep-related injury, quetiapine and amantadine use were more common in those patients reporting SFOB. Twenty-two patients (44%) fulfilled criteria for high risk for RBD, 12 of which (55%) reported SFOB. Five patients reported injuries related to SFOB. SFOB patients had higher RBDSQ scores than non-SFOB patients (8.2±3.0 vs. 3.3±2.0, p<0.01). For every one unit increase in RBDSQ score, the likelihood of SFOB increased two-fold (OR 2.4, 95% CI 1.3-4.2, p<0.003). CONCLUSIONS: SFOB may be a clinical marker of RBD in PD and should prompt confirmatory polysomnography and pharmacologic treatment to avoid imminent injury. Larger prospective studies are needed to identify risk factors for initial and recurrent SFOB in PD.

Racial and geographic differences in fish consumption: the REGARDS study.

BACKGROUND: Omega-3 fatty acids from fish have been shown to have favorable effects on platelet aggregation, blood pressure, lipid profile, endothelial function, and ischemic stroke risk, but there are limited data on racial and geographic differences in fish consumption. METHODS: Reasons for Geographic and Racial Differences in Stroke (REGARDS) is a national cohort study that recruited 30,239 participants age ≥45 years with oversampling from the southeastern Stroke Belt and Buckle and African Americans (AAs). Centralized phone interviewers obtained medical histories and in-home examiners measured weight and height. Dietary data for this cross-sectional analysis were collected using the self-administered Block98 Food Frequency Questionnaire (FFQ). Adequate intake of nonfried fish was defined as consumption of ≥2 servings per week based on American Heart Association guidelines. After excluding the top and bottom 1% of total energy intake and individuals who did not answer 85% or more of questions on the FFQ, the analysis included 21,675 participants. RESULTS: Only 5,022 (23%) participants consumed ≥2 servings per week of nonfried fish. In multivariable analysis, factors associated with inadequate intake of nonfried fish included living in the Stroke Belt (vs non-Belt) (odds ratio [OR] 0.83, 95% confidence interval [CI] 0.77-0.90) and living in the Stroke Buckle (vs non-Belt) (OR 0.89, 95% CI 0.81-0.98); factors associated with ≥2 servings per week of fried fish included being AA (vs white) (OR 3.59, 95% CI 3.19-4.04), living in the Stroke Belt (vs non-Belt) (OR 1.32, 95% CI 1.17-1.50), and living in the Stroke Buckle (vs non-Belt) (OR 1.17, 95% CI 1.00-1.36). CONCLUSIONS: Differential consumption of fish may contribute to the racial and geographic disparities in stroke.

Risk factors associated with major cerebrovascular complications after intracranial stenting.

BACKGROUND: There are limited data on the relationship between patient and site characteristics and clinical outcomes after intracranial stenting. METHODS: We performed a multivariable analysis that correlated patient and site characteristics with the occurrence of the primary endpoint (any stroke or death within 30 days of stenting or stroke in the territory of the stented artery beyond 30 days) in 160 patients enrolled in this stenting registry. All patients presented with an ischemic stroke, TIA, or other cerebral ischemic event (e.g., vertebrobasilar insufficiency) in the territory of a suspected 50-99% stenosis of a major intracranial artery while on antithrombotic therapy. RESULTS: Cerebral angiography confirmed that 99% (158/160) of patients had a 50-99% stenosis. In multivariable analysis, the primary endpoint was associated with posterior circulation stenosis (vs anterior circulation) (hazard ratio [HR] 3.4, 95% confidence interval [CI] 1.2-9.3, p = 0.018), stenting at low enrollment sites (< 10 patients each) (vs high enrollment site) (HR 2.8, 95% CI 1.1-7.6, p = 0.038), < or = 10 days from qualifying event to stenting (vs > or = 10 days) (HR 2.7, 95% CI 1.0-7.8, p = 0.058), and stroke as a qualifying event (vs TIA/other) (HR 3.2, 95% CI 0.9-11.2, p = 0.064). There was no significant difference in the primary endpoint based on age, gender, race, or percent stenosis (50-69% vs 70-99%). CONCLUSIONS: Major cerebrovascular complications after intracranial stenting may be associated with posterior circulation stenosis, low volume sites, stenting soon after a qualifying event, and stroke as the qualifying event. These factors will need to be monitored in future trials of intracranial stenting.

Diabetic autoimmune markers in children and adolescents with type 2 diabetes.

BACKGROUND: There is an increase in the incidence of type 2 diabetes in children and adolescents. Absence of known diabetes autoimmune markers is sometimes required to confirm the diagnosis. OBJECTIVE: To identify clinical and autoimmune characteristics of type 2 diabetes in a pediatric population. METHOD: We report an analysis of 48 children and adolescents with type 2 diabetes, compared with 39 randomly selected children with type 1 diabetes, diagnosed and followed at the Loma Linda University Pediatric Diabetes Center. Ethnic, familial, seasonal, and autoimmune marker characteristics are outlined. To determine the reliability of antibody testing in confirming the type of diabetes at diagnosis, we studied the incidence of positive islet cell antibodies (ICAs), glutamic acid decarboxylase antibodies (GADs), and insulin autoantibodies (IAAs) at diagnosis in both groups. ICA512, GADs, and IAAs were measured by radioimmunoassay. RESULTS: The cohort with type 2 diabetes had a similar gender distribution as the group with type 1 diabetes but a significantly higher age at diagnosis. Ethnic background was significantly different between the 2 groups, predominantly Hispanic in type 2 and white in type 1. Body mass index was significantly higher in type 2 diabetes (mean = 31.24 kg/m(2)). Among the patients with type 2 diabetes, 33% presented in diabetic ketoacidosis, random blood glucose at diagnosis ranged from 11.4 to 22.25 mmol/L (228-445 mg/dL), fasting C-peptide levels ranged from 0.89 to 2.7 nmol/L (2.7-8.2 ng/mL; normal: <1.36 nmol/L), and hemoglobin A(1C) was 10.8 +/- 3.5% (normal: <6.6%). None of these parameters was significantly different from the type 1 diabetes group. Although the incidence of diabetes antibody markers was significantly lower in type 2 versus type 1 diabetes, 8.1% of patients with type 2 diabetes had positive ICAs, 30.3% had positive GADs, and 34.8% had positive IAAs without ever being treated with insulin. In the type 2 diabetes group, none of the Hispanic patients had ICAs. However, there was no significant correlation between any of the diabetes antibodies and obesity, presence of acanthosis nigricans, or family history of diabetes. The frequency of thyroid antibodies was not significantly different from the group with type 1 diabetes. Daily insulin requirements 1 year after diagnosis were significantly lower in type 2 diabetes, ranging from 0 to 1.2 U/kg with a mean of 0.33. CONCLUSION: Absence of diabetes autoimmune markers is not a prerequisite for the diagnosis of type 2 diabetes in children and adolescents.

Serotonergic decompensation in the akinetic expression of Parkinson's disease.

The current diagnostic and treatment paradigm for the akinetic form of Parkinson's disease asserts that the majority of symptoms and treatment phenomena arise from a dysfunctional dopaminergic system. Recent studies have attempted to determine the roles of other biogenic amine neurotransmitters such as serotonin and norepinephrine. Metabolic breakdown product studies of Parkinsonian and non-Parkinsonian cerebrospinal fluid (CSF) samples indicate significant differences in the levels of serotonin and norepinephrine in addition to the levels of dopamine. Such changes may suggest that current pharmacologic therapies that attempt to restore only dopamine are inadequate, and require accompanying therapies to elevate serotonin and norepinephrine levels.

Diabetic autoimmunity in infants and pre-schoolers with type 1 diabetes.

The incidence of type 1 diabetes is increasing most rapidly in children under 5 yrs of age, a group where the disease appears to be more accelerated than traditional type 1 diabetes. Little is known about demographics, and markers of diabetes autoimmunity, in infants and pre-schoolers with type 1 diabetes. We report an analysis of 47 children diagnosed with type 1 diabetes prior to 5 yrs of age compared with a representative cohort (n=49) diagnosed after 5 yrs of age, and all were followed at Loma Linda University (LLU) Children's Hospital. Ethnic, familial, seasonal, and autoimmune marker characteristics are outlined. To determine the prevalence of diabetes autoimmune markers, ICA512, GAD65 and insulin autoantibodies (IAA) antibodies were measured. Children with early-onset diabetes had a significantly higher incidence of viral illness symptoms (p=0.005) and diabetic ketoacidosis (DKA; p=0.017) at the time of diagnosis. However, hemoglobin A1C (HbA1c) levels at diagnosis were significantly higher in the later-onset group (p=0.001). A honeymoon period was reported in 14.8% of children diagnosed before 5 yrs of age compared with 42.1% in those diagnosed over 5 yrs of age (p=0.038). Islet-cell antibodies (ICAs) and glutamic acid decarboxylase (GAD) antibody titers were significantly different between early- and later-onset groups. ICA titers were positive in 35.29%, and GAD in 41.38% of the early-onset group versus 70.83 and 71.74% in children with later-onset disease, (p=0.001 and 0.009, respectively). IAA titers, drawn after instituting insulin therapy, were not significantly different between the two groups. GAD and ICA512 antibody results suggest a relative lack of diabetes immune markers in infants and toddlers with new-onset diabetes. This finding, and the apparent shorter pre-clinical phase reflected in the lower HbA1c values, may indicate age-related differences in type 1 diabetes autoimmunity or the existence of non-autoimmune diabetogenic mechanisms in younger children.