De novo expansion of a (CAG)n repeat in sporadic Huntington's disease.

Huntington's disease (HD) chromosomes contain an expanded unstable (CAG)n repeat in chromosome 4p16.3. We have examined nine families with potential de novo expression of the disease. With one exception, all of the affected individuals had 42 or more repeat units, well above the normal range. In four families, elderly unaffected relatives inherited the same chromosome as that containing the expanded repeat in the proband, but had repeat lengths of 34-38 units, spanning the gap between the normal and HD distributions. Thus, mutation to HD is usually associated with an expansion from an already large repeat.

Research priorities in neurocritical care.

This summary of the last session of the First Neurocritical Care Research Conference reviews the discussions about research priorities in neurocritical care. The first presentation reviewed current projects funded by the National Institute of Neurological Disorders and Stroke at the National Institutes of Health and potential models to follow including an independent Neurocritical Care Network or the creation of such a network with the goal of collaborating with already existing ones. Experienced neurointensivists then presented their views on the most common and important research questions that need to be answered and investigated in the field. Finally, utility of clinical registries was discussed emphasizing their importance as hypothesis generators. During the group discussion, interests in comparative effectiveness research, the use of physiological endpoints from monitoring and alternate trial design were expressed.

Heat shock protects cultured neurons from glutamate toxicity.

Expression of heat shock proteins (HSPs) occurs in brain after ischemia and status epilepticus. We report that induction of the heat shock response in cortical cultures protects neurons from glutamate-induced excitotoxicity. Cultures heated to 42.2 degrees C for 20 min showed an overall decrease in protein synthesis but an increase in the synthesis of approximately 72 and approximately 85 kd proteins and in the levels of HSP70 mRNA. Heat shock inhibited excitotoxicity in cells exposed to glutamate at 3 or 24 hr following heat exposure, but not when the interval between heat and glutamate exposure was shortened to 15 min or lengthened to 48 hr. Protection due to heat shock required new protein synthesis, since it did not occur when protein or RNA synthesis inhibitors were added. By ameliorating excitotoxic processes, HSPs may attenuate brain injury in certain pathologic conditions.

Ion channel expression by white matter glia: the type-1 astrocyte.

We describe the electrophysiological properties of acutely isolated type-1 astrocytes using a new "tissue print" dissociation procedure. Because the enzymes used did not destroy or modify the ion channels, and the cells retained many processes, the properties may reflect those in vivo. The types of ion channels in type-1 astrocytes changed rapidly during the first 10 postnatal days, when they attained their adult phenotype. This change was dependent on the presence of neurons. In culture, most of these channel types were not expressed, but a phenotype more typical of that in vivo could be induced by co-culture with neurons. The electrophysiological properties of astrocytes make some existing hypotheses of astrocyte function less likely.

Ion channel expression by white matter glia: the O-2A glial progenitor cell.

We describe electrophysiological properties of the O-2A glial progenitor cell in a new serum-free culture system. O-2A progenitors have many properties characteristic of neurons: they have glutamate-activated ion channels, express the neuronal form of the sodium channel, fire single regenerative potentials, and synthesize the neurotransmitter GABA by an alternative synthetic pathway. Nearly identical properties were observed in acutely isolated O-2A progenitors, indicating that this phenotype is not an artifact of culture. The O-2A did not express a simple subset of channel types found in its descendant cells, the type-2 astrocyte and oligodendrocyte, studied in the same culture system. During development, these electrophysiological properties may contribute to O-2A function in vivo.

Magnetic resonance imaging criteria for thrombolysis in acute cerebral infarct.

BACKGROUND AND PURPOSE: Magnetic resonance imaging (MRI) selection of stroke patients eligible for thrombolytic therapy is an emerging application. Although the efficacy of therapy within 3 hours after onset of symptoms with intravenous (IV) tissue plasminogen activator (tPA) has been proven for patients selected with computed tomography (CT), no randomized, double-blinded MRI trial has been published yet. SUMMARY OF REVIEW: MRI screening of acute stroke patients before thrombolytic therapy is performed in some cerebrovascular centers. In contrast to the CT trials, MRI pilot studies demonstrate benefit of therapy up to 6 hours after onset of symptoms. This article reviews the literature that has lead to current controlled MRI-based thrombolysis trials. We examined the MRI criteria applied in 5 stroke centers. Along with the personal views of clinicians at these centers, the survey reveals a variety of clinical and MRI technical aspects that must be further investigated: the therapeutic consequence of microbleeds, the use of magnetic resonance angiography, dynamic time windows, and others. CONCLUSION: MRI is an established application in acute evaluation of stroke patients and may suit as a brain clock, replacing the currently used epidemiological time clock when deciding whether to initiate thrombolytic therapy. MRI criteria for thrombolytic therapy are applied in some cerebrovascular centers, but the results of ongoing clinical trials must be awaited before it is possible to reach consensus.

Emerging treatments for stroke in humans.

Ischaemic stroke causes loss of brain function in millions of people worldwide each year. Despite the enormity of the problem, no currently approved therapy reduces stroke size or neurological disability. This contrasts with a number of recently developed agents, reviewed here by Walter Koroshetz and Michael Moskowitz, which limit infarct size in animal stroke models. Therapies that dissolve clot and restore blood flow, block excitatory neurotransmission, prevent the ischaemic inflammatory response or scavange free radicals have the potential to revolutionize stroke treatment if proven beneficial in ongoing, placebo-controlled clinical trials. Developments in the experimental arena continue to reinforce the need to characterize the pathophysiological stages leading to brain infarction and recovery.

Predicting tissue outcome in acute human cerebral ischemia using combined diffusion- and perfusion-weighted MR imaging.

BACKGROUND AND PURPOSE: Tissue signatures from acute MR imaging of the brain may be able to categorize physiological status and thereby assist clinical decision making. We designed and analyzed statistical algorithms to evaluate the risk of infarction for each voxel of tissue using acute human functional MRI. METHODS: Diffusion-weighted MR images (DWI) and perfusion-weighted MR images (PWI) from acute stroke patients scanned within 12 hours of symptom onset were retrospectively studied and used to develop thresholding and generalized linear model (GLM) algorithms predicting tissue outcome as determined by follow-up MRI. The performances of the algorithms were evaluated for each patient by using receiver operating characteristic curves. RESULTS: At their optimal operating points, thresholding algorithms combining DWI and PWI provided 66% sensitivity and 83% specificity, and GLM algorithms combining DWI and PWI predicted with 66% sensitivity and 84% specificity voxels that proceeded to infarct. Thresholding algorithms that combined DWI and PWI provided significant improvement to algorithms that utilized DWI alone (P=0.02) but no significant improvement over algorithms utilizing PWI alone (P=0.21). GLM algorithms that combined DWI and PWI showed significant improvement over algorithms that used only DWI (P=0.02) or PWI (P=0.04). The performances of thresholding and GLM algorithms were comparable (P>0.2). CONCLUSIONS: Algorithms that combine acute DWI and PWI can assess the risk of infarction with higher specificity and sensitivity than algorithms that use DWI or PWI individually. Methods for quantitatively assessing the risk of infarction on a voxel-by-voxel basis show promise as techniques for investigating the natural spatial evolution of ischemic damage in humans.

Utility of perfusion-weighted CT imaging in acute middle cerebral artery stroke treated with intra-arterial thrombolysis: prediction of final infarct volume and clinical outcome.

BACKGROUND AND PURPOSE: The goal of this study was to evaluate the utility of perfusion-weighted CT (PWCT) in predicting final infarct volume and clinical outcome in patients with acute middle cerebral artery (MCA) stroke. METHODS: Twenty-two consecutive patients with MCA stem occlusion who underwent intra-arterial thrombolysis within 6 hours of stroke onset had noncontrast CT and CT angiography with whole-brain PWCT imaging before treatment. Infarct volumes were computed from the initial PWCT and follow-up scans; clinical outcome was measured with the modified Rankin scale. RESULTS: Initial PWCT lesion volumes correlated significantly with final infarct volume (P=0.0002) and clinical outcome (P=0.01). For the 10 patients with complete recanalization, the relationship between initial and final lesion volume was especially strong (R(2)=0.94, P<0.0001, slope of regression line=0.92). For those without complete recanalization, there was progression of lesion volume on follow-up imaging (R(2)=0.50, P=0.01, slope of regression line=1.61). All patients with either initial PWCT lesion volumes >100 mL or no recanalization had poor outcomes (Rankin scores, 4 to 6). Mean admission NIH Stroke Scale scores and mean lesion volumes in the poor outcome group were significantly different compared with the good or fair outcome (Rankin scores, 0 to 3) group (21+/-4 versus 17+/-5, P=0.05, and 106+/-79 versus 29+/-37 mL, P=0.01). Patients with initial volumes <100 mL and partial or complete recanalization all had good (Rankin scores, 0 to 2) or fair (Rankin score, 3) outcomes. CONCLUSIONS: Lesion volumes on admission PWCT images approximate final infarct volume for patients with early complete recanalization of MCA stem occlusion. For those without complete recanalization, there is subsequent enlargement of lesion volume on follow-up. Initial PWCT lesion volumes also have predictive value; volumes >100 mL are associated with a poor clinical outcome. In these highly selected patients, initial PWCT lesion volume was a stronger predictor of clinical outcome than was initial NIH Stroke Scale score.

Increased levels of plasma cholesteryl ester hydroperoxides in patients with subarachnoid hemorrhage.

The pathophysiology of subarachnoid hemorrhage (SAH) may involve free radical production and lipid peroxidation. We examined plasma levels of cholesteryl ester hydroperoxides (CEOOH) and antioxidants in 25 patients with SAH, and 10 neurologic controls with lacunar stroke. Patients with SAH had significantly increased plasma levels of CEOOH, which peaked on day 5 after the ictus. Concentrations of CEOOH were significantly increased, and ascorbic acid concentrations were significantly decreased in patients who developed vasospasm compared with patients without vasospasm. Increased levels of CEOOH were associated with increased mortality and correlated with clinical outcome scales. These results implicate oxidative stress in the pathogenesis of SAH and suggest that measurements of CEOOH in plasma may be useful both prognostically as well as in monitoring therapeutic interventions.

Increased plasma levels of lipid hydroperoxides in patients with ischemic stroke.

A large body of experimental research indicates that the generation of free radicals leading to oxidative stress plays a role in the pathogenesis of ischemic brain injury, but evidence in humans is limited. We examined plasma levels of lipid hydroperoxides (measured as cholesteryl ester hydroperoxides, CEOOH) and ascorbic acid in 32 patients with cortical stroke, as compared with 13 patients with lacunar infarct. Patients with cortical stroke had significantly increased levels of CEOOH, which peaked on Day 5 after the ictus. Small decreases in ascorbic acid concentrations were not significant. There was a significant positive correlation of CEOOH with the NIH stroke scale, and a significant negative correlation with the Glasgow coma scale. Concentrations of CEOOH were significantly higher in patients with total anterior cerebral syndrome as compared with patients with partial anterior cerebral syndrome or posterior cerebral syndrome. Stroke volumes computed from CT or MRI scans were significantly correlated with plasma CEOOH levels. These findings implicate oxidative stress in ischemic brain injury in humans and suggest that measurements of CEOOH in plasma may be useful both prognostically as well as in monitoring therapeutic interventions.

Factors associated with slow progression in Huntington's disease.

The rate of disease progression was assessed for 42 persons affected by Huntington's disease who had been neurologically examined at least six times and followed up for at least 3 years. Disease progression was assessed by a disability rating scale administered at each examination. Slow progression was associated with older age at onset of disease and with heavier weight (body mass index) at the first examination. Men tended to have a slower disease progression than did women, and this was particularly evident among men inheriting Huntington's disease from affected mothers. Neither the butyrophenone haloperidol nor the tricyclic antidepressant imipramine were related to rate of progression. Assessments of depression, hostility, and tobacco use were also unrelated to rate of progression. Clinical trials in Huntington's disease should consider these factors when designing therapeutic studies.

Diffusion-weighted magnetic resonance imaging identifies the "clinically relevant" small-penetrator infarcts.

BACKGROUND: Most patients initially seen with a clinical syndrome consistent with a small-penetrator infarct (SPI) also harbor multiple, chronic, hyperintense, white matter lesions on conventional magentic resonance imaging (ie, T2-weighted image [T2WI] and fluid-attenuation inversion recovery [FLAIR] imaging). Diffusion-weighted imaging (DWI) can identify the clinically relevant "index infarction" in such circumstances, since it differentiates between acute and chronic lesions. OBJECTIVE: To determine the clinical and radiological predictors associated with misidentification of an SPI as acute using T2WI and FLAIR images in patients with an acute SPI seen on DWI. PATIENTS: Sixty-seven consecutive patients who had an SPI. METHODS: Two independent examiners, provided with brief clinical information, but blinded to DWI findings, sought a clinically appropriate lesion on T2WI and FLAIR imaging in 67 consecutive patients found to have an SPI seen on DWI. RESULTS: The index infarction based on evaluation of T2WI or FLAIR images was in a different location than the acute lesion as identified by DWI in 9 (13%) and 11 (16%) of 67 patients, respectively. Both T2WI and FLAIR imaging were rated normal in another 9% of the patients. Multivariate analysis showed that small lesion size (<10 mm) was the only predictor of misidentifying the clinically appropriate lesion on conventional magnetic resonance imaging (P<.01). CONCLUSIONS: T2-weighted imaging and FLAIR imaging fail to identify the clinically relevant SPI in almost one quarter of the patients found to have a lesion on DWI. The characteristics of DWI make it well suited for the detection of acute small infarcts. Diffusion-weighted imaging is necessary to consistently define the clinical-anatomical relations in patients initially seen with SPIs.

Artery-to-artery embolism causing stroke in the posterior circulation.

The features of strokes caused by embolism from the vertebral artery (VA) to the posterior cerebral artery (PCA) are reported in 12 patients ("local" or "artery-to-artery embolism"). Occipital infarction occurred with prominent, fluctuating brainstem ischemic symptoms in six; with minor, transient brainstem symptoms in five; and with basilar artery occlusion in one. Visual field abnormalities were found on initial examination in eight and several days after the onset of brainstem symptoms in four. Radiographic studies in 11 identified extracranial (5 patients) or intracranial (3 patients) VA disease, or occlusion of both segments (3 patients) as sources of emboli to the PCA. Mural thrombus in the VA or embolic occlusion of distal branches of the PCA was visualized in five.

Diffusion-weighted MRI characterizes the ischemic lesion in transient global amnesia.

We present a patient with transient global amnesia (TGA) whose diffusion-weighted MRI (DWI) showed increased signal in the splenium of the corpus callosum and in the left parahippocampal gyrus. The absence of high signal on the corresponding apparent diffusion coefficient (ADC) images supports the diagnosis of an acute infarction. This finding provides a temporal relation between cerebral ischemia and infarction in the territory of posterior cerebral artery and in certain cases of TGA. An early means of detecting ischemia in TGA by DWI may influence clinical decisions made in patient evaluation and management.

Evidence for impairment of energy metabolism in vivo in Huntington's disease using localized 1H NMR spectroscopy.

The Huntington's disease (HD) gene mutation has recently been found; however, the biochemical defect that leads to neurodegeneration is still unknown. A progressive impairment of neuronal energy metabolism is a possible etiologic factor. We tested this possibility using localized proton nuclear magnetic resonance (NMR) spectroscopy in 18 patients at high risk for, or suffering from, HD as compared with normal controls. Lactate concentrations were increased in the occipital cortex of symptomatic HD patients when compared with normal controls, and the lactate level correlated with duration of illness. In addition, several patients showed highly elevated lactate levels in the basal ganglia. Basal ganglia levels of N-acetylaspartate were lowered and choline dramatically elevated, relative to creatine, reflecting neuronal loss and gliosis in this brain region. These findings are consistent with a possible defect in energy metabolism in HD, which could contribute to the pathogenesis of the disease. The presence of elevated lactate in HD brains may provide a simple marker that can be followed over time noninvasively and repeatedly to aid in devising and monitoring possible therapies for HD patients.

A pilot study of drug-induced hypertension for treatment of acute stroke.

The aim of this pilot study was to determine whether the use of induced hypertension in acute stroke is feasible and associated with neurologic improvement. Phenylephrine was used to raise the systolic blood pressure in patients with acute stroke by 20%, not to exceed 200 mmHG: Of 13 patients treated, 7 improved by 2 points on the NIH Stroke SCALE: No systemic or neurologic complications were seen. The authors conclude that induced hypertension in acute stroke is feasible and likely safe and can improve the neurologic examination in some patients.

Diagnostic tests for choreoacanthocytosis.

Two patients with striatal atrophy and a clinical syndrome consistent with choreoacanthocytosis had normal dried blood smears but their red cells demonstrated an abnormal sensitivity to various conditions known to promote discocyte-echinocyte transformation. Dilution in normal saline, in vitro aging, and contact with glass caused a great proportion of these patients' red cells to develop multiple spiny or rounded projections. Under identical conditions, such shape changes did not occur in normal patients or in those with Huntington's disease. Scanning electron microscopy showed that the age-induced increase in acanthocytic-appearing cells could be reversed with chlorpromazine. These data suggest that the red cells from these patients with striatal degeneration are deficient in their ability to preserve normal shape in the face of echinocytic stress and that this observation has diagnostic and, possibly, pathophysiologic significance.

Posterior leukoencephalopathy without severe hypertension: utility of diffusion-weighted MRI.

OBJECTIVE: Standard MRI confirms the diagnosis of posterior leukoencephalopathy syndrome (PLES), recently associated with an increasing number of medical conditions. In PLES, T2-weighted MRI demonstrates hyperintensity spreading out from posterior brain regions; the pathophysiology remains mysterious. In the acute setting, diffusion-weighted imaging (DWI), but not standard MR imaging, can distinguish ischemic injury from those conditions known to cause vasogenic brain edema. DWI is potentially valuable in understanding the pathophysiology of PLES and in diagnosing patients who do not have previously known risk factors. METHODS: Serial CT and MRI studies (including DWI, apparent diffusion coefficient [ADC] maps, and, in one instance, perfusion-weighted imaging) were performed in three female patients with a neurologic syndrome consistent with PLES while hospitalized for treatment of other conditions. RESULTS: None of the patients had previously described risk factors for PLES; all had only mild elevations in blood pressure. MRI showed large, abnormal, T2 hyperintense regions in the posterior cerebrum with corresponding hyperintensity on ADC maps-signal characteristics predominantly consistent with vasogenic edema. There were also smaller patchy posterior cortical regions with decreased ADC and bright DWI consistent with infarction in one, and dramatic conversion of a large region to an ischemic pattern in another. CONCLUSIONS: ADC maps and DWI can successfully differentiate PLES from early cerebral ischemia, thus playing a pivotal role in treatment decisions. PLES is associated with a wider variety of conditions than has been previously reported and is not always reversible. Hyperintense DWI signal in patients with the syndrome likely marks a tissue stage of permanent brain injury.

1H NMR spectroscopy studies of Huntington's disease: correlations with CAG repeat numbers.

Huntington's disease (HD) is the result of an expanded (CAG) repeat in a gene on chromosome 4. A consequence of the gene defect may be progressive impairment of energy metabolism. We previously showed increased occipital cortex lactate in HD using localized 1H spectroscopy. We have now extended these studies to show an almost threefold elevation in occipital cortex lactate in 31 HD patients as compared with 17 normal control subjects (p < 10(-11)). The spectra in three presymptomatic gene-positive patients were identical to normal control subjects in cortical regions, but three in eight showed elevated lactate in the striatum. Similar to recently reported increases in task-related activation of the striatum in the dominant hemisphere, we found that striatal lactate levels in HD patients were markedly asymmetric (higher on the left side). Markers of neuronal degeneration, decreased N-acetylaspartate (NAA)/creatine and increased choline/creatine levels, were symmetric. Both decreased NAA and increased lactate in the striatum significantly correlated with duration of symptoms. When divided by his or her age, an individual's striatal NAA loss and lactate increase were found to directly correlate with the subject's CAG repeat number, with correlation coefficients of 0.8 and 0.7, respectively. Similar correlations were noted between postmortem cell loss and age versus CAG repeat length. Together, these data provide further evidence for an interaction between neuronal activation and a defect in energy metabolism in HD that may extend to presymptomatic subjects.