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Steven M Greenberg

Publications and source records attributed to Steven M Greenberg.

30 records · Page 2Linked to original sources
PubMed2004

Hemorrhage burden predicts recurrent intracerebral hemorrhage after lobar hemorrhage.

BACKGROUND AND PURPOSE: Small asymptomatic cerebral hemorrhages detectable by gradient-echo MRI are common in patients with intracerebral hemorrhage (ICH), particularly lobar ICH related to cerebral amyloid angiopathy (CAA). We sought to determine whether hemorrhages detected at the time of lobar ICH predict the major clinical complications of CAA: recurrent ICH or decline in cognition and function. METHODS: Ninety-four consecutive survivors of primary lobar ICH (age > or =55) with gradient-echo MRI at presentation were followed in a prospective cohort study for 32.9+/-24.0 months. A subset of 34 subjects underwent a second MRI after a stroke-free interval of 15.8+/-6.5 months. Study endpoints were recurrent symptomatic ICH or clinical decline, defined as onset of cognitive impairment, loss of independent functioning, or death. RESULTS: The total number of hemorrhages at baseline predicted risk of future symptomatic ICH (3-year cumulative risks 14%, 17%, 38%, and 51% for subjects with 1, 2, 3 to 5, or > or =6 baseline hemorrhages, P=0.003). Higher numbers of hemorrhages at baseline also predicted increased risk for subsequent cognitive impairment, loss of independence, or death (P=0.002) among subjects not previously demented or dependent. For subjects followed after a second MRI, new microhemorrhages appeared in 17 of 34 and predicted increased risk of subsequent symptomatic ICH (3-year cumulative risks 19%, 42%, and 67% for subjects with 0, 1 to 3, or > or =4 new microhemorrhages, P=0.02), but not subsequent clinical decline. CONCLUSIONS: Hemorrhages identified by MRI predict clinically important events in survivors of lobar ICH. Detection of microhemorrhages may be useful for assessing risk in ICH patients and as a surrogate marker for clinical studies.

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PubMed2004

Clinical manifestations of cerebral amyloid angiopathy-related inflammation.

To explore the clinical effects of inflammation associated with vascular deposits of the amyloid beta peptide (A beta), we analyzed 42 consecutive patients with pathologically diagnosed cerebral amyloid angiopathy (CAA) for evidence of an inflammatory response. Inflammation with giant-cell reaction surrounding amyloid-laden vessels was identified in 7 of the 42 cases. The clinical symptoms in each of the seven were subacute cognitive decline or seizure rather than hemorrhagic stroke, the primary clinical presentation in 33 of 35 patients with noninflammatory CAA (p < 0.001). Inflammatory CAA also was associated with radiographic white matter abnormalities, significantly younger age at presentation, and a marked overrepresentation of the apolipoprotein E epsilon 4/epsilon 4 genotype (71% vs 4%, p < 0.001). Of the six inflammatory CAA patients with available follow-up information, five demonstrated clinical and radiographic improvement after immunosuppressive treatment. The syndrome of CAA-related perivascular inflammation appears to represent a subset of CAA with clinically distinct symptoms that may respond to immunosuppressive treatment. These data add to evidence that inflammation against A beta can cause vascular dysfunction, a potential mechanism for the toxic response recently observed in clinical trials of A beta immunization.

Adrenal Cortex Hormones↗
PubMed2003

Can patients be anticoagulated after intracerebral hemorrhage? A decision analysis.

