Antoine M. Hakim

Dementia in Parkinson disease: a neuropathologic study.

Thirty-four autopsy cases conforming to the standard neuropathologic criteria of Parkinson disease were sex- and age-matched with controls who had died of infarct or trauma. All brains were reviewed for changes compatible with Alzheimer disease, and available clinical data were retrospectively reviewed. Nineteen (56 percent) of the Parkinson cases had shown some degree of dementia. The average parkinsonian brain weight was 1281 gm; it was 1365 gm for the controls (p < 0.02). Plaques, neurofibrillary tangles, granulovacuolar degeneration, and cortical cell loss were present in all but one of the parkinsonian brains; these pathologic changes were present in fewer controls and to a lesser degree. The higher incidence of dementia in patients with Parkinson disease may be explained by the simultaneous presence of Alzheimer disease.

Anatomical-Functional Correlation Using an Adjustable MRI-Based Region of Interest Atlas with Positron Emission Tomography

A procedure is described for combining anatomical information from magnetic resonance imaging (MRI) or computerized tomography (CT) and functional information from positron emission tomography (PET) in a rapid fashion. MRI data are combined with a procedure for the definition, storage, and recall of anatomically based regions of interest. An atlas of standard regions of interest, defined for a set of 18 parallel planes spaced at 6-mm intervals, provides an initial region of interest template for each patient slice. Global adjustments to scale, orientation, and position are applied to obtain an initial match. Individual regions of interest may then be moved, deleted, or redrawn as needed. The ability to store region of interest templates ensures reproducibility of analysis over long periods and introduces a standardization of analysis technique. In 25 brain structures, the mean coefficient of variation in cerebral glucose utilization rate (CMRGlc) measurements among five neuroanatomically trained observers was reduced from 8.1% for manual region of interest definition to 4.0% using the template approach with MRI. Template analysis for space-occupying lesions such as tumors or infarcts is illustrated with PET data from a stroke study, emphasizing the facility for rapid, reproducible analysis of multifunctional studies. MRI-PET matching for a structurally intact caudate nucleus having reduced CMRGlc in Huntingtons disease emphasizes the accuracy of anatomical localization required to quantify small structures.

Immediate anticoagulation of embolic stroke: brain hemorrhage and management options

The clinical implications of hemorrhagic transformation of embolic brain infarction were explored by studying 30 patients with cardiogenic brain embolism and either hemorrhagic infarct (HI) or intracerebral hematoma (ICH) on CT. At the time of identification of hemorrhage, 19 patients were receiving anticoagulants and 11 were not. Eight anticoagulated patients and three nonanticoagulated patients developed late HI without attendant worsening after an initial CT was nonhemorrhagic. Hemorrhagic transformation without worsening most often occurred after 12 hours but before 48 hours following stroke onset and was associated with large infarcts (82%) but not with age, blood pressure or embolic source. Seven anticoagulated patients, six with large infarcts, and one nonanticoagulated patient with a small infarct abruptly worsened from eight hours to 11 days after stroke, with CT revealing ICH or severe HI. Excessive anticoagulation or acute hypertension potentially contributed to hemorrhagic transformation in four of five patients who were receiving heparin. Brain hemorrhage in embolic strokes most often occurs with large infarcts. Early CT may not allow the identification of large embolic infarcts that are destined to later undergo spontaneous hemorrhagic transformation. For large embolic infarcts, a delay of several days before anticoagulation and special efforts to avoid excessive anticoagulation and hypertension may be prudent. The initial administration of large, bolus doses of heparin should perhaps be avoided.

Nestin expression in reactive astrocytes following focal cerebral ischemia in rats

During central nervous system (CNS) development, intermediate filaments are subjected to a sequential remodelling process. Nestin is a distinct intermediate filament which is transiently expressed in proliferating neuroepithelial stem cells during the neurulation stage of development. Nestin re-expression in the adult rat was studied following transient (2 h) middle cerebral artery occlusion. Seven days after the ischemic insult, nestin reactive astrocytes were found in the border zone surrounding cerebral infarction. Nestin immunoreactivity delineated a zone between infarction and the surrounding intact cerebral parenchyma. In situ hybridization for nestin mRNA showed early changes in small cells in the surround of the ischemic lesion. These results with nestin, along with other stem cell markers expressed by reactive astrocytes, suggest an embryonic reversion of the mature cytoskeleton as a response of astrocytes to cerebral injury.

APAF1 is a key transcriptional target for p53 in the regulation of neuronal cell death

p53 is a transcriptional activator which has been implicated as a key regulator of neuronal cell death after acute injury. We have shown previously that p53-mediated neuronal cell death involves a Bax-dependent activation of caspase 3; however, the transcriptional targets involved in the regulation of this process have not been identified. In the present study, we demonstrate that p53 directly upregulates Apaf1 transcription as a critical step in the induction of neuronal cell death. Using DNA microarray analysis of total RNA isolated from neurons undergoing p53-induced apoptosis a 5–6-fold upregulation of Apaf1 mRNA was detected. Induction of neuronal cell death by camptothecin, a DNA-damaging agent that functions through a p53-dependent mechanism, resulted in increased Apaf1 mRNA in p53-positive, but not p53-deficient neurons. In both in vitro and in vivo neuronal cell death processes of p53-induced cell death, Apaf1 protein levels were increased. We addressed whether p53 directly regulates Apaf1 transcription via the two p53 consensus binding sites in the Apaf1 promoter. Electrophoretic mobility shift assays demonstrated p53–DNA binding activity at both p53 consensus binding sequences in extracts obtained from neurons undergoing p53-induced cell death, but not in healthy control cultures or when p53 or the p53 binding sites were inactivated by mutation. In transient transfections in a neuronal cell line with p53 and Apaf1 promoter–luciferase constructs, p53 directly activated the Apaf1 promoter via both p53 sites. The importance of Apaf1 as a p53 target gene in neuronal cell death was evaluated by examining p53-induced apoptotic pathways in primary cultures of Apaf1-deficient neurons. Neurons treated with camptothecin were significantly protected in the absence of Apaf1 relative to those derived from wild-type littermates. Together, these results demonstrate that Apaf1 is a key transcriptional target for p53 that plays a pivotal role in the regulation of apoptosis after neuronal injury.

The association of hyperglycemia with cerebral edema in stroke.

A retrospective review of stroke patients admitted to our hospital revealed 39 patients diagnosed as suffering an acute completed ischemic stroke who also had had fasting (AC) serum glucose determinations and sequential computer tomography (CT) studies. The patients were divided into three groups on the basis of mean AC serum glucose: Group 1 (n = 12) mean serum AC glucose greater than 150 mg/dl; Group 2 (n = 13) mean serum AC glucose 100-150 mg/dl; and Group 3 (n = 14) mean serum AC glucose less than 100 mg/dl. CT scans performed on each patient were studied for the presence of midline shift and/or ventricular compression, which were interpreted as evidence of cerebral edema. The three groups were comparable with respect to mean age, average mean arterial blood pressure and initial infarct size. Our results show that in Group 1, 42% of the patients died within the first week following their CVA with clinical evidence of transtentorial herniation confirmed by CT or autopsy. In contrast, none of the Group 3 patients died and only one showed radiological evidence for cerebral edema. Group 2 patients showed intermediate mortality and evidence of cerebral edema. These trends were statistically significant at p less than 0.005. In addition, the combined hyperglycemic group (1 and 2) had a significantly higher rate of development of hypodensity on CT (p less than 0.05) than the normoglycemic group. Our findings suggest that patients with hyperglycemia in association with their CVA develop more pronounced cerebral edema and have a worse clinical outcome. Possible pathophysiological mechanisms that may underlie this observation are discussed.

Cortical Spreading Depression Protects against Subsequent Focal Cerebral Ischemia in Rats

The possibility that cortical spreading depression (CSD) may have neuroprotective action during subsequent focal cerebral ischemia was examined in rats. Three days before the imposition of focal cerebral ischemia CSDs were elicited by applying potassium chloride (KCl) for 2 h through a microdialysis probe implanted in the occipital cortex. Control animals were handled identically except that saline was infused instead of KCl. Focal ischemia was produced by the intraluminal suture method and cortical and subcortical infarct volumes were measured 7 days later. Neocortical infarct volume was reduced from 124.8 ± 49.5 mm3 in the controls to 62.9 ± 59.5 mm3 in the animals preconditioned with CSD (p = 0.012). There was no difference between the two groups in the subcortical infarct volume or in CBF, measured by the hydrogen clearance method, during or immediately after the ischemic interval. Our data indicate that preconditioning CSD applied 3 days before middle cerebral artery occlusion may increase the brains resistance to focal ischemic damage and may be used as a model to explore the neuroprotective molecular responses of neuronal and glial cells.

The Effect of Nimodipine on the Evolution of Human Cerebral Infarction Studied by PET

Fourteen patients were studied by positron emission tomography (PET) within 48 h of onset of a hemispheric ischemic stroke and again 7 days later. After the first set of PET scans, the patients were randomized to receive either nimodipine (n = 7) or a carrier solution (n = 7) by intravenous infusion. The infusions were maintained until the end of the second PET studies. CBF, cerebral blood volume (CBV), oxygen extraction ratio (OER), CMRO2, and CMRglc were measured each time. These metabolic and perfusion measurements were performed by standard methods. A surface map of each metabolic and perfusion measurement in the cortical mantle was generated by interpolating between the available slices. The various surface maps representing the physiological characteristics determined in the same or subsequent studies were aligned so that all data sets could be analyzed identically using an array of square regions of interest (ROIs). The functional status of each ROI was recorded at the two intervals following the cerebrovascular accident to characterize the evolution of the infarct, penumbra, and normal brain regions. We presumed the ischemic penumbra to be cortical regions in the proximity of the infarct and perfused at CBF values between 12 and 18 ml/100 g/min on the first PET scan, while densely ischemic regions had CBF of <12 nl/100 g/min and normally perfused brain >18 ml/100 g/min. In the densely ischemic zone, CBF increased more in the nimodipine-treated group than in the carrier group. As well, in this region nimodipine reversed the decline in CMRO2 noted in the carrier group, the difference in the changes being significant. In the penumbra zone, comparable trends were noted in OER and CMRO2 but the difference in the changes between the two groups did not reach statistical significance. Changes in CMRglc and CBV were comparable between the two groups in both cortical regions.

Transient Forebrain Ischemia Protects Against Subsequent Focal Cerebral Ischemia Without Changing Cerebral Perfusion

BACKGROUND AND PURPOSE The possibility that the brain may be preconditioned to be more tolerant of ischemia is an important concept with important clinical implications. Exploring the concept offers the possibility of advancing our understanding of protective molecular responses in the brain. This article compares two preconditioning methods and explores the role that changes in regional cerebral blood flow (rCBF) may play in conferring ischemic protection. METHODS Temporary occlusion of the middle cerebral artery (MCA) using the thread model was preceded 4 days earlier by short-lasting focal or global ischemia or by sham surgery. rCBF was measured in the frontoparietal region of the ischemic hemisphere during all focal ischemia episodes. Four days after the second ischemic exposure, animals were killed, and the size of infarction was determined. RESULTS rCBF was significantly higher in the frontoparietal region during MCA occlusion when it was preceded by prior focal ischemia (36.8 +/- 7.6 mL x 100 g-1 at 30 minutes) compared with controls (24.7 +/- 4.0 mL x 100 g-1.min-1, P = .0008). Despite this, there was no significant difference in the resulting infarct volume. In contrast, when MCA occlusion was preceded by global ischemia, infarct volume was significantly reduced (68.1 +/- 30.9 mm3 in the controls versus 22.9 +/- 22.1 mm3 in the preconditioned group, P = .002) without significant change in rCBF. CONCLUSIONS Protection from ischemic injury requires specific conditions of prior exposure to ischemia. Improved perfusion would not seem to be a sufficient or necessary accompaniment to providing neuroprotection.

Cerebral vulnerability is associated with selective increase in extracellular glutamate concentration in experimental thiamine deficiency.

Abstract: Microdialysis in the awake, freely moving rat was used to determine the effect of pyrithiamine‐induced thiamine deficiency on the levels of amino acids in the brain. Studies were carried out on (a) presymptomatic animals immediately before the development of behavioral changes and (b) acute symptomatic animals within 6 h following loss of righting reflexes. This latter stage precedes the appearance of histological lesions. The results were compared with pair‐fed controls. Dialysis probes were implanted in one vulnerable structure [ventral posterior medial thalamus (VPMT)] and one nonvulnerable area [frontal parietal cortex (FPC)] on the contralateral side. In VPMT of acute symptomatic animals, the glutamate concentration was significantly increased (3.37 ± 0.64 μM; p < 0.005) compared with control values (0.93 ± 0.09 μM), whereas in FPC no change in glutamate content was evident. These results suggest that glutamate plays a significant role in the development of central thiamine deficiency lesions. The absence of any increase in glutamate levels in the nonvulnerable FPC suggests that a glutamate‐mediated excitotoxic mechanism may be responsible for the selective cerebral vulnerability in thiamine deficiency.