Focally administered succinate improves cerebral metabolism in traumatic brain injury patients with mitochondrial dysfunction

Following traumatic brain injury (TBI), raised cerebral lactate/pyruvate ratio (LPR) reflects impaired energy metabolism. Raised LPR correlates with poor outcome and mortality following TBI. We prospectively recruited patients with TBI requiring neurocritical care and multimodal monitoring, and utilised a tiered management protocol targeting LPR. We identified patients with persistent raised LPR despite adequate cerebral glucose and oxygen provision, which we clinically classified as cerebral ‘mitochondrial dysfunction’ (MD). In patients with TBI and MD, we administered disodium 2,3-¹³C₂ succinate (12 mmol/L) by retrodialysis into the monitored region of the brain. We recovered ¹³C-labelled metabolites by microdialysis and utilised nuclear magnetic resonance spectroscopy (NMR) for identification and quantification.Of 33 patients with complete monitoring, 73% had MD at some point during monitoring. In 5 patients with multimodality-defined MD, succinate administration resulted in reduced LPR(−12%) and raised brain glucose(+17%). NMR of microdialysates demonstrated that the exogenous ¹³C-labelled succinate was metabolised intracellularly via the tricarboxylic acid cycle. By targeting LPR using a tiered clinical algorithm incorporating intracranial pressure, brain tissue oxygenation and microdialysis parameters, we identified MD in TBI patients requiring neurointensive care. In these, focal succinate administration improved energy metabolism, evidenced by reduction in LPR. Succinate merits further investigation for TBI therapy.     

Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers

Decreased dopaminergic function has been postulated to underlie cocaine addiction. To examine the possibility that dysfunction of brain regions subserved by the dopamine system could promote cocaine self-administration, positron emission tomography and a dual-tracer approach was used to examine dopamine D₂ receptor availability and regional brain glucose metabolism in cocaine abusers. When compared to normal controls, cocaine abusers showed significant decreases in dopamine D₂ receptor availability which persisted 3-4 months after detoxification. Decreases in dopamine D₂ receptor availability were associated with decreased metabolism in several regions of the frontal of these brain areas which are involved in the channeling of drive and affect could lead to loss of control resulting in compulsive drug-taking behavior. © 1993 Wiley-Liss, Inc.     

Progressive behavioral deficits in DJ-1-deficient mice are associated with normal nigrostriatal function

Loss-of-function mutations in the DJ-1 gene account for an autosomal recessive form of Parkinson's disease (PD). To investigate the physiological functions of DJ-1 in vivo, we generated DJ-1 knockout (DJ-1^−/−) mice. Younger (< 1 year) DJ-1^−/− mice were hypoactive and had mild gait abnormalities. Older DJ-1^−/−, however, showed decreased body weight and grip strength and more severe gait irregularities compared to wild-type littermates. The basal level of extracellular dopamine, evoked dopamine release and dopamine receptor D2 sensitivity appeared normal in the striatum of DJ-1^−/− mice, which was consistent with similar results between DJ-1^−/− and controls in behavioral paradigms specific for the dopaminergic system. An examination of spinal cord, nerve and muscle tissues failed to identify any pathological changes that were consistent with the noted motor deficits. Taken together, our findings suggest that loss of DJ-1 leads to progressive behavioral changes without significant alterations in nigrostriatal dopaminergic and spinal motor systems.     

Childhood poverty is associated with altered hippocampal function and visuospatial memory in adulthood

Childhood poverty is a risk factor for poorer cognitive performance during childhood and adulthood. While evidence linking childhood poverty and memory deficits in adulthood has been accumulating, underlying neural mechanisms are unknown. To investigate neurobiological links between childhood poverty and adult memory performance, we used functional magnetic resonance imaging (fMRI) during a visuospatial memory task in healthy young adults with varying income levels during childhood. Participants were assessed at age 9 and followed through young adulthood to assess income and related factors. During adulthood, participants completed a visuospatial memory task while undergoing MRI scanning. Patterns of neural activation, as well as memory recognition for items, were assessed to examine links between brain function and memory performance as it relates to childhood income. Our findings revealed associations between item recognition, childhood income level, and hippocampal activation. Specifically, the association between hippocampal activation and recognition accuracy varied as a function of childhood poverty, with positive associations at higher income levels, and negative associations at lower income levels. These prospective findings confirm previous retrospective results detailing deleterious effects of childhood poverty on adult memory performance. In addition, for the first time, we identify novel neurophysiological correlates of these deficits localized to hippocampus activation.     

Metabolic and vascular risk factors are associated with reduced cerebral blood flow and poorer midlife memory performance

Midlife metabolic and vascular risk factors (MVRFs) predict cognitive decline and dementia; however, these risk factors tend to overlap, and the mechanisms underlying their effects on cognitive performance are not well understood. This cross‐sectional study investigates the contributions of MVRFs to regional cerebral blood flow (CBF) and verbal learning & memory among middle‐aged adults. We used partial least squares (PLS) analysis to create latent risk factor profiles and examine their associations to CBF in 93 regions of interest among 451 participants (age 50.3 ± 3.5 years) of the Coronary Artery Risk Development in Young Adults. This multivariate analysis revealed regional CBF was lower in relation to obesity (higher body mass index and waist circumference), dysregulated glucose homeostasis (higher fasting glucose, oral glucose tolerance, and higher fasting insulin), and adverse fasting lipid profile (lower high‐density lipoprotein cholesterol and higher triglycerides). In a sensitivity analysis, we found that significant associations between MVRFs and CBF were prominent in the hypertension‐medicated subgroup. In a mediation model, the PLS‐based MVRFs profile was associated with memory performance (rey auditory verbal learning test); however, CBF was not a significant mediator of this association. The results describe an adverse midlife metabolic profile that might set the stage for incipient dementia and contribute to widespread changes in CBF.     

A genetic variation in the dysbindin gene (DTNBP1) is associated with memory performance in healthy controls

Schizophrenia is a common psychiatric disorder characterized by disturbances of cognition, emotion and social functioning. There are few studies investigating a possible genetic basis for the underlying mechanism of cognitive dysfunctions. A genetic variation in the dysbindin gene (DTNBP1: dystrobrevin binding protein 1), a susceptibility gene for schizophrenia, has been reported to be associated with general cognitive ability and cognitive decline in patients with schizophrenia. Although profound disturbances of memory performance are observed in schizophrenia, only one study has reported a relationship between this gene and spatial working memory in a Caucasian population. We examined a possible association between a protective haplotype of DTNBP1 for developing schizophrenia and memory performance measured by the Wechsler Memory Scale-Revised (WMS-R) and the Wechsler Adult Intelligence Scale-Revised (WAIS-R) in 165 healthy volunteers and 70 patients with schizophrenia in a Japanese population. Healthy controls that carry the protective haplotype showed higher performance in several memory domains measured by the WMS-R than those who did not. Genotype effect on memory performance was not observed in patients with schizophrenia. This haplotype did not affect IQ and its sub-scores as measured by the Wechsler Adult Intelligence Scale-Revised in both groups. These data suggest that DTNBP1 may have impact on parts of memory functions.     

Augmentation of the noradrenergic system in alpha-2 adrenergic receptor deficient mice: anatomical changes associated with enhanced fear memory

We have investigated sensitivity to the conditioned fear procedure of mice is influenced by the genetic deletion of alpha2A adrenoceptors (ARs). We observed a heightened freezing response in the discrete cue memory test in alpha2A AR knockout (alpha2A AR KO) mice and in D79N mice, a transgenic mouse strain with functionally impaired alpha2A ARs. No significant differences in contextual memory were observed between control and alpha2A AR KO or D79N mice suggesting a minimal role for the noradrenergic system in contextual memory. We speculated that the increased freezing response of the alpha2A AR KO and D79N mice in the discrete cue setting was due to increased release of norepinephrine evoked by the unconditioned footshock stimulus. In alpha2A AR KO mice we measured a doubling in the number of noradrenergic neurons in the locus coeruleus (LC) and a large increase in the cell volume of tyrosine hydroxylase positive neurons, likely due to selective preservation of large, multipolar neurons in the subcoeruleus. Hyperplasia of the noradrenergic neurons in the nucleus tractus solitarius, A5 and A7, was also observed. Alpha2A AR KO mice exhibit greater c-Fos expression in the LC compared to wild type mice suggesting that the LC neurons in the alpha2A AR KO mice were spontaneously more active. This study suggests that alpha2A ARs are involved in the development of the central noradrenergic system and raises the possibility that alterations in alpha2A AR expression may contribute to variations in fear and stress responses.     

Dynamin 1 depletion and memory deficits in rats treated with Aβ and cerebral ischemia

Alzheimer's disease (AD) is progressive dementia with senile plaques composed of β‐amyloid (Aβ). Recent studies suggest that synaptic dysfunction is one of the earliest events in the pathogenesis of AD. Here we provide the first experimental evidence that a change in the level of dynamin 1 induced by Aβ correlates with memory impairment in vivo. We treated rats with transient cerebral ischemia with oligomeric forms of Aβ (Aβ oligomers), including dimers, trimers, and tetramers, intracerebroventricularly. The combination of Aβ oligomers and cerebral ischemia, but not cerebral ischemia alone, significantly impaired memory and decreased the level of dynamin 1, which plays a critical role in synaptic vesicle recycling, but did not affect the levels of other synaptic proteins, such as synaptophysin and synaptobrevin, in the hippocampus. Furthermore, the N‐methyl‐D ‐aspartate (NMDA) receptor antagonist memantine prevented memory impairment and dynamin 1 degradation, suggesting that these changes might be mediated by NMDA receptors. These results suggest that Aβ oligomers induce memory impairment via dynamin 1 degradation, which may imply that dynamin 1 degradation is one of the causes of synaptic dysfunction in AD. © 2010 Wiley‐Liss, Inc.     

Event-related brain potential indices of cognitive function and brain resource reallocation during working memory in patients with Multiple Sclerosis

Objective

To examine event-related brain potentials (ERPs) in Multiple Sclerosis (MS) during a visual n-back working memory (WM) task, and test the hypothesis that compensatory brain function may be associated with variance in task performance in MS patients.

Amyloid-beta deposition is associated with decreased hippocampal glucose metabolism and spatial memory impairment in APP/PS1 mice

In Alzheimer disease (AD) patients, early memory dysfunction is associated with glucose hypometabolism and neuronal loss in the hippocampus. Double transgenic (Tg) mice co-expressing the M146L presenilin 1 (PS1) and K670N/M671L, the double "Swedish" amyloid precursor protein (APP) mutations, are a model of AD amyloid-beta deposition (Abeta) that exhibits earlier and more profound impairments of working memory and learning than single APP mutant mice. In this study we compared performance on spatial memory tests, regional glucose metabolism, Abeta deposition, and neuronal loss in APP/PS1, PS1, and non-Tg (nTg) mice. At the age of 2 months no significant morphological and metabolic differences were detected between 3 studied genotypes. By 8 months, however, APP/PS1 mice developed selective impairment of spatial memory, which was significantly worse at 22 months and was accompanied by reduced glucose utilization in the hippocampus and a 35.8% dropout of neurons in the CA1 region. PS1 mice exhibited a similar degree of neuronal loss in CA1 but minimal memory deficit and no impairment of glucose utilization compared to nTg mice. Deficits in 22 month APP/PS1 mice were accompanied by a substantially elevated Abeta load, which rose from 2.5% +/- 0.4% at 8 months to 17.4% +/- 4.6%. These findings implicate Abeta or APP in the behavioral and metabolic impairments in APP/PS1 mice and the failure to compensate functionally for PS1-related hippocampal cell loss.     

Decreased blood flow and oxygen metabolism in the cerebellum, brain stem and thalamus in a case with Menkes kinky hair disease

Cerebral blood flow and oxygen metabolism were measured in a five-year-old boy with atypical Menkes kinky hair disease (MKHD) by using positron emission tomography (PET). The patient was diagnosed as having atypical MKHD because of low serum and urinary copper levels, and clinical symptoms. The CT revealed mild to moderate degrees of brain atrophy predominantly in the cerebellum. The PET demonstrated marked decreases of cerebral blood flow and oxygen metabolism in the cerebellum, brain stem and thalamus. These findings seem to reflect the neuropathological abnormalities observed in MKHD. PET seems to be more sensitive than CT in detecting abnormalities in the affected structures. However, because this case is atypical the question of whether typical cases show similar features on the PET remains.     

Cognitive function and its relