Roger E. Kelley

Elevated platelet microparticles in transient ischemic attacks, lacunar infarcts, and multiinfarct dementias

Platelets release microparticles (PMP) upon activation. Elevated levels of PMP were observed in patients with immune thrombocytopenic purpura (ITP), sometimes associated with a syndrome resembling transient ischemic attack (TIA), suggesting a thrombogenic potential for PMP. To determine if this association applies to TIA and other cerebrovascular accidents (CVA) without ITP, we studied PMP profiles in 71 patients with ischemic CVA: 28 with small vessel CVA (SCVA), either lacunar infarcts or TIA; 24 with large vessel CVA (LCVA); 19 with multiinfarct dementia (MID); 12 with Alzheimers dementia (AD); and 31 healthy controls. The mean PMP values were: MID = 3.71 +/- 0.51; SCVA = 3.48 +/- 0.63; LCVA = 1.97 +/- 0.28; AD = 1.19 +/- 0.27; controls = 0.88 +/- 0.09, (all units x 10(7)/mL). PMP values in all groups except AD were significantly above normal (p < 0.01). However, the elevation in SCVA was more marked than in LCVA (p < 0.01). Administration of the calcium channel blocker, nifedipine, to 11 TIA patients reduced PMP significantly.

Relation Between Blood Pressure and Outcome in Intracerebral Hemorrhage

BACKGROUND AND PURPOSE Controversy continues to exist regarding optimal blood pressure control in acute hypertensive intracerebral hemorrhage. Persistent marked elevation of the blood pressure can promote further bleeding, increase cerebral blood flow, and raise intracranial pressure. Relative hypotension, on the other hand, may promote hypoperfusion with secondary ischemia. This study was designed to assess outcome in patient groups defined by the degree of elevation in their pretreatment and posttreatment blood pressures. METHODS We retrospectively assessed 87 patients who were categorized according to an initial mean arterial pressure > 145 mm Hg (n = 34) compared with those with a pressure < or = 145 mm Hg (n = 53). We also studied blood pressure control within the first 2 to 6 hours of presentation with subjects categorized according to a mean arterial pressure > 125 mm Hg (n = 40) or < or = 125 mm Hg (n = 47). RESULTS An improved outcome in both mortality and severe morbidity was observed in the < or = 145 (chi 2 = 7.0, P < .005) and the < or = 125 mm Hg (chi 2 = 6.7, P < .005) groups. CONCLUSIONS Markedly elevated blood pressure on admission and persistent inadequate blood pressure control adversely affect the prognosis in hypertensive intracerebral hemorrhage.

Transcranial Doppler assessment of cerebral flow velocity during cognitive tasks.

Background and Purpose The purpose of this study was to assess the ability of transcranial Doppler ultrasonography to detect selective circulatory changes during cognitive activity. Methods We measured cerebral artery flow velocity in 21 normal volunteers by transcranial Doppler ultrasonography during rest followed by cerebral activation. Mean and peak systolic flow velocities of the anterior, middle, and posterior cerebral arteries were measured during the performance of a commercial video game. We also measured flow velocity of the anterior cerebral arteries in 18 subjects during a mental arithmetic task. Serial measurements of the right and left sides were made with a headband with two probes. Results We observed a global increase in the flow velocity above baseline measurements during task performance. During the video game, both middle cerebral arteries (f=2.6,p=0.02 for the left; f=33,p=0.004 for the right) and the left posterior cerebral artery (l=2.2, p=0.004) had selective increase in mean flow velocity compared with the ipsilateral anterior cerebral artery. This selective activation was most prominent in the right middle cerebral artery, which had a greater degree of activation than the right posterior cerebral artery (f=2.8, p=0.013). We did not observe a statistically significant difference between the right and left middle cerebral arteries, but there was a trend toward a greater activation on the right for both the mean velocity (t=1.7, p=0.098) and the peak velocity (f=1.9,p=0.079). Conclusions Our preliminary investigation suggests that this noninvasive technique has the potential to correlate selective cerebral artery flow dynamics with cognitive activity.

Serum from patients with multiple sclerosis downregulates occludin and VE-cadherin expression in cultured endothelial cells

Disruption of the blood -brain barrier (BBB) and transendothelial migration of inflammatory cells are crucial steps in the development of demyelinating lesions in multiple sclerosis (MS). O ccludin and vascular endothelial-cadher in (VE-cadherin) are two major components of the tight junctions (TJs) in the brain microvasculature that help to create the BBB. In the present study, we investigated the effect of serum from MS patients on the expression of these two junctional markers and on the endothelial integrity. Serum from six MS patients in exacerbation, six in remission, and six normal controls (10% by volume) was incubated with cultured endothelial cells, and the expression of occludin and VE-cadherin was measured by immunoblotting. Serum from MS patients in exacerbation significantly reduced the expression of occludin and VE-cadherin compared with patients in remission and normal controls. This disintegrating effect was more pronounced for occludin than for VE-cadherin. We assume that the elevation in cytokines or other serum-soluble factors in MS patients in exacerbation likely provokes downregulation of occludin and VE-cadherin. This downregulation of TJs proteins may, therefore, contribute to the disruption of the BBB in this condition.

Ultrasound densitometric analysis of carotid plaque composition. Pathoanatomic correlation.

BACKGROUND AND PURPOSE The components of a carotid artery plaque might affect the risk of ipsilateral stroke. The accuracy of carotid duplex scan in assessing stroke risk reflects the experience of the scan reader. Thus, methods that can enhance ultrasonic evaluation of plaque morphology might allow a more objective means of determining carotid-mediated stroke risk. METHODS We performed densitometric analysis of B-mode images of carotid plaques in nine patients scheduled for carotid endarterectomy. All patients had preoperative duplex color imaging and cerebral arteriography. The surgical specimen was analyzed histologically to determine the plaque components (soft plaque/organized thrombus, intraplaque hemorrhage/lipid deposition, fibrosis, and calcification). The specimen findings were correlated with the densitometric measurements to determine whether the density analysis would allow a reliable determination of the plaque substratum. RESULTS With 1.0 as a reference point for the moving column of blood, the mean acoustic densities (+/-SD) were as follows: organized thrombus, 1.8 +/- 0.5; intraplaque hemorrhage/lipid deposition, 5.15 +/- 0.9; fibrosis, 9.51 +/- 2.9; and calcification, 15.5 +/- 8.6. CONCLUSIONS We conclude that densitometric evaluation allows differentiation of the various possible components of carotid plaque. The determination of plaque composition, based on density measurement, may provide information about its potential for thromboembolization.

Acute Leukocyte and Temperature Response in Hypertensive Intracerebral Hemorrhage

BACKGROUND AND PURPOSE We undertook this study to investigate the relationship between outcome, hematoma volume, and admission peripheral white blood cell count and body temperature in acute hypertensive intracerebral hemorrhage. METHODS Eighty-two consecutive patients who presented with hypertensive intracerebral hemorrhage within 72 hours of onset were retrospectively assessed. The peripheral white blood cell count, polymorphonuclear leukocytes, and the body temperature on admission were measured. The outcome at 30 days after ictus was determined with a modified Glasgow Outcome Scale. Correlation analysis was performed between these measurements and hematoma volume, which was calculated by brain computed tomography. We also looked at the presence or absence of intraventricular extension. RESULTS The mean hematoma volume was significantly greater in those patients who died compared with those with a good, moderate, and severe outcome (79.6 cm3 versus 10.7, 18.3, and 19.9 cm3, respectively; P < .0005). The mean peripheral white blood cell count was higher in those who died than in the other three groups (12.580 +/- 0.521 versus 8.160 +/- 0.543, 8.565 +/- 0.543, and 7.427 +/- 0.786 x 10(9)/L, respectively; P < .0005). The mean body temperature of those who died tended to be higher than those in the good-outcome group (99.12 +/- 0.21 versus 98.18 +/- 0.21 degrees F, P < .05). A positive linear correlation was observed between hematoma volume and white blood cell count (r = .506, df = 77, P < .001), as well as the polymorphonuclear leukocyte count (r = .561, df = 76, P < .001). A trend was also observed for admission temperature (r = .265, df = 74, P < .05). The leukocyte response was enhanced by the presence of intraventricular extension. CONCLUSIONS There is a relationship between the size of the hematoma and the degree of leukocytosis in hypertensive intracerebral hemorrhage. This relationship appears to most likely represent a stress-induced reaction of the white blood cell count.

Evaluation of kinetic therapy in the prevention of complications of prolonged bed rest secondary to stroke.

We performed a prospective, controlled study of kinetic therapy in acute, severe stroke. This therapy involved continuous mobilization of a bedridden patient by means of a specially designed rotating bed. All patients with acute stroke presenting to the Neurology Service over an 18-month period were screened, and those that qualified were assigned to confinement in either a routine hospital bed or a rotating bed. We found that the most common complication of stroke with bed confinement of 4 days or longer was bacterial infection consisting of either pneumonia, sepsis, or urinary tract infection. The two variables found to be of greatest significance in affecting the rate of infection were length of bed confinement, especially for greater than 13 days (2.3-fold increased risk, p less than 0.04), and placement in a routine hospital bed (2.9-fold increased risk, p = 0.023).

Design of a multicenter randomized trial for the stroke prevention in atrial fibrillation study

Individuals with nonvalvular atrial fibrillation are at increased risk of stroke. The Stroke Prevention in Atrial Fibrillation Study is a 15-center randomized clinical trial examining the risks and benefits of low-intensity warfarin (prothrombin time of 1.3-1.8 times control) and aspirin (325 mg/day) in patients with constant or intermittent atrial fibrillation. Candidates for anticoagulation (group I) are randomized to receive warfarin in an open-label fashion, aspirin, or placebo; the last two treatments are given in a double-blind fashion. Warfarin-ineligible patients (group II) are randomized to receive aspirin or placebo in a double-blind fashion. Primary end points are ischemic stroke and systemic embolism. Secondary end points are death, transient ischemic attack, myocardial infarction, and unstable angina pectoris. Analysis is based on the intention-to-treat principle. The anticipated rate of primary end points in patients receiving placebo is 6%/yr. The sample size of 1,644 patients is based on a projected reduction in the rate of primary end points of 50% by warfarin and of 33% by aspirin (beta = 0.2, alpha = 0.05). Patient entry commenced in June 1987 and will continue for 3 years, with an additional year of follow-up. High-risk subsamples identified by clinical and echocardiographic criteria are sought prospectively.

Pathogenesis of Brain and Spinal Cord Atrophy in Multiple Sclerosis

For more than a century, multiple sclerosis was viewed as a disease process characterized by oligodendrocyte and myelin loss, and research into the pathogenesis of multiple sclerosis was mainly focused on the mechanisms of inflammation. However, with development of more sophisticated neuroimaging and molecular biology techniques, attention has shifted to new aspects of pathogenesis of multiple sclerosis: axonal loss and neurodegeneration. Evidence is increasing that tissue destruction, primarily axonal loss and neurodegeneration, is a key element in the pathogenesis of multiple sclerosis. In addition, it is now known that brain and spinal cord atrophy begins early in the disease process of multiple sclerosis and advances relentlessly throughout the course of the disease. Cumulative data suggest that axonal loss is the major determinant of progressive neuro logic disability in patients with multiple sclerosis. Magnetic resonance imaging and magnetic resonance spectroscopy in patients with multiple sclerosis for < 5 years indicate brain atrophy and loss of axonal integrity. Neurodegeneration and axonal loss in patients with multiple sclerosis are initially accompanied by a local response from oligodendrocyte progenitor cells and some remyelination. However, these repair mechanisms eventually fail, and patients typically develop generalized brain atrophy, cognitive decline, and permanent disability. Although the exact mechanisms underlying central nervous system atrophy in patients with multiple sclerosis are largely unknown, evidence exists that atrophy may represent an epiphenomenon related to the effects of dynamic inflammation within the central nervous system, including demyelination, axonal injury, neuronal loss, Wallerian degeneration, and possibly iron deposition. This article summarizes the potential mechanisms involved in central nervous system atrophy in patients with multiple sclerosis.

The role of stem cell factor and granulocyte-colony stimulating factor in brain repair during chronic stroke

Chronic stroke is a highly important but under-investigated scientific problem in neurologic research. We have reported earlier that stem cell factor (SCF) in combination with granulocyte-colony stimulating factor (G-CSF) treatment during chronic stroke improves functional outcomes. Here we have determined the contribution of bone marrow-derived cells in angiogenesis and neurogenesis, which are enhanced by SCF + G-CSF treatment during chronic stroke. Using bone marrow tracking, flow cytometry, 2-photon live brain imaging, and immunohistochemistry, we observed that the levels of circulating bone marrow stem cells (BMSCs) (CD34+ /c-kit +) were significantly increased by SCF +G-CSF treatment. In addition, live brain imaging revealed that numerous bone marrow-derived cells migrate into the brain parenchyma in the treated mice. We also found that bone marrow-derived cells, bone marrow-derived endothelial cells, vascular density, and bone marrow-derived neurons were significantly augmented by SCF + G-CSF. It is interesting that, in addition to the increase in bone marrow-derived endothelial cells, the number of bone marrow-derived pericytes was reduced after SCF + G-CSF treatment during chronic stroke. These data suggest that SCF + G-CSF treatment can enhance repair of brain damage during chronic stroke by mobilizing BMSCs, and promoting the contribution of bone marrow-derived cells to angiogenesis and neurogenesis.