BACKGROUND AND PURPOSE: Warfarin increases both the likelihood and the mortality of intracerebral hemorrhage (ICH), particularly in patients with a history of prior ICH. In light of this consideration, should a patient with both a history of ICH and a clear indication for anticoagulation such as nonvalvular atrial fibrillation be anticoagulated? In the absence of data from a clinical trial, we used a decision-analysis model to compare the expected values of 2 treatment strategies-warfarin and no anticoagulation-for such patients. METHODS: We used a Markov state transition decision model stratified by location of hemorrhage (lobar or deep hemispheric). Effectiveness was measured in quality-adjusted life years (QALYs). Data sources included English language literature identified through MEDLINE searches and bibliographies from selected articles, along with empirical data from our own institution. The base case focused on a 69-year-old man with a history of ICH and newly diagnosed nonvalvular atrial fibrillation. RESULTS: For patients with prior lobar ICH, withholding anticoagulation therapy was strongly preferred, improving quality-adjusted life expectancy by 1.9 QALYs. For patients with prior deep hemispheric ICH, withholding anticoagulation resulted in a smaller gain of 0.3 QALYs. In sensitivity analyses for patients with deep ICH, anticoagulation could be preferred if the risk of thromboembolic stroke is particularly high. CONCLUSIONS: Survivors of lobar ICH with atrial fibrillation should not be offered long-term anticoagulation. Similarly, most patients with deep hemispheric ICH and atrial fibrillation should not receive anticoagulant therapy. However, patients with deep hemispheric ICH at particularly high risk for thromboembolic stroke or low risk of ICH recurrence might benefit from long-term anticoagulation.

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PubMed2003

Clinical diagnosis of cerebral amyloid angiopathy: validation of the Boston criteria.

Cerebral amyloid angiopathy is a disorder in which deposition of amyloid within the arterial media and adventitia leads to intracerebral hemorrhage. Diagnosis during life has been hampered by the requirement for post-mortem examination for definitive diagnosis. The Boston Criteria for the diagnosis of cerebral amyloid angiopathy-related hemorrhage were developed in 1995 and 1996 in order to meet the need for a standardized set of diagnostic criteria that can be applied to living patients. Using a combination of clinical, radiologic, and pathologic data, these criteria reliably differentiate lobar intracerebral hemorrhage into categories of possible, probable, or definite based on the likelihood of underlying cerebral amyloid angiopathy. These criteria will be crucial for disease classification for future clinical studies.

Brain↗
PubMed2002

Abeta species, including IsoAsp23 Abeta, in Iowa-type familial cerebral amyloid angiopathy.

Mutations within the Abeta sequence of the AbetaPP gene are associated with familial forms of cerebral amyloid angiopathy (CAA). One mutation, Abeta D23N, was identified in a family in Iowa with a clinical history of early-onset dementia. We analyzed the pattern of Abeta deposition in the hippocampus of an individual with Iowa CAA. In addition to strong amyloid angiopathy, we found unusual diffuse Abeta deposits in the CA4, and in the parenchyma near amyloid-laden vessels. ELISA of cortical brain extracts showed that Abeta40 was nearly 20-fold higher than Abeta42, in both soluble and insoluble fractions. We identified an Abeta antibody that recognized wild-type Abeta but not Iowa Abeta. With this antibody, we found that wild-type Abeta was present in the Abeta deposits, but limited to the strongest deposits in the cerebrovasculature. Previous in vitro studies suggested that the presence of an asparagine at position 23 of Abeta favored formation of an isoAsp residue, which was associated with increased Abeta fibrillogenesis. Using isoAsp-specific antibodies in immunohistochemical studies, we examined the distribution of isoAsp Abeta in the Iowa brain. IsoAsp7 Abeta was present in both the parenchymal and vascular deposits, whereas isoAsp23 Abeta was present only in vascular deposits. These data suggest that alteration of Abeta Asn23 to isoAsp may be an important determinant in the deposition of Abeta in cerebral blood vessels.

Amyloid beta-Peptides↗
PubMed2002

Vascular changes in Iowa-type hereditary cerebral amyloid angiopathy.

Vascular dysfunction due to cerebral amyloid angiopathy (CAA) may contribute to cognitive impairment. The Iowa D694N amyloid precursor protein mutation, a recently identified cause of hereditary CAA with dementia, offers an opportunity to explore the anatomic basis of CAA-related vascular dysfunction. Examination by immunolabeling and confocal microscopy demonstrated extensive loss of smooth muscle cells in affected segments as well as a perivascular inflammatory reaction of astrocytes and microglia. On 3-D reconstruction, vessels appeared tortuous with twiglike projections that may represent areas of vascular degeneration. The observed changes in the Iowa brain suggest pathophysiologic mechanisms for vascular dysfunction in CAA and possible approaches to treatment of CAA-related cognitive impairment.

Cerebral Amyloid Angiopathy, Familial↗
PubMed2002

Cerebral amyloid angiopathy and vessel dysfunction.

Cerebral amyloid angiopathy (CAA), defined by deposition of the beta-amyloid peptide in medium and small cortical and meningeal vessels, is a well-recognized cause of hemorrhagic stroke. This paper reviews the accumulating evidence supporting an additional role for CAA in producing vessel dysfunction, reduced cerebral blood flow and ischemia. Ischemic lesions are characteristic of several hereditary CAA syndromes, including a recently described mutation of the amyloid precursor protein associated with dementia (but not hemorrhagic stroke) in an Iowa family. Ischemic lesions are seen in some sporadic CAA patients as well, and recent data from transgenic mice suggest potential mechanisms by which beta-amyloid may alter vessel physiology. Future studies will seek to define the clinical importance of vascular beta-amyloid as a potential target for drug therapy in dementia.

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PubMed2002

Dynamic single-section CT demonstrates reduced cerebral blood flow in acute intracerebral hemorrhage.

Optimum blood pressure (BP) management in acute intracerebral hemorrhage (ICH) remains controversial. BP reduction may limit hematoma expansion, but may also exacerbate ischemia. Reduced regional cerebral blood flow (rCBF) has been reported in ICH. Its extent and precise pattern, however, remain uncertain. Dynamic single-section CT perfusion (CTP) is rapid, easily performed and offers superior spatial resolution to PET, SPECT and MRI. It may be the most applicable method for assessing the effects of BP management on rCBF in ICH. We sought to assess whether CTP can identify rCBF abnormalities in acute ICH in 5 patients with ICH who underwent CTP within 24 h of symptom onset. rCBF was measured in serially expanded 2-mm rings around the hematoma and compared with rCBF in the uninvolved hemisphere. Mean time to CTP was 9 h (range 3-23). Mean ICH volume was 25 ml (range 9-64). Perihematoma perfusion was reduced in all patients compared with contralateral hemisphere rCBF. rCBF reduction was most pronounced immediately adjacent to the hematoma (p < 0.05 at 2 mm, p = 0.084 at 4 mm, p > 0.2 at 6 and 8 mm). Perihematoma rCBF increased as a function of the distance from hematoma perimeter. Rate of rCBF increase over distance correlated with time from onset (p = 0.006). We conclude that CTP identifies a rim of reduced rCBF in ICH. A gradient of hypoperfusion appears to extend at least 4 mm beyond the hematoma edge and may be time dependent. Whether reduced CBF is associated with perihematoma ischemia requires additional study.

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PubMedDate not supplied

A phase 2 study of tramiprosate for cerebral amyloid angiopathy.

BACKGROUND AND PURPOSE: No treatments have been identified to lower the risk of intracerebral hemorrhage due to cerebral amyloid angiopathy (CAA). A potential approach to prevention is the use of agents that interfere with the pathogenic cascade initiated by the beta-amyloid peptide (Abeta). Tramiprosate (3-amino-1-propanesulfonic acid) is a candidate molecule shown in preclinical studies to reduce CAA in a transgenic mouse model. METHODS: We performed a 5-center phase 2 double-blinded trial to evaluate the safety, tolerability, and pharmacokinetics of tramiprosate in subjects with lobar intracerebral hemorrhage. Twenty-four subjects age > or =55 years with possible or probable CAA were randomized to receive 12 weeks of tramiprosate at 1 of 3 oral doses (50, 100, or 150 mg twice daily). Subjects were followed for clinical adverse effects, laboratory, vital sign, electrocardiogram, cognitive, or functional changes, appearance of new symptomatic or asymptomatic hemorrhages, and pharmacokinetic parameters. RESULTS: Enrolled subjects were younger (mean age 70.8+/-5.4, range 61 to 78) and had more advanced baseline disease (measured by number of previous hemorrhages) than consecutive subjects in a CAA natural history cohort. No concerning safety issues were encountered with treatment. Nausea and vomiting were the most common adverse events and were more frequent at high doses. Nine subjects had new symptomatic or asymptomatic hemorrhages during treatment; all occurred in subjects with advanced baseline disease, with no apparent effect of drug dosing assignment. CONCLUSIONS: These data suggest that tramiprosate can be given safely to subjects with suspected CAA and support future efficacy trials.

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