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1.  The Aging Brain and Cognition 
JAMA neurology  2013;70(4):488-495.
β-Amyloid (Aβ) deposition and vascular brain injury (VBI) frequently co-occur and are both associated with cognitive decline in aging. Determining whether a direct relationship exists between them has been challenging. We sought to understand VBI’s influence on cognition and clinical impairment, separate from and in conjunction with pathologic changes associated with Alzheimer disease (AD).
To examine the relationship between neuroimaging measures of VBI and brain Aβ deposition and their associations with cognition.
Design and Setting
A cross-sectional study in a community- and clinic-based sample recruited for elevated vascular disease risk factors.
Clinically normal (mean age, 77.1 years [N=30]), cognitively impaired (mean age, 78.0 years [N=24]), and mildly demented (mean age, 79.8 years [N=7]) participants.
Magnetic resonance imaging, Aβ (Pitts-burgh Compound B–positron emission tomographic [PiB-PET]) imaging, and cognitive testing.
Main Outcome Measures
Magnetic resonance images were rated for the presence and location of infarct (34 infarct-positive participants, 27 infarct-negative participants) and were used to quantify white matter lesion volume. The PiB-PET uptake ratios were used to create a PiB index by averaging uptake across regions vulnerable to early Aβ deposition; PiB positivity (29 PiB-positive participants, 32 PiB-negative participants) was determined from a data-derived threshold. Standardized composite cognitive measures included executive function and verbal and nonverbal memory.
Vascular brain injury and Aβ were independent in both cognitively normal and impaired participants. Infarction, particularly in cortical and subcortical gray matter, was associated with lower cognitive performance in all domains (P<.05 for all comparisons). Pittsburgh Compound B positivity was neither a significant predictor of cognition nor interacted with VBI.
Conclusions and Relevance
In this elderly sample with normal cognition to mild dementia, enriched for vascular disease, VBI was more influential than Aβ in contemporaneous cognitive function and remained predictive after including the possible influence of Aβ. There was no evidence that VBI increases the likelihood of Aβ deposition. This finding highlights the importance of VBI in mild cognitive impairment and suggests that the impact of cerebrovascular disease should be considered with respect to defining the etiology of mild cognitive impairment.
PMCID: PMC3771392  PMID: 23400560
2.  Associations between vascular risk factors, carotid atherosclerosis and cortical volume and thickness in older adults 
Background and Purpose
To investigate whether the Framingham Cardiovascular Risk Profile (FCRP) and carotid artery intima-media thickness (CIMT) are associated with cortical volume and thickness.
Consecutive subjects participating in a prospective cohort study of aging and mild cognitive impairment enriched for vascular risk factors for atherosclerosis underwent structural MRI scans at 3T and 4T MRI at three sites. Freesurfer (v5.1) was used to obtain regional measures of neocortical volumes (mm3) and thickness (mm). Multiple linear regression was used to determine the association of FCRP and CIMT with cortical volume and thickness
152 subjects (82 men) were aged 78 (±7) years old, 94 had a CDR of 0, 58 had a clinical dementia rating (CDR) of 0.5 and the mean mini-mental status examination (MMSE) was 28 ± 2. FCRP score was inversely associated with total gray matter (GM) volume, parietal and temporal GM volume (adjusted p<0.04). FCRP was inversely associated with parietal and total cerebral GM thickness (adjusted p<0.03). CIMT was inversely associated with thickness of parietal GM only (adjusted p=0.04). Including history of myocardial infarction or stroke and radiologic evidence of brain infarction, or apoE genotype did not alter relationships with FCRP or CIMT.
Increased cardiovascular risk was associated with reduced GM volume and thickness in regions also affected by Alzheimer’s disease (AD), independent of infarcts and apoE genotype. These results suggest a “double hit” toward developing dementia when someone with incipient AD also has high cardiovascular risk.
PMCID: PMC3732460  PMID: 22984010
Framingham cardiovascular risk profile; carotid intima media thickness; gray matter; cortical volume; cortical thickness; atrophy
3.  Associations between White Matter Hyperintensities and β Amyloid on Integrity of Projection, Association, and Limbic Fiber Tracts Measured with Diffusion Tensor MRI 
PLoS ONE  2013;8(6):e65175.
The goal of this study was to assess the relationship between Aβ deposition and white matter pathology (i.e., white matter hyperintensities, WMH) on microstructural integrity of the white matter. Fifty-seven participants (mean age: 78±7 years) from an ongoing multi-site research program who spanned the spectrum of normal to mild cognitive impairment (Clinical dementia rating 0–0.5) and low to high risk factors for arteriosclerosis and WMH pathology (defined as WMH volume >0.5% total intracranial volume) were assessed with positron emission tomography (PET) with Pittsburg compound B (PiB) and magnetic resonance and diffusion tensor imaging (DTI). Multivariate analysis of covariance were used to investigate the relationship between Aβ deposition and WMH pathology on fractional anisotropy (FA) from 9 tracts of interest (i.e., corona radiata, internal capsule, cingulum, parahippocampal white matter, corpus callosum, superior longitudinal, superior and inferior front-occipital fasciculi, and fornix). WMH pathology was associated with reduced FA in projection (i.e., internal capsule and corona radiate) and association (i.e., superior longitudinal, superior and inferior fronto-occipital fasciculi) fiber tracts. Aβ deposition (i.e., PiB positivity) was associated with reduced FA in the fornix and splenium of the corpus callosum. There were interactions between PiB and WMH pathology in the internal capsule and parahippocampal white matter, where Aβ deposition reduced FA more among subjects with WMH pathology than those without. However, accounting for apoE ε4 genotype rendered these interactions insignificant. Although this finding suggests that apoE4 may increase amyloid deposition, both in the parenchyma (resulting in PiB positivity) and in blood vessels (resulting in amyloid angiopathy and WMH pathology), and that these two factors together may be associated with compromised white matter microstructural integrity in multiple brain regions, additional studies with a longitudinal design will be necessary to resolve this issue.
PMCID: PMC3675157  PMID: 23762308
4.  Benefits of Hemicraniectomy Seen Many Years After Malignant Stroke in a Young Patient 
The benefits of hemicraniectomy for malignant middle cerebral artery (MCA) stroke may not be apparent in the 3- to 6-months in which final outcomes are assessed in research studies. We present the case of a 15-year-old who underwent hemicraniectomy for malignant MCA stroke and was significantly disabled 3 and 6 months after event. Over the long-term she was able to graduate from university, play tennis, and live an independent life. Although functional independence with only minor disability is relatively rare in adult hemicraniectomy patients, this outcome may be more easily achieved in children during a longer period of follow-up.
PMCID: PMC3449491  PMID: 23015800
stroke; middle cerebral artery; hemicraniectomy
We examined the correlation of angiographic collaterals in acute stroke with the presence, extent, and distribution of white matter changes, so called Leukoaraiosis, in an effort to determine if Leukoaraiosis indicates chronic cerebral hypoperfusion and/or is associated with the development of cerebral collateral circulation.
Consecutive acute strokes due to large vessel occlusion on angiography had pre-procedure CT or MRI white matter changes graded utilizing the Fazekas scale incorporating deep and periventricular components. Angiographic collaterals evaluated with a 5-point scale were correlated with leukoaraiosis.
Collaterals were evaluated in 102 cases (51 men, 51 women; mean age 66 (SD 18) years with acute occlusions of the proximal MCA (47%), distal ICA (28%), distal MCA (9%), basilar (7%), proximal ICA (7%), vertebral (1%), PCA (1%), and CCA (1%). Collateral grade was well distributed across the scale. Periventricular and deep white matter changes were evident in 34% and 51% of cases, respectively. Collateral grade exhibited no relationship with either the presence or extent of periventricular disease (p=.772, r=.029) or deep white matter changes (p=.559, r=−.059).
Leukoaraisosis exhibits no overt relationship with the extent of collaterals measured at angiography in acute ischemic stroke. Chronic small vessel disease may be a distinct pathophysiologic entity unrelated to arteriogenesis and compensatory aspects of collateral flow.
PMCID: PMC3030936  PMID: 20977524
Stroke; Leukoaraiosis; Collateral
Background and Purpose
To provide the first correlative study of the hyperdense MCA sign (HMCAS) and gradient-echo (GRE) MRI blooming artifact (BA) with pathology of retrieved thrombi in acute ischemic stroke.
Noncontrast CT and GRE MRI studies prior to mechanical thrombectomy in 50 consecutive cases of acute MCA ischemic stroke were reviewed, blinded to clinical and pathology data. Occlusions retrieved by thrombectomy underwent histopathologic analysis, including automated quantitative and qualitative rating of proportion composed of red blood cells (RBC), white blood cells (WBC), and fibrin on microscopy of sectioned thrombi.
Among 50 patients, mean age was 66 years and 48% were female. Mean (SD) proportion was 61% (±21) fibrin, 34% (±21) RBC, and 4% (±2) WBC. Of retrieved clots, 22 (44%) were fibrin-dominant, 13 (26%) RBC-dominant and 15 (30%) mixed. HMCAS was identified in 10/20 MCA stroke cases with CT, with mean Hounsfield Unit (HU) density of 61 (SD±8). BA occurred in 17/32 with GRE MRI. HMCAS was more commonly seen with RBC-dominant and mixed than fibrin-dominant clots (100% vs. 67% vs. 20%, p=0.016). Mean percent RBC composition was higher in clots associated with HMCAS (47% vs. 22%, p=0.016). BA was more common in RBC-dominant and mixed clots compared to fibrin-dominant clots (100% vs. 63% vs. 25%, p=0.002). Mean percent RBC was greater with BA (42% vs. 23%, p=0.011).
CT HMCAS and GRE MRI BA reflect pathology of occlusive thrombus. RBC content determines appearance of HMCAS and BA, whereas absence of HMCAS or BA may indicate fibrin-predominant occlusive thrombi.
PMCID: PMC3094751  PMID: 21393591
Stroke; cerebral ischemia; thrombus; CT; MRI
7.  Randomized Controlled Trial of an Intervention to Enable Stroke Survivors Throughout the Los Angeles County Safety Net to “Stay With the Guidelines” 
Stroke is the leading cause of adult disability. Inpatient programs optimize secondary stroke prevention care at the time of hospital discharge, but such care may not be continued following hospital discharge.
To improve the delivery of secondary stroke preventive services after hospital discharge, we have designed a chronic care model-based program called SUSTAIN (Systemic Use of STroke Averting INterventions). This care intervention includes group clinics, self-management support, report cards, decision support through care guides and protocols, and coordination of ongoing care. The first specific aim is to test via a randomized-controlled trial whether SUSTAIN improves blood pressure control among an analytic sample of 268 patients with a recent stroke or transient ischemic attack discharged from four Los Angeles County public hospitals. Secondary outcomes consist of control of other stroke risk factors, lifestyle habits, medication adherence, patient perceptions of care quality, functional status, and quality of life. A second specific aim is to conduct a cost analysis of SUSTAIN from the perspective of the Los Angeles County Department of Health Services, using direct costs of the intervention, cost equivalents of associated utilization of county system resources, and cost equivalents of the observed and predicted averted vascular events.
If SUSTAIN is effective, we will have the expertise and findings to advocate for its continued support at Los Angeles county hospitals and to disseminate the program to other settings serving indigent, minority populations.
PMCID: PMC3065242  PMID: 21406671
stroke; secondary prevention; risk factors; self-management; care coordination
9.  Simultaneous Ring Voice-over-Internet Phone System Enables Rapid Physician Elicitation of Explicit Informed Consent in Prehospital Stroke Treatment Trials 
Cellular phone conversations between on-scene patients or their legally authorized representatives (LARs) and off-scene enrolling physician-investigators require immediate and reliable connection systems to obtain explicit informed research consent in prehospital treatment trials.
The NIH Field Administration of Stroke Therapy – Magnesium (FAST-MAG) Trial implemented a voice-over-internet protocol (VOIP) simultaneous ring system (multiple investigator cell phones called simultaneously and first responder connected to call) to enable physician-investigators to elicit consent immediately from competent patients or LARs encountered by 228 ambulances enrolling patients in a multicenter prehospital stroke trial. For 1 month, the number, origin, duration, and yield of enrolling line calls were monitored prospectively.
Six investigators were connected to 106 enrolling line calls, with no identified unanswered calls. Thirty-five percent of new patient calls yielded an enrollment. The most common reasons for non-enrollment were last known well >2 h (n = 7) and uncon sentable patient without LAR available (n = 7). No non-enrollments were directly attributable to the VOIP system. In enrollments, consent was provided by the patient in 67% and a LAR in 33%. The duration of enrollment calls (mean ± SD: 8.4 ± 2.5 min, range 6–14) was longer than non-enrollment calls (5.5 ± 3.5, range 2–13; p < 0.001). The median interval from last known well to study agent start was 46 min, and 70% were enrolled within 60 min of onset.
The simultaneous ring system was reliable and effective, permitting enrollment of a substantial number of patients within the first hour after stroke onset. VOIP cellular networks with simultaneous ring are a preferred means of facilitating consent in prehospital treatment trials.
PMCID: PMC2914352  PMID: 19844092
Prehospital trials; Stroke; Magnesium; Informed consent; Clinical trial
10.  Ruptured Intracranial Mycotic Aneurysm in Infective Endocarditis: A Natural History 
Case Reports in Medicine  2010;2010:168408.
Mycotic aneurysms are a rare cause of intracranial aneurysms that develop in the presence of infections such as infective endocarditis. They account for a small percentage of all intracranial aneurysms and carry a high-mortality rate when ruptured. The authors report a case of a 54-year-old man who presented with infective endocarditis of the mitral valve and acute stroke. He subsequently developed subarachnoid hemorrhage during antibiotic treatment, and a large intracranial aneurysm was discovered on CT Angiography. His lesion quickly progressed into an intraparenchymal hemorrhage, requiring emergent craniotomy and aneurysm clipping. Current recommendations on the management of intracranial Mycotic Aneurysms are based on few retrospective case studies. The natural history of the patient's ruptured aneurysm is presented, as well as a literature review on the management and available treatment modalities.
PMCID: PMC2946581  PMID: 20885918
11.  Prevalence and risk factors for cerebrovascular disease in community-dwelling Latinos 
Clinical neurology and neurosurgery  2008;110(10):985-987.
Surveys on stroke prevalence may provide valuable information for planning of healthcare services. Few such studies have been conducted in Latinos and none have been performed in Los Angeles, a County that contains the largest population of Latinos in the United States. We sought to assess the prevalence of self-reported stroke in a population-based sample of community-dwelling Latinos in Los Angeles.
Patients and methods
The group comprised of self-identified Latinos aged 40 years and older from six census tracts in Los Angeles participating in a population-based cross-sectional study of ocular disease in Latinos, The Los Angeles Latino Eye Study (LALES). The prevalence of stroke and its association with demographic, biological and behavioral risk factors was determined. Univariate and multiple stepwise logistic regression models were used to calculate odds ratios (ORs).
The prevalence of self-reported stroke in 6954 community-dwelling Latinos in Los Angeles was 3.3%. Stroke prevalence increased with age (1.4% age 40–50, 3.3% age 50–65, 7.1% age >65), history of hypertension (OR 2.6, p < 0.001), heart disease (OR 4.8, p < 0.001) and diabetic retinopathy (OR 2.1, p = 0.01).
Renewed efforts directed at early identification and treatment of hypertension and heart disease within the Latino community will mitigate the burden of stroke.
PMCID: PMC2763560  PMID: 18657897
Stroke; Latino; Prevalence
12.  A Brief Prehospital Stroke Severity Scale Identifies Ischemic Stroke Patients Harboring Persisting Large Arterial Occlusions 
Background and Purpose
The Los Angeles Motor Scale (LAMS) is a brief 3-item stroke severity assessment measure designed for prehospital and Emergency Department use.
The LAMS and NIHSS were scored in under-12-hour acute anterior circulation ischemic stroke patients. Stroke severity ratings were correlated with cervicocerebral vascular occlusion on CTA, MRA, and catheter angiography. Receiver operating curves, c statistics, and likelihood ratios were used to evaluate the predictive value for vascular occlusion of stroke severity ratings.
Among 119 patients, mean age was 67 (±18), 45% were male. Time from onset to ED arrival was mean 190 minutes (range 10 to 660). Persisting large vessel occlusions (PLVOs) were present in 62% of patients. LAMS stroke severity scores were higher in patients harboring a vascular occlusion, median 5 (IQR 4 to 5) versus 2 (IQR 1 to 3). Similarly, NIHSS stroke severity scores were higher in PLVO patients, 19 (14 to 24) versus 5 (3 to 7). ROC curves demonstrated that the LAMS was highly effective in identifying patients with PLVOs, c statistic 0.854. At the optimal threshold of 4 or higher, LAMS scores showed sensitivity 0.81, specificity 0.89, and overall accuracy 0.85. LAMS performance was comparable to NIHSS performance (c statistic 0.933). The positive likelihood ratio associated with a LAMS score ≥4 was 7.36 and the negative likelihood ratio 0.21.
Stroke severity assessed by the LAMS predicts presence of large artery anterior circulation occlusion with high sensitivity and specificity. The LAMS is a promising instrument for use by prehospital personnel to identify select stroke patients for direct transport to Comprehensive Stroke Centers capable of endovascular interventions. (Stroke.2008;39:2264-2267.)
PMCID: PMC2743906  PMID: 18556587
acute stroke; cerebral infarct; scales; LAMS (Los Angeles Motor Scale); NIHSS

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