Therapeutic time window for the neuroprotective effects of NGF when administered after focal cerebral ischemia

In the present study, we evaluated the neuroprotection time window for nerve growth factor (NGF) after ischemia/reperfusion brain injury in rabbits as related to this anti-apoptosis mechanism. Male New Zealand rabbits were subjected to 2 h of middle cerebral artery occlusion (MCAO), followed by 70 h of reperfusion. NGF was administered after injury to evaluate the time window. Neurological deficits, infarct volume, neural cell apoptosis and expressions of caspase-3 and Bcl-2 were measured. Compared to saline-treated control, NGF treatment at 2, 3 and 5 h after MCAO significantly reduced infarct volume, neural cell apoptosis and expression of caspase-3 (P < 0.01), up-regulated the expression of Bcl-2 and improved functional recovery (P < 0.01). However, treatment at latter time points did not produce significant neuroprotection. Neuroprotection treatment with NGF provides an extended time window of up to 5 h after ischemia/reperfusion brain injury, in part by attenuating the apoptosis.     

Long-term cognitive dysfunction following experimental subarachnoid hemorrhage: new perspectives

Cognitive dysfunction is increasingly recognized as a significant long-term complication following subarachnoid hemorrhage (SAH), affecting up to 60% of survivors. We proposed to determine the incidence and explore potential mechanisms of cognitive dysfunction in a rat model. The effects of intracisternal blood, saline and sham injections were compared. At five weeks, Morris water maze escape latency (P = 0.001) and swimming distance (P = 0.001) were significantly different between groups, with increased latencies and distances recorded in the blood group in spite of increased swimming speed. The number of morphologically intact cortical (r = − 0.75, P = 0.0001) and hippocampal CA1 (r = − 0.80, P < 0.0001) neurons correlated with escape latency. In spite of only slight early reductions in proximal cerebral arterial diameters, pronounced and prolonged reductions in regional cerebral blood flow were observed in SAH rats, suggesting microvascular dysfunction. In concordance, cerebral microangiographic perfusion remained incomplete even after 2 weeks. 8-hydroxydeoxyguanosine immunohistochemistry also revealed microvascular as well as neuronal oxidative DNA damage. These results provide new insights into the pathogenesis of cognitive dysfunction in SAH. They reveal a surprisingly prolonged time course of diffuse cerebrovascular insufficiency, most likely due to reversible microvascular dysfunction. Similar to findings in experimental models of vascular dementia, the data indicate a potentially important role for prolonged cerebrovascular insufficiency, probably due to microvascular dysfunction, and selective cortical and subcortical neuronal loss in cognitive failure following SAH.     

Atorvastatin Pretreatment Attenuates Ischemic Brain Edema by Suppressing Aquaporin 4

Background: Cerebral edema, a serious complication of acute cerebral infarction, has a crucial impact on morbidity and mortality in the early stage of cerebral infarction. And aquaporin 4 (AQP4), a bidirectional water transporting protein, plays a pivotal role in edema formation. At experimental model, it has proven that atorvastatin could exert pleiotropic neuroprotection on acute cerebral infarction independent of its cholesterol-lowering action. It was a common protective manifestation that atorvastatin can reduce the infarct volume and cerebral edema. However, little is known about atorvastatin improving ischemic brain edema by regulating AQP4 expression. This study intended to investigate the neuroprotection effects of atorvastatin pretreatment in rats with cerebral ischemia and further explore the potential relationship between atorvastatin and AQP4 expression. Methods: Fifty-one adult male Sprague Dawley rats were randomly divided into 3 groups: sham, middle cerebral artery occlusion (MCAO), and atorvastatin pretreatment (Ator) group. For Ator group, 20 mg/kg of atorvastatin injectable suspension was administered once for 7days by gavage before operation, whereas the others were administered the same volume of saline matching. Except for sham group, MCAO and Ator groups were subjected to permanent MCAO by modified intraluminal suture method. Infarct volume, neurological deficit, brain water content (BWC), immunohistochemistry, western blot, and polymerase chain reaction (PCR) were measured at 24 hours after MCAO. Results: Compared with sham group, the mNSS, infarct volume, and BWC of ischemic hemisphere were significantly increased (P < 0.001) in MCAO group. Positive cells and protein levels of p-p38MAPK and AQP4 in peri-infarction were significantly increased (P < 0.01). The mRNA levels of p38MAPK and AQP4 were also prominently upregulated (P < 0.01). Interestingly, preadministration of atorvastatin dramatically decreased infarct volume and the BWC of ischemic hemisphere compared with MCAO group (P < 0.05). The overexpressions of p-p38MAPK and AQP4 in peri-infarction were significantly decreased (P < 0.05) and their mRNA levels were downregulated by atorvastatin pretreatment (P < 0.05). Neurological deficits were also dramatically improved (P < 0.001). Conclusion: To the best of our knowledge, this is the first study that demonstrates an effect of atorvastatin on expression of AQP4, and we propose that decreased AQP4 expression through a p38MAPK-suppression pathway may be the mechanism of atorvastatin alleviating ischemic cerebral edema.     

Postoperative memory prediction in left temporal lobe epilepsy: The Wada test is of no added value to preoperative neuropsychological assessment and MRI

The contribution of the Wada test (intracarotid amytal procedure, IAP) to predicting postoperative memory outcome in left temporal lobe epilepsy (LTLE) is becoming increasingly controversial when preoperative neuropsychological evaluation and MRI findings are available. We retrospectively analyzed 59 patients with LTLE who underwent en bloc temporal lobe resection. All patients had valid bilateral IAP test results, complete pre- and postoperative neuropsychological evaluation, and MRI grading on a 5-point scale integrating T 2 signal increase and degree of atrophy. Thirty percent of patients showed postoperative memory decline. Multiple regression analysis revealed that significant predictors of decline [F(2.56) = 22.71, P < 0.001, r² = 0.448] included preoperative memory learning score [t = −5.89, P < 0.001] and MRI classification [t = 3.10, P < 0.003], but not IAP scores. The IAP is of no added value in the prediction of postoperative memory outcome in LTLE in the presence of comprehensive neuropsychological and MRI data.     

Post-ischemic leakiness of the blood–brain barrier: A quantitative and systematic assessment by Patlak plots

The Patlak plot analysis of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) allows estimation of blood–brain barrier (BBB) leakage following temporary focal cerebral ischemia. Thus far, a systematic and quantitative in vivo evaluation of post-ischemic BBB leakage is lacking. Here, using DCE-MRI and the Patlak plot method, we quantitatively assessed BBB leakage in rats at the following time-points after reperfusion: 25 min, 2, 4, 6, 12, 18, 24, 36, 48, and 72 h, and 1, 2, 3, 4, and 5 weeks. Sham-operated animals served as controls. Data collected for each time-point were: the blood-to-brain transfer rate constant (K_i) of the contrast agent gadolinium, distribution volume (V_p), ischemic lesion volume, and apparent diffusion coefficient (ADC) values. Compared to controls, K_i, measured at all time-points, except for 5 weeks, appeared significantly different (p < 0.001). At several time-points (25 min, 48 and 72 h, 4 and 5 weeks), V_p was similar compared to that of controls, but for the remaining groups the difference was significant (p < 0.001). Analyzing the relationship of K_i values to time-points, we observed a trend towards a decrease over time (r = − 0.61, p = 0.014). Both ADC values (r = − 0.58, p = 0.02) and ischemic lesion volumes (r = 0.75, p = 0.0015) correlated with K_i values. These results suggest that after ischemia–reperfusion in rats, BBB leakage is continuous during a 4-week period. Its magnitude diminishes over time and correlates with severity and extent of ischemic injury.     

Glutamate transporter type 3 mediates isoflurane preconditioning-induced acute phase of neuroprotection in mice

A pre-exposure to isoflurane reduces ischemic brain injury in rodents (isoflurane preconditioning). This neuroprotection has acute and delayed phases. Our previous in vitro studies suggest that the acute phase may involve excitatory amino acid transporters (EAATs). We determine whether this protection involves EAAT3, the major neuronal EAAT. Adult male EAAT3 knockout mice and their wild-type littermates were exposed or were not exposed to 1.5% isoflurane for 30 min. Sixty minutes later, they were subjected to a 90- or 60-min middle cerebral arterial occlusion (MCAO). Their neurological outcomes were evaluated 24 h after the MCAO. In another experiment, cerebral cortex was harvested for Western blotting at 30 min after animals were exposed to 1.5% isoflurane for 30 min. Here, we showed that isoflurane reduced brain infarct volumes and improved neurological functions of wild-type mice after a 90-min MCAO. However, isoflurane pre-exposure did not change the neurological outcome of EAAT3 knockout mice no matter whether the MCAO was for 90 min or 60 min. Isoflurane increased phospho-Akt, a survival-promoting protein, in the wild-type mice but not in the EAAT3 knockout mice. The isoflurane-induced neuroprotection in the wild-type mice was abolished by LY294004, an Akt activation inhibitor. LY294004 alone did not affect the neurological outcome of the wild-type or EAAT3 knockout mice after focal brain ischemia. These results suggest that the isoflurane preconditioning-induced acute phase of neuroprotection involves EAAT3. The downstream event includes Akt activation.     

Neuroprotection afforded by a combination of eliprodil and a thrombolytic agent, rt-PA, in a rat thromboembolic stroke model

In the present study, we have assessed the efficacy of eliprodil, a neuroprotective agent which blocks both the modulatory polyamine site of the NMDA receptor and neuronal voltage-sensitive calcium channels, alone or in combination with the thrombolytic agent, rt-PA, in a rat embolic stroke model using a neurological score and the volume of the infarct as endpoints. Embolization was induced by intracarotid injection of an arterial blood clot. Eliprodil, administered at the dose of 1 mg/kg, iv, 10 min and 2 h 30 after embolization, reduced the neurological deficit by 54% (P<0.01) and the total volume of the brain lesion by 49%. Thrombolysis with rt-PA (2.5 mg/kg, as a 30 min iv infusion beginning 1 h after embolization) decreased the neurological deficit by 48% (P<0.05) and the size of the total infarct by 55% (P<0.05). Combined therapy greatly improved the degree of neuroprotection as assessed by neurological and histological outcomes (70% (P<0.001) and 89% (P<0.01) neuroprotection, respectively). These results demonstrate that the administration of a neuroprotective drug (eliprodil) or a thrombolytic agent (rt-PA) similarly reduce the volume of brain damage and the neurological deficit in a rat embolic stroke model. Combined cytoprotective therapy and thrombolysis markedly improved the degree of neuroprotection and may, thus, represent a valuable approach for the treatment of stroke in humans.     

Myeloperoxidase propagates damage and is a potential therapeutic target for subacute stroke

Few effective treatment options exist for stroke beyond the hyperacute period. Radical generation and myeloperoxidase (MPO) have been implicated in stroke. We investigated whether pharmacologic reduction or gene deletion of this highly oxidative enzyme reduces infarct propagation and improves outcome in the transient middle cerebral artery occlusion mouse model (MCAO). Mice were treated with 4-aminobenzoic acid hydrazide (ABAH), a specific irreversible MPO inhibitor. Three treatment regimens were used: (1) daily throughout the 21-day observational period, (2) during the acute stage (first 24 hours), or (3) during the subacute stage (daily starting on day 2). We found elevated MPO activity in ipsilateral brain 3 to 21 days after ischemia. 4-Aminobenzoic acid hydrazide reduced enzyme activity by 30% to 40% and final lesion volume by 60% (P<0.01). The MPO-knockout (KO) mice subjected to MCAO also showed a similar reduction in the final lesion volume (P<0.01). The ABAH treatment or MPO-KO mice also improved neurobehavioral outcome (P<0.001) and survival (P=0.01), but ABAH had no additional beneficial effects in MPO-KO mice, confirming specificity of ABAH. Interestingly, inhibiting MPO activity during the subacute stage recapitulated most of the therapeutic benefit of continuous MPO inhibition, suggesting that MPO-targeted therapies could be useful when given after 24 hours of stroke onset.     

Antioxidant status in the serum of persons with intellectual disability and hypothyroidism: a pilot study

Hypothyroidism (HPO) in humans is widely believed to impair health. The biochemical factors mediating decline in health, however, are poorly elucidated. Pathological consequences of HPO point to a high potential for antioxidant imbalance. The objectives of this study were to investigate the major antioxidants in persons with intellectual disability (ID) and HPO in order to find the effect of chronic disease on the level of antioxidative parameters. This is a prospective, nonrandomized study. A total of 11 people with HPO and 11 age-matched healthy participants were examined. The following antioxidative defense were examined: superoxide dismutase (SOD), catalase, glutathione peroxidase (GSH-Px), and glutathione reductase (GR) as well as two biochemical parameters creatinine and albumin. Compared to healthy control subjects without complications, persons with ID and HOP had significantly lower SOD (p < 0.05), catalase (p < 0.05), GSH-Px (p < 0.05), except the GR level (p = NS). A significant correlation was found between age and gender and AO values in experimental group SOD (r = −0.882), catalase (r = −0.724) and GSH-Px (r = −0.782). Our preliminary results confirm the hypothesis that there is a reduction of the antioxidative defense in persons with HPO and in particularly among males.     

Iron intake increases infarct volume after permanent middle cerebral artery occlusion in rats

Experimental and clinical data suggest an important role of iron in cerebral ischaemia. We measured infarct volume and analysed the oxidative stress, and also the excitatory and inflammatory responses to brain injury in a rat stroke model after an increased oral iron intake. Permanent middle cerebral artery occlusion (MCAO) was performed in ten male Wistar rats fed with a diet containing 2.5% carbonyl iron for 9 weeks, and in ten control animals. Glutamate, interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) were determined in blood samples before and at 2, 4, 6, 8, 24 and 48 h after MCAO, and thiobarbituric acid reaction substances (TBARS) were analysed at 48 h. Infarct volume was measured at 48 h by image analysis on brain slices stained with 1% TTC. Tissue iron was measured by atomic absorption spectrophotometry. Infarct volume was 66% greater in the iron fed rats than in the control group (178±49 mm³ versus 107±53 mm³, P<0.01). Significant higher levels of glutamate, IL-6 and TNF-α were observed in the group with iron intake (peak values were obtained at 6, 8 and 4 h, respectively). Iron-fed animals also showed significantly higher levels of TBARS than those receiving a normal diet (6.52±0.59 vs. 5.62±0.86 μmol/l, P=0.033) Liver iron stores (3500±199 vs. 352±28 μg Fe/g, P<0.0001), but not brain iron stores (131 vs. 139 μg Fe/g, P=0.617), were significantly higher in the iron fed rats group. These results suggest that iron intake is associated with larger infarct volumes after MCAO in the rat. This effect seems to be associated with higher oxidative stress, excitotoxicity and inflammatory responses.     

Dose-response analysis of the effect of 21-aminosteroid tirilazad mesylate (U-74006F) upon neurological outcome and ischemic brain damage in permanent focal cerebral ischemia

The protective effects of the 21-aminosteroid tirilazad mesylate (U-74006F), one of the most efficacious inhibitors of free radical-initiated lipid peroxidation, against ischmic brain damage particularly in permanent focal cerebral ischemia still remain controversial. The present study was designed to determine the degree of neuroprotection produced by various doses of U-74006F in permanent middle cerebral artery occlusion. Focal cerebral ischemia was achieved mby permanent occlusion of the left middle cerebral artery in male Sprague-Dawley rats. Four groups of rats were studied: viz. vehicle-administered controls (n = 7), and U-74006F-treated animals at doses of 0.3 mg/kg (n = 7), 1.0 mg/kg (n = 7) and 3.0 mg/kg (n = 7) (i.v. 15 min, 2 h and 6 h post occlusion, and 3.3 times higher than the first 3 doses, i.p. 12 h post occlusion). Twenty-four hours after surgery, the animals were subjected to neurological examination using a grading scale of 0 to 3, and sacrificed to assess ischemic damage by means of tetrazolium chloride staining. A dose-related attenuation of neurological deficits and ischemic damage was observed. At the two highest doses, the volume of ischemic damage in the cerebral hemisphere was reduced by 25.3% (P < 0.05) and 32.9% (P < 0.005), compared to the controls. The neurological deficit score for animals treated with U-74006F (3.0 mg/kg) was also significantly lower than for the controls (1.7 ± 1.1 vs. 2.7 ± 0.8; P < 0.05). This study shows that U-74006F ameliorates postischemic neurologic deficits and provides dose-dependent neuroprotection against ischemic brain damage in focal cerebral infarction.     

Substantia nigra hyperechogenicity in depressive subjects relates to motor asymmetry and impaired word fluency

Background  Substantia nigra hyperechogenicity (SNH) is a characteristic transcranial sonography (TCS) finding in Parkinson’s disease (PD). SNH, found also in about 10% of healthy adults, was related to a subclinical malfunction of the nigrostriatal dopaminergic system on positron emission tomography studies. Both, liability for developing PD and frequency of SNH were found to be increased in depressed subjects. Here, we investigated whether SNH in depression is related to motor or cognitive abnormalities resembling early PD. Methods  Fourty-one patients with major depressive disorder and 15 with adjustment disorder with depressed mood were studied clinically and with TCS. Results  Frequency of SNH was similar in both groups (39, 33%; Chi-square test, P = 0.70). Larger SN echogenic size correlated with larger right-to-left asymmetry of finger tapping (Spearman test, r = 0.37, P = 0.009) and lower verbal fluency (r = −0.35, P = 0.038). These correlations were stronger in patients at ages ≥ 50 years (r = 0.52, P = 0.007; r = −0.50, P = 0.020), and, independently from age, in patients with reduced echogenicity of brainstem raphe suggested to reflect alteration of the serotonergic system (r = 0.40, P = 0.045; r = −0.51, P = 0.044). Whereas bilateral sum score of finger tapping was negatively correlated with severity of depression on the beck depression inventory (r = −0.50, P = 0.001) and the Hamilton depression rating scale (r = −0.34, P = 0.019), no correlation was found between depression severity and tapping asymmetry, or between depression severity and verbal fluency. Conclusion  Data suggest that TCS detects a subgroup of patients with depression characterized by symptoms of early parkinsonism who are possibly at an elevated risk of later developing definite PD.     

Delayed institution of hypertension during focal cerebral ischemia: effect on brain edema

Summary The effect of induced hypertension instituted after a 2-h delay following middle cerebral artery occlusion (MCAO) on brain edoma formation and histochemical injury was studied. Under isoflurane anesthesia, the MCA of 14 spontaneously hypertensive rats was occluded. In the control group (n=7), the mean arterial pressure (MAP) was not manipulated. In the hypertensive group (n=7), the MAP was elevated by 25–30 mm Hg beginning 2 h after MCAO. Four hours after MCAO, the rats were killed and the brains harvested. The brains were sectioned along coronal planes spanning the distribution of ischemia produced by MCAO. Specific gravity (SG) was determined in the subcortex and in two sites in the cortex (core and periphery of the ischemic territory). The extent of neuronal injury was determined by 2,3,5-triphyenyltetrazolium staining. In the ischemic core, there was no difference in SG in the subcortex and cortex in the two groups. In the periphery of the ischemic territory, SG in the cortex was greater (less edema accumulation) in the hypertensive group (1.041±0.001 vs 1.039±0.001, P < 0.05). The area of histochemical injury (as a percent of the cross-sectional area of the hemisphere) was less in the hypertensive group (33±3% vs 21±2%, P < 0.05). The data indicate that phenylephrine-induced hypertension instituted 2 h after MCAO does not aggravate edema in the ischemic core, that it improves edema in the periphery of the ischemic territory, and that it reduces the area of histochemical neuronal dysfunction.Supported in part by a grant to JCD from the VA Research Service. PMP is the recipent of a fellowship grant from the Heart and Stroke Foundation of Canada     

Associated factors in neonatal hypoglycemic brain injury

Although associated factors are important for the occurrence of neural damage in neonatal hypoglycemia, they are not fully understood. Sixty patients with neonatal hypoglycemia were studied through a review of their medical records in Tottori University Hospital. The patients were classified into two main groups: Group I were patients who had mental retardation, developmental delay, cerebral palsy or epilepsy while Group II were those who were normal in their follow-up. Group I consisted of 12 patients while Group II consisted of 48 patients. The median gestational age was 38 weeks in Group I and 36.7 weeks in Group II. The frequencies of small for gestational age were similar in both groups. Blood glucose levels less than 15 mg/dl were more frequent in Group 1 (50.0%) than in Group 2 (14.6%) (P = 0.015). Duration of hypoglycemia was longer in Group I (median, 14 h) than in Group II (median, 1.75 h) (p < 0.001). The following factors were more frequent in Group I than in Group II: toxemia (33.3% and 8.3%, p = 0.043), fetal distress (58.3% and 14.5%, p = 0.004), an Apgar score of less than 5 at 1 min (33.3% and 6.4%, p = 0.025), neonatal seizure (53.8% and 4.3%, p < 0.001) and pathological jaundice (41.7% and 6.4%, p = 0.006). Cranial CT or MRI revealed cerebral lesions in 8 of the 9 Group I patients in follow-up examinations. This study indicates that severe and prolonged neonatal hypoglycemia can cause cerebral lesions and other perinatal risk factors, such as hypoxia, neonatal seizure and pathological jaundice, would exacerbate hypoglycemic brain injuries.     

Impact of severity of personality disorder on the outcome of depression

The influence of severity of personality disorder on outcome of depression is unclear. Four hundred and ten patients with depression in 9 urban and rural communities in Finland, Ireland, Norway, Spain and the United Kingdom, were randomised to individual problem-solving treatment (n = 121), group sessions on depression prevention (n = 106) or treatment as usual (n = 183). Depressive symptoms were recorded at baseline, 6 and 12 months. Personality assessment was performed using the Personality Assessment Schedule and analysed by severity (no personality disorder, personality difficulty, simple personality disorder, complex personality disorder). Complete personality assessments were performed on 301 individuals of whom 49.8% had no personality disorder; 19.3% had personality difficulties; 13.0% had simple personality disorder; and 17.9% had complex personality disorder. Severity of personality disorder was correlated with Beck Depression Inventory (BDI) scores at baseline (Spearman's r = 0.21; p < 0.001), 6 months (r = 0.14; p = 0.02) and 12 months (r = 0.21; p = 0.001). On multi-variable analysis, BDI at baseline (p < 0.001) and type of treatment offered (individual therapy, group therapy, treatment as usual) (p = 0.01) were significant independent predictors of BDI at 6 months. BDI at baseline was the sole significant independent predictor of BDI at 12 months (p < 0.001). There was no interaction between personality disorder and treatment type for depression.While multi-variable analyses indicate that depressive symptoms at baseline are the strongest predictor of depressive symptoms at 6 and 12 months, the strong correlations between severity of personality disorder and depressive symptoms make it difficult to establish the independent effect of personality disorder on outcome of depression.     

Conjugation of brain-derived neurotrophic factor to a blood–brain barrier drug targeting system enables neuroprotection in regional brain ischemia following intravenous injection of the neurotrophin

Neurotrophins such as brain-derived neurotrophic factor (BDNF) are potential neuroprotective agents that could be used in the treatment of acute stroke, should these proteins be made transportable through the blood–brain barrier (BBB) in vivo. One approach to the BBB problem is to attach the nontransportable peptide to a brain targeting vector, which is a peptide or peptidomimetic monoclonal antibody (MAb), that is transported into brain from blood via an endogenous BBB transport system. The present studies describe a conjugate of BDNF and the OX26 monoclonal antibody (MAb) to the transferrin receptor. Avidin–biotin technology is used to link the BDNF and the MAb. The surface of the BDNF is conjugated with 2000 Da polyethylene glycol at carboxyl residues to optimize the plasma pharmacokinetics of the neurotrophin. Adult rats subjected to 24 h of permanent middle cerebral artery occlusion (MCAO) were treated intravenously with either unconjugated BDNF, unconjugated MAb, or the BDNF–OX26 conjugate at a dose of 1, 5 and 50 μg/rat of the BDNF. These doses decreased the infarct volume by 6% (not significant), 43% (P<0.01), and 65% (P<0.01), respectively. Significant reduction in stroke volume was still observed if the administration of the BDNF conjugate was delayed for 1–2 h after MCAO, although the pharmacological effect was progressively diminished in proportion to the time delay between MCAO and treatment. In conclusion, these studies demonstrate that large reductions in stroke volume can be achieved with the noninvasive intravenous administration of neurotrophins such as BDNF, providing the peptide is conjugated to a BBB drug targeting system.     

Mechanical reperfusion is associated with post-ischemic hemorrhage in rat brain

A major complication of recanalization therapy after an acute arterial occlusion in brain is hemorrhagic transformation (HT). Although it is known that prolonged ischemia is important in the development of HT, the role of reperfusion in ischemia–reperfusion induced HT is less well studied. To address the effect of reperfusion on HT, we assessed the incidence and severity of hemorrhage in rats after 5 h of middle cerebral artery occlusion (MCAO) followed by 19-hour reperfusion compared to rats with permanent occlusion (PMCAO) at the same 24-hour time point. The incidence and amount of hemorrhage, neurological function, and mortality rates were measured. MCAO (5 h) with 19-hour reperfusion was associated with a significantly higher incidence of cortical hemorrhage compared to PMCAO (81.8% vs 18.2%, p < 0.05). Hemorrhage scores were higher in the 5-hour MCAO/reperfusion group compared to PMCAO rats (17.6 ± 11.5 vs 2.4 ± 5.3 in cortex, 20.4 ± 4.6 vs 9.7 ± 4.5 in striatum, p < 0.01). Neurological function was worse in the ischemia–reperfusion group compared to PMCAO (p < 0.05) and mortality rates were insignificantly higher in the 5-hour MCAO/reperfusion group vs PMCAO group (54.5% vs18.1%; p < 0.08). The results suggest that reperfusion after prolonged ischemia is associated with increased hemorrhagic transformation and neurological deterioration as compared to permanent ischemia. Whether pharmacological treatments prior to reperfusion attenuate post-ischemic HT requires further study.     

Impaired response of cerebral oxygen metabolism to visual stimulation in Huntington’s disease

Huntington’s disease (HD) is a neurodegenerative disease caused by a CAG triplet repeat expansion in the Huntingtin gene. Metabolic and microvascular abnormalities in the brain may contribute to early physiological changes that subserve the functional impairments in HD. This study is intended to investigate potential abnormality in dynamic changes in cerebral blood volume (CBV) and cerebral blood flow (CBF), and cerebral metabolic rate of oxygen (CMRO₂) in the brain in response to functional stimulation in premanifest and early manifest HD patients. A recently developed 3-D-TRiple-acquisition-after-Inversion-Preparation magnetic resonance imaging (MRI) approach was used to measure dynamic responses in CBV, CBF, and CMRO₂ during visual stimulation in one single MRI scan. Experiments were conducted in 23 HD patients and 16 healthy controls. Decreased occipital cortex CMRO₂ responses were observed in premanifest and early manifest HD patients compared to controls (P < 0.001), correlating with the CAG-Age Product scores in these patients (R² = 0.4, P = 0.001). The results suggest the potential value of this reduced CMRO₂ response during visual stimulation as a biomarker for HD and may illuminate the role of metabolic alterations in the pathophysiology of HD.