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The iodinated benzamide epidepride, which shows a picomolar affinity binding to dopamine D(2) receptors, has been designed for in vivo studies using SPECT. The aim of the present study was to apply a steady-state condition by the bolus/infusion approach with [(123)I]epidepride for the quantification of striatal and extrastriatal dopamine D(2) receptors in humans. In this way the distribution volume of the tracer can be determined from a single SPECT image and one blood sample. Based on bolus experiments, an algorithm using conventional convolution arguments for prediction of the outcome of a bolus/infusion (B/I) experiment was applied. It was predicted that a B/I protocol with infusion of one-third of the initial bolus per hour would be appropriate. Steady-state conditions were attained in extrastriatal regions within 3-4 h but the infusion continued up to 7 h in order to minimize the significance of individual differences in plasma clearance and binding parameters. A steady-state condition, however, could not be attained in striatal brain regions using a B/I protocol of 20 h, even after 11 h. Under near steady-state conditions a striatal:cerebellar ratio of 23 was demonstrated. Epidepride has a unique signal-to-noise ratio compared to [(123)I]IBZM but present difficulties for steady-state measurements of striatal regions. The bolus/infusion approach is particularly feasible for quantification of the binding potential in extrastriatal regions., (Copyright 2000 Wiley-Liss, Inc.)

The value of SPECT scanning in diagnosis and growth potential of vestibular schwannoma (VS) was investigated in a series of 29 patients. SPECT demonstrated all tumours > 0.8 cm3, but had limitations as a diagnostic modality of small intracanalicular tumours, when compared to gadolinium DTPA enhanced MR. SPECT was found to be valuable in determining VS growth potential as it reflects tumour vascularity, which is essential for tumour growth. A high radioactive tracer uptake in the tumour corresponded to high tumour vascularity, indicating a high growth rate and vice versa. It seems that we now have an in vivo functional radiological modality capable of providing data on VS vascularity and determination of growth potential in the individual tumour.

In the clinical setting it has been shown that activation will increase cerebral glucose uptake in excess of cerebral oxygen uptake. To study this phenomenon further, this study presents an experimental setup that enables precise determination of the ratio between cerebral uptake of glucose and oxygen in the awake rat. Global CBF was measured by the Kety-Schmidt technique, and the ratio between cerebral uptake rates for oxygen, glucose, and lactate was calculated from cerebral arterial-venous differences. During baseline conditions, rats were kept in a closed box designed to minimize interference. During baseline conditions CBF was 1.08 +/- 0.25 mL x g(-1) x minute(-1), and the cerebral oxygen to glucose uptake ratio was 5.5. Activation was induced by opening the sheltering box for 6 minutes. Activation increased CBF to 1.81 mL x g(-1) x minute(-1). During activation cerebral glucose uptake increased disproportionately to cerebral oxygen uptake, and the cerebral oxygen to glucose uptake ratio was 4.2. The accumulated excess glucose uptake during 6 minutes of activation amounted to 2.4 micromol/g. Activation was terminated by closure of the sheltering box. In the postactivation period, the cerebral oxygen to glucose uptake ratio rose to a maximum of 6.4. This response is exactly opposite to the excess cerebral glucose uptake observed during activation.

PET (positron emission tomography) and SPECT (single photon emission computed tomography) are isotopic methods in which the distribution is registered of radiolabelled tracers given in such small amounts that they are without effect on the organism or the organism's disposal of them. Thus, a series of important biological processes in the intact organism can be studied. The methods have been used in many disciplines but in particular for neurobiological research on the brain--e.g., the brain's regional blood circulation and mapping of the brain's functional structure. The methods have also been used in the investigation of glucose and amino acid metabolism in the brain and receptor conditions.

Thallium chloride 201Tl combined with SPECT was performed in a series of 29 patients with neuroradiological evidence of vestibular schwannoma (VS). The relative tumor uptake (U) and relative tumor concentration (C) of the radiotracer 201Tl was determined, and the cerebellum served as a reference. The relative tracer concentration and uptake were correlated to tumor volume determined by gadolinium DTPA enhanced MR, to prediagnostic duration of symptoms, to tumor vascularity expressed by the average number of intratumoral vessels using the endothelial marker CD31, and to the proliferative activity in the tumors expressed by positive staining with the monoclonal antibody MIB-1 for Ki-67. A positive 201TI enhancement was detected in 17 tumors (n = 17). Tumors U and C were statistically unrelated to tumor volume (p = 0.236 and p = 0.439). SPECT demonstrated all tumors > 0.8 cm3, but it had its limitation as a diagnostic modality of small intracanalicular tumors, when compared with gadolinium DTPA enhanced MR. Relating U and C in all tumors (n = 29) and the prospectively registered data on the prediagnostic duration of symptoms, a statistical significance was found (p = 0.012 and p = 0.015). No statistically significant correlation was observed between U and C and the proliferative activity of the tumors expressed by positive staining with the monoclonal antibody MIB-1 for Ki-67 (p = 0.063 and p = 0.086). A statistically significant correlation was noted between C and U in the operated group (n = 12) and tumor vascularity expressed by the average number of the intratumoral vessels (p = 0.003 and p = 0.014). SPECT was found to be superior to MR in determining VS growth potentials as it expresses tumor vascularity, which is essential for tumor growth. It seems that we now have an in vivo functional radiological modality capable of providing data on VS vascularity and determination of growth potential in the individual tumor. A high radioactive tracer uptake in the tumor corresponded to high tumor vascularity, indicating a high growth rate and vice versa.

Background and Purpose: [123I]Iomazenil is a specific radioligand for the central benzodiazepine receptor that may be useful as an indicator of the intactness of cortical neurons after focal cerebral ischemia. We evaluated the binding of this receptor in reperfused cortex among patients with ischemic stroke to detect viable neurons in cortex that appeared structurally intact on conventional neuroimaging studies., Methods: Fourteen patients were selected by (1) angiography within 24 hours of onset showing embolic occlusion of an intracranial artery, (2) cerebral blood flow showing ischemia of moderate severity in 12 cases and spontaneous reflow in 2 cases, and (3) thrombolysis with reperfusion within 24 hours in most cases. Thirty reperfused cortical areas that remained structurally intact, 7 infarcted cortical areas, and 6 contralateral cerebellar areas with reduced blood flow were selected as regions of interest to estimate receptor binding 5 days to 23 months after the stroke. A two-compartment model was used to compute the distribution volume (Vd) of iomazenil in relative units, with Vd proportional to benzodiazepine receptor concentration. The side-to-side asymmetry ratio of Vd was calculated., Results: The mean asymmetry ratio was 0.89 +/- 0.11 (range, 0.64 to 1.05), 0.50 +/- 0.15 (range, 0.23 to 0.67), and 0.97 +/- 0.05 (range, 0.90 to 1.04) in reperfused cortex, infarcted cortex, and contralateral cerebellum, respectively. Compared with unity, both reperfused cortex and infarcted cortex showed significant decrease of Vd (P < .001). Contralateral cerebellum showing diaschisis had no reduction of Vd. On MRI, obtained 3 or 6 months after the stroke, mild cortical atrophy was observed in two reperfused areas where the asymmetry ratio was moderately reduced (0.64 and 0.80)., Conclusions: The reduction of benzodiazepine receptor concentration in reperfused cortex that remained structurally intact is likely to be the result of injury involving only a limited number of neurons (ie, incomplete infarction). Our data suggest that the degree of viability of ischemic cortex apparently salvaged by early reperfusion can be quantified by iomazenil.

During dynamic exercise, mean blood velocity (Vmean) in the middle cerebral artery (MCA) demonstrates a graded increase to work rate and reflects regional cerebral blood flow. At a high work rate, however, vasoactive levels of plasma catecholamines could mediate vasoconstriction of the MCA and thereby elevate Vmean at a given volume flow. To evaluate transcranial Doppler-determined Vmean at high plasma catecholamine levels, seven elite cyclists performed a maximal performance test on a bicycle ergometer. Results were compared with those elicited during five incremental exercise bouts and during rhythmic handgrip when plasma catecholamines are low. During rhythmic handgrip the Vmean was elevated by 21 +/- 3% (mean +/- SE), which was not statistically different from that established during moderate cycling. However, at the highest submaximal and maximal work intensities on the bicycle ergometer. Vmean increased by 31 +/- 3% and 48 +/- 4%, respectively, and this was significantly higher compared to handgrip (P < 0.05). During maximal cycling, plasma adrenaline increased from 0.21 +/- 0.04 nmol L-1 at rest to 4.18 +/- 1.46 nmol L-1, and noradrenaline increased from 0.79 +/- 0.08 to 12.70 +/- 1.79 nmol L-1. These levels were 12- to 16-fold higher than those during rhythmic handgrip (adrenaline: 0.34 +/- 0.03 nmol L-1; noradrenaline: 0.78 +/- 0.05 nmol L-1). The increase in Vmean during intense ergometer cycling conforms to some middle cerebral artery constriction elicited by plasma catecholamines. Such an influence is unlikely during rhythmic handgrip compared with low intensity cycling.

Iodine-123 labelled iomazenil (IMZ) is a specific tracer for the GABAA receptor, the dominant inhibitory synapse of the brain. The cerebral distribution volume (Vd) of IMZ may be taken as a quantitative measure of these synapses in Alzheimer's disease (AD), where synaptic loss tends indiscriminately to affect all cortical neurons, albeit more so in some areas than in others. In this pilot study we measured Vd in six patients with probable AD and in five age-matched controls using a brain-dedicated single-photon emission tomography scanner allowing all cortical levels to be sampled simultaneously. Reduced values were found in all regions except in the occipital (visual) cortex. In particular, temporal and parietal cortex Vd was significantly (P<0.02) reduced: temporal Vd averaged 69 ml/ml in normals and 51 ml/ml in AD, and parietal Vd averaged 71 ml/ml in normals and 48 ml/ml in AD. These results accord well with emission tomographic studies of blood flow or labelled glucose. This supports the idea that while only measuring a subpopulation of synapses, the IMZ method reflects synaptic loss and hence functional loss in AD. The method constitutes an in vivo version of synaptic quantitation that in histopathological studies has been shown to correlate closely with the mental deterioration in AD.

The fractional increase in cerebral blood flow (CBF) velocity (VCBF) from the control value with 5-min steps of isocapnic hypoxia and hyperoxic hypercapnia was measured by transcranial Doppler in six sea-level native men before and during a 5-day sojourn at 3,810 m altitude to determine whether cerebral vasoreactivity to low arterial O2 saturation (SaO2) gradually increased [as does the hypoxic ventilatory response (HVR)] or diminished (adapted, in concert with known slow fall of CBF) at altitude. A control resting PCO2 value was chosen each day during preliminary hyperoxia to set ventilation at 140 ml.kg-1.min-1 for this and the parallel HVR study, attempting to establish control cerebrospinal fluid (CSF) and brain extracellular fluid pH values unaltered by acclimatization. The relationship of CBF to SaO2 was nonlinear, steepening at a lower SaO2. A hyperbolic equation was used to describe hypoxic cerebrovascular reactivity: fractional VCBF = x[60/ (SaO2-40)-1], where X is the fractional increase of VCBF at 70%.X rose from 0.346 +/- 0.104 (SD) at sea level to 0.463 +/- 0.084 on altitude day 5 (P < 0.05 by paired t-test, justified by the a priori experimental plan). For comparison with CO2 sensitivity, from these X values, we estimate the rise in CBF in response to a 1% fall in SaO2 at 80% to be 1.30% at sea level and 1.74% after 5 days at altitude. CBF sensitivity to increased end-tidal PCO2 rose from 4.01 +/- 0.62%/Torr at sea level to 5.12 +/- 0.79%/Torr on day 5 (P < 0.05), as expected, at the lower PCO2 due to the logarithmic relationship of PCO2 to CSF pH. This change was not significant after correction to log PCO2. We conclude that the cerebral vascular response to acute isocapnic hypoxia may increase during acclimatization at high altitude. The mechanism is unknown but is presumably unrelated to the parallel carotid chemosensitization that, in these subjects, increased the HVR by 60% in the same 5-day period from 0.91 +/- 0.38 to 1.46 +/- 0.59 l.min-1.% fall in SaO2-1).

Background: The concept of selective vulnerability or selective loss o f individual neurons, with survival of glial and vascular elements as one of the consequences of a systemic ischemic-hypoxic insult (eg, transient cardiac arrest or severe hypotension), has been recognized for decades. In contrast, selective neuronal death as one of the lesions that may develop in the brain after occluding an intracranial artery is an idea not readily acknowledged in the current medical literature dealing with human stroke., Summary of Review: A review of pertinent publications reveals that selective neuronal injury after middle cerebral artery occlusion was observed in autopsy specimens over 40 years ago, although its pathogenesis remains unclear. Recent observations in both humans and animals suggest that selective neuronal necrosis (rather than infarct) is the consequence of either a short-term arterial occlusion or permanent occlusion accompanied by ischemia of moderate severity. During the acute and subacute states of an ischemic stroke, the loss of a limited number of neurons (ie, incomplete infarction) does not result in structural changes discernible by either CT or conventional MRI. However, the loss of a selected number of neurons may be demonstrable in vivo by calculating the corresponding loss of benzodiazepine receptors. The use of specific radiotracers in combination with single-photon emission CT or positron emission tomography allows demonstration of a decrease in gamma-aminobutyric acid-ergic receptor sites at places where many neurons have been lethally injured., Conclusions: We aim to alert physicians to the potential development of incomplete brain infarctions in patients with intracranial arterial occlusions. Recognizing incomplete infarcts is particularly important in the context of stroke therapy with thrombolytic and neuroprotective agents. This brain lesion is likely to be the consequence of an arterial occlusion with a resultant ischemia of moderate severity (eg, regional blood flows in the range of 15 to 20 mL x 100 g-1 x min-1).

Stroke-in-progression, SIP, occurs in about 30% of patients with acute stroke and negatively affects the prognosis and mortality. The underlying caused are thought to be clot propagation, cerebral haemorrhage or oedema. In some cases these rather obvious mechanisms cannot be demonstrated, and other variables such as a decrease in blood pressure must be considered as major factors. In this paper the basic haemodynamic mechanisms of cerebral blood flow and the relevant pathophysiology of focal cerebral infarcts are described with emphasis on the penumbra. In addition, available clinical studies are reviewed and current treatment discussed. Our main conclusion is that to assure sufficient collateral flow a high perfusion pressure must be maintained, and we advocate withholding antihypertensive therapy during the acute phase of focal cerebral ischaemia.

The study was performed to investigate how often reduction of high blood pressure (> or = 220 mmHg systolic and or > or = 120 mmHg diastolic) was attempted in patients with acute stroke or transient ischemic attacks (TIA). Of 1351 consecutive patients with acute stroke or TIA 119 had high blood pressure on admission. In 15 patients the stroke was so severe that treatment was not considered. In the remaining 104 patients reduction of the blood pressure was attempted in 28 (27%); in 23 patients immediately following admission. None of the patients had symptoms or signs of hypertensive encephalopathy. It is concluded that reduction of high blood pressure in patients with stroke or TIA is attempted too often. As autoregulation is commonly impaired in acute stroke, reduction of systemic blood pressure may enhance ischaemic tissue damage. Reduction of blood pressure in acute stroke should be considered only in case of hypertensive encephalopathy.

Patients with acute stroke often present with high blood pressure (BP) on hospital admission. Because hypertension is a risk factor for stroke, and because severe BP elevation may increase oedema and the risk of haemorrhage, acute antihypertensive therapy might seem reasonable. On the other hand, the increase in BP in the acute stage might be considered a beneficial pathophysiological response maintaining the perfusion pressure to the ischaemic area and, in particular, the surrounding penumbra. As illustrated in the case presented here, lowering the BP in the early stage may be associated with progression of neurological deficits, very likely due to a reduction of perfusion to the penumbra thus enlarging the infarct.

Global cerebral blood flow (CBF), global cerebral metabolic rates for oxygen (CMRO2), and for glucose (CMRglc), and lactate efflux were measured during rest and during cerebral activation induced by the Wisconsin card sorting test. Measurements were performed in healthy volunteers using the Kety-Schmidt technique. Global CMRO2 was unchanged during cerebral activation, whereas global CBF and global CMRglc both increased by 12%, reducing the molar ratio of oxygen to glucose consumption from 6.0 during baseline conditions to 5.4 during activation. Data obtained in the period following cerebral activation showed that the activation-induced resetting of the relation between CMRglc and CMRO2 persisted virtually unaltered for > or = 40 min after the mental activation task was terminated. The activation-induced increase in cerebral lactate efflux measured over the same time period accounted for only a small fraction of the activation-induced excess glucose uptake. These data confirm earlier reports that brain activation can induce resetting of the cerebral oxygen/glucose consumption ratio, and indicate that the resetting persists for a long period after cerebral activation has been terminated and physiologic stress indicators returned to baseline values. Activation-induced resetting of the cerebral oxygen/glucose uptake ratio is not necessarily accounted for by increased lactate production from nonoxidative glucose metabolism.

The importance of smooth muscle cell pHi and pHo for the hypercapnic vasodilation of rat cerebral arteries was evaluated in vitro. Vessel segments were mounted in a myograph for isometric tension recording; pHi was measured by loading the smooth muscle cells with the fluorescent dye BCECF, and pHo was measured with a glass electrode. In all studies, Ca(2+)-dependent basal tension (in the absence of any agonist) and tension in the presence of arginine vasopressin were investigated. Control solution was physiological saline bubbled with 5% CO2 and containing 25 mmol/L HCO3- (pH 7.45 to 7.50). Induction of hypercapnic acidosis (10% CO2) or normocapnic acidosis (15 mmol/L HCO3-) caused significant inhibition of smooth muscle tension, and both conditions reduced pHi as well as pHo. N-Nitro-L-arginine significantly inhibited the relaxation to hypercapnic acidosis but had no significant effect on relaxation to normocapnic acidosis. Predominant extracellular acidosis, induced by reducing [HCO3-] from 25 to 9 mmol/L and CO2 from 5% to 2.5%, also caused inhibition of tension in steady state. By contrast, predominant intracellular acidosis, induced by increasing [HCO3-] from 25 to 65 mmol/L and CO2 from 5% to 15%, induced a small increase of basal tension and a small decrease of tension in the presence of arginine vasopressin. The responses to predominant intracellular or extracellular acidosis were qualitatively similar in the presence and absence of endothelium and in the presence and absence of N-nitro-L-arginine. It is concluded that the extracellular acidosis and not smooth muscle intracellular acidosis is responsible for the relaxation to hypercapnic acidosis.

Dynamic exercise enhances regional cerebral artery mean flow velocity. J. Appl. Physiol. 78(1): 12-16, 1995.--Anterior (ACA) and middle (MCA) cerebral artery mean flow velocities (Vmean) and pulsatility indexes were determined using transcranial Doppler in 14 subjects during dynamic exercise after assessment of the carbon dioxide reactivity for both arteries. Right hand contractions provoked an elevation in left MCA Vmean [19% (12-28); P < 0.01], whereas the pulsatility decreased in all four arteries (P < 0.05). During right foot movement, left ACA Vmean increased by 23% (11-37; P < 0.01) with lesser (approximately 10%; P < 0.05) increases in the other arteries, and pulsatility index decreased (P < 0.05). During cycling, ACA and MCA Vmean increased bilaterally by 23% (10-49) and 18% (5-32), respectively (P < 0.01), and the pulsatility was also elevated (P < 0.05). Cerebral artery pulsatility did not demonstrate a focal response but depended did not demonstrate a focal response but depended on the muscle mass involved during exercise. The data demonstrate a significant increase in Vmean for the artery supplying the cortical projection of the exercising limb. Insignificant and marginally significant increases in Vmean may be related to sympathetically mediated vasoconstriction and/or coactivation of untargeted muscle groups.

Carbon-11-labeled flumazenil combined with positron emission tomography (PET) was used to measure the concentration (Bmax) of the benzodiazepine (Bz) receptor in the brain and its equilibrium dissociation constant (KD) for flumazenil in five normal subjects. The steady-state approach was used injecting the tracer as a bolus of high specific activity. In each subject two studies were carried out. The first study was performed at essentially zero receptor occupancy, the tracer alone study. The second study was performed at a steady-state receptor occupancy of about 50%, achieved by a prolonged constant infusion of nonlabeled ("cold") flumazenil starting 2h before the bolus tracer injection and continuing until the end of scanning period. In this second study the free concentration of unmetabolized flumazenil in plasma water was measured in multiple blood samples. The observed tissue and plasma tracer curves, calibrated in the same units of radioactivity per millimeter, were analyzed in two ways: (a) by the noncompartmental (stochastic) approach making no assumptions regarding number of compartments in the tissue, and (b) by the single-compartment approach assuming rapid exchange (mixing) of tracer between all tissue compartments. The noncompartmental and the compartmental analyses gave essentially the same values for the distribution volume of the tracer, the parameter used for quantitation of the Bz receptor. As the compartmental approach could be applied to a shorter observation period (60 min instead of 120 min) it was preferred. The five subjects had a mean KD value of 12 nM/L of water and Bmax values of the grey matter ranging from 39 +/- 11 in thalamus to 120 +/- 14 nM/L of brain in occipital cortex. Most previous studies have been based on the pseudoequilibrium approach using the brain stem as a receptor-free reference region. This yields practically the same KD but lower Bmax values than the steady-state approach presented here.

The relaxant effect of hypercapnia (15% CO2) was studied in isolated circular segments of rat basilar arteries with intact endothelium. The nitric oxide synthase inhibitor nitro-L-arginine (L-NOARG) and the cytosolic guanylate cyclase inhibitor methylene blue (MB), significantly reduced this relaxation by 54% and 70%, respectively. The effect of L-NOARG was completely reversed by L-arginine. Blockade of nerve excitation with tetrodotoxin (TTX) had no affect on the 15% CO2 elicited vasodilatation. Measurements of cGMP in vessel segments showed no significant increase in cGMP content in response to hypercapnia. L-NOARG and MB, but not TTX, significantly reduced the basal cGMP content in cerebral vessels. Adding 1.5% halothane to the incubation medium did not result in a significant increase in cGMP content. Lowering the pH by cumulative application of 0.12 M HCl resulted in relaxation identical to that obtained by lowering the pH with 15% CO2. In vessel segments in which the endothelium had been removed beforehand 15% CO2 induced relaxation that was not different from that seen in vessels with intact endothelium. L-NOARG had no affect in endothelium denuded vessels. The results suggest that high CO2 elicits vasodilatation of isolated rat basilar arteries by a mechanism independent of nitric oxide synthase (NOS) activity. The markedly reduced basal cGMP levels in cerebral vessels by L-NOARG and MB suggest that there exists a basal NO formation in the cerebral vessel wall.

In a prospective MRI study the presence, appearance, volume, and regional cerebral blood flow (rCBF) correlates of periventricular hyperintensities (PVHs) and deep white matter hyperintensities (DWMHs) were examined in 18 patients with probable Alzheimer's disease and in 10 age matched healthy control subjects, all without major cerbrovascular risk factors. The 133Xe inhalation method and the [99mTc]-d,l-hexamethyl-propylene-amine-oxime (HMPAO) technique with single photon emission computed tomography (SPECT) were used to measure rCBF. Rating scores for PVHs were significantly higher in the Alzheimer's disease group (p < 0.01) and correlated significantly with the volume of ventricles (p < 0.05) and with systolic arterial blood pressure (p < 0.01), but not with rCBF. By contrast, there was no significant difference in the rating scores or volumes of DWMHs between the two groups, although three patients had extensive DWMH lesions in the central white matter. In the group of patients with Alzheimer's disease as a whole, the volume of DWMHs correlated well with rCBF in the hippocampal region ( r = -0.72; p < 0.001), but not with frontal, temporal, parietal, or occipital rCBF. Postmortem histopathology of extensive DWMH lesions in one patient with definite Alzheimer's disease showed a partial loss of myelin and astrocytic gliosis, but no ischaemic changes. It is concluded that DWMH lesions may be associated with reduced rCBF in the hippocampal region. The heterogenous topography of neocortical rCBF deficits in Alzheimer's disease could not be explained by deafferentation from underlying white matter hyperintensities and therefore may reflect variations in the topography of cortical abnormalities.

Neurons synthesize NO, which may act as a retrograde messenger, involved in either potentiating or depressing neuronal excitability. NO may also play a role in the cerebral vasodilatory response to increased neuronal activity (i.e., seizures). In this study, two questions were asked: (1) is NO an endogenous anticonvulsant or proconvulsant substance? and (2) is the cerebral blood flow (CBF) increase accompanying bicuculline (BC)-induced seizures mediated by NO? The experiments were performed in 300-400-g Wistar rats anesthetized with 0.6% halothane and 70% N2O/30% O2. CBF was measured using the intracarotid 133Xe clearance method or laser-Doppler flowmetry. EEG activity was recorded. Chronic treatment (4 days) with nitro-L-arginine (L-NA), a potent NO synthase (NOS) inhibitor (400 mg/kg total), suppressed brain NOS by > 97% and prolonged seizure duration from 6 +/- 1 (saline-treated controls) to 12 +/- 2 min. In the L-NA-treated group, the CBF increase was sustained as long as seizure activity remained, indicating that CBF was still tightly coupled to seizure activity. Interestingly, the supposed inactive enantiomer of L-NA, D-NA, also showed an inhibition of brain NOS activity, ranging from 87 to 100%. The duration of seizures in this group (average 8 +/- 2 min) corresponded directly to the magnitude of reduction in NOS activity (r = 0.83, P < 0.05). Specifically, the D-NA results indicated that NOS inhibition had to exceed 95% before any effect on seizure duration could be seen.(ABSTRACT TRUNCATED AT 250 WORDS)

In 92 migraine patients and 44 healthy control subjects we recorded regional cerebral blood flow (rCBF) with single photon emission computerized tomography and (133) Xe inhalation or with i.v. (99m) Tc-HMPAO. Migraine patients were studied interictally. A quantitated analysis of right-left asymmetry indices in a fixed set of regions of interest was compared with the normal asymmetry indices in the healthy controls. An asymmetry index deviating more than ± 2.5 S.D.s in normals was defined as pathological asymmetry. By quantitated analysis 47% of images from patients with aura attacks and 48% of images from patients without aura attacks were established to contain higher rate of asymmetries, the difference being statistically significant (p < 0.05, Wilcoxon). A blinded visual analysis and scoring by a four level scale were done by four experienced observers. rCBF images from 18% of patients having attacks with aura and from 19% of patients without aura attacks was scored as containing abnormal right-left asymmetries by the visual analysis. Images from healthy controls were all scored to be normal. In 37% of the images (all from patients) there was lack of consensus among observers (κ = 0.28). There was no correlation between visual or quantitated abnormalities and age, duration of migraine, frequency of attacks or prophylactic medication. No correlation could be established between asymmetries and the usual side of headache or aura symptoms. Two conclusions emerged: (1) visual evaluation of interictal migraine rCBF images is insufficient to pick up abnormalities; (2) almost 50% of the migraine sufferers had abnormal rCBF/asymmetries. However, these are discrete compared with those typically seen during the aura phase of a migraine attack. One explanation to the patchy rCBF patterns might be that they reflect interictal cerebrovascular dysregulation which might to be a common feature in both types of migraine., (1994 Lippincott Williams & Wilkins.)

Individual cognitive profiles and correlations between cognitive functions and regional cerebral blood flow (rCBF) were analyzed in 20 consecutive patients with a clinical diagnosis of probable Alzheimer's disease (AD). CBF was measured with high resolution single photon emission computed tomography (SPECT) and [(99m) Tc]d,l-HMPAO. The analysis of cognitive profiles was based on the composite scores for six cognitive domains, derived from a detailed neuropsychological test battery, as compared with corresponding test data obtained in a control group of 28 age-matched healthy volunteers. The cognitive profiles displayed a marked heterogeneity as concerned the general level of cognitive impairment, the number of significantly affected cognitive domains, the spectrum of affected and non-affected cognitive domains, and the severity of each cognitive dysfunction. Statistically significant correlations with rCBF were found for memory scores (right frontal and temporal cortex), abstraction scores (frontal/parietal ratio of rCBF), language scores (left frontal and temporal cortex), visual perception scores (rCBF throughout the right hemisphere), and for visuo-construction scores (side-to-side asymmetry of parietal rCBF). We conclude that the previously observed topographical heterogeneity of rCBF distribution patterns in probable AD was reflected by differences in cognitive profiles. The observed heterogeneities stress the relevance of analyzing individual cognitive and rCBF data, as a supplement to group comparisons of data, in the investigation of diseases with potential heterogeneous affections of the brain., (1994 Lippincott Williams & Wilkins.)

Regional cerebral blood flow distribution (rCBF) in 24 first admissions with schizophrenia or schizophreniform disorder and in 17 healthy volunteers was examined. Single photon emission computed tomography with a brain-retained tracer, technetium-99m-d,l-hexamethyl-propylene amine oxime, was used to study subjects under resting conditions and during performance of the Wisconsin Card Sorting Test. The study is a replication of a previous investigation in an independent series of patients and healthy volunteers. The patients had significantly lower relative blood flow in prefrontal regions during activation than did the healthy volunteers. An earlier series of 19 patients and 7 healthy volunteers was studied using exactly the same procedure. Analyses of the combined samples from the two studies (43 patients and 24 healthy volunteers) showed the patients to have significantly lower relative flow in prefrontal regions both at rest and during activation and higher flow in the left striatum during activation. The same finding emerged when analyses were confined to drug-naive patients and patients educationally matched to the healthy volunteers. The study suggests a defective frontostriatal interrelationship in schizophrenia and schizophreniform disorder.

Background and Purpose: The aura phase of migraine is associated with focal blood flow changes, but it has been largely unknown whether these changes are correlated to changes in the cerebral metabolism., Methods: Eight patients required carotid angiography for evaluation of transient neurological attacks. Cerebral blood flow (CBF) results, angiography, and clinical observations subsequently suggested the diagnosis: migraine with aura and occasional aura attacks without headache. In the same setting the cerebral angiography was followed by four to six repeated recordings of regional CBF using the intra-arterial 133Xe injection method. Blood samples were drawn from the carotid artery and the internal jugular vein to measure oxygen extraction fraction and cerebral metabolic rate for oxygen., Results: The intracarotid regional CBF technique provoked aura symptoms and typical, migraine-related, posterior focal hypoperfusion in four patients, followed by typical unilateral headache in three patients. The remaining four patients had no symptoms or regional CBF changes during the examination. There was a significant increase (mean, 13%) of global oxygen extraction fraction in the four patients during aura symptoms, whereas no significant changes of oxygen extraction fraction were found in the nonsymptomatic group. The increase in global oxygen extraction fraction in the symptomatic group coincided with a drop of hemispheric CBF (mean, 12%). Cerebral metabolic oxygen rate remained essentially unchanged, as did PaCO2., Conclusions: The data presented suggest that the focal flow reduction during the migraine-aura phase is not a secondary phenomenon of reduced cerebral metabolism. However, arteriolar vasoconstriction might offer a possible explanation for the regional CBF changes observed during the migraine aura.

The effects of NG-nitro-L-arginine (NOLAG), an inhibitor of nitric oxide synthase (NOS), and of indomethacin, an inhibitor of cyclooxygenase, on the rise in cerebral blood flow (CBF) accompanying increasing levels of hypercapnia (paCO2 = 40-135 mmHg) were studied in anesthetized rats. CBF was measured by intracarotid injection of 133Xe. Progressive increases in paCO2 of 10 mmHg, at intervals of about 8-10 minutes, were associated with gradual increases in CBF until a paCO2 level of 115 mmHg was reached. No further CBF changes (from the maximum value of 446 +/- 70 ml 100 g-1 min-1) were seen with additional step increase in paCO2. Intracarotid infusion of 7.5 mg/kg NOLAG significantly attenuated the CO2-elicited CBF increase by about 45-65% at paCO2 values below 115 mmHg. Beyond this level, there was a lesser inhibition of about 27-35%. 30 mg/kg NOLAG had essentially the same effect as 7.5 mg/kg NOLAG. 50 mg/kg NOLAG, given intraperitoneally (i.p.) twice daily for 4 days, also caused an attenuated CBF response to CO2, but the inhibitory effect was significantly less than with acute NOLAG administration in the paCO2 range of 61-90 mmHg. Infusion of L-arginine, 1 g/kg/h, prevented the effect of 7.5 mg/kg NOLAG. Indomethacin, 10 mg/kg, i.v. produced a more dramatic attenuation of the response, to the extent that the steady rising curve of CBF as a function of paCO2 was almost completely abolished. With indomethacin, a moderate increase (50%) in CBF was seen at the lowest level of hypercapnia, but raising paCO2 above this level did not result in further increases in CBF. This effect could not be prevented by L-arginine. When combining 7.5 mg/kg NOLAG with 10 mg/kg indomethacin, the response to hypercapnia was totally blocked. The results suggest that NOLAG and indomethacin act through different mechanisms on the hypercapnic CBF response, and that indomethacin is the more powerful inhibitor.

Regional cerebral blood flow (rCBF) was measured with high resolution brain dedicated single photon emission computer tomography (SPECT) and [99mTc]-d,l-hexamethyl-propylene-amine-oxime (HMPAO) in 25 patients with probable Alzheimer's disease and in 25 control subjects, selected according to rigorous inclusion and exclusion criteria. The aim was to analyse the topography of rCBF deficits in individual patients. In the group of patients with Alzheimer's disease as a whole, global CBF was reduced, but a factorial analysis of variance did not show disproportionate reduction of rCBF in any brain region. A parametric analysis of the rCBF data in individual patients was carried out with reference to normal values for internal rCBF ratios and to 13 different abnormal rCBF patterns. These theoretical patterns were predefined by showing significant hypoperfusion in at least one, or in any relevant combination of two, three, or four, of four major brain regions (a left and right frontal and a left and right posterior region). All patients with Alzheimer's disease and none of the control subjects had an abnormal rCBF pattern. Eleven of the 13 different patterns were seen in the patients. Frontal changes were seen in 19 (76%) of the patients, more often than previously reported. No single Alzheimer's disease pattern could be derived from our data. The number of regions with hypoperfusion, but not the presence of frontal changes, correlated significantly with the duration of disease. It is concluded that a clinical diagnosis of probable Alzheimer's disease is associated with heterogeneous patterns of rCBF deficits as measured with SPECT and [99mTc]-d,l-HMPAO. This heterogeneity may reflect different stages of the disease or cognitive subtypes and help explain published discrepancies concerning the topography of hypoperfusion in Alzheimer's disease. An analysis of individual rCBF data may add important information in the investigation of diseases with heterogeneous effects on the brain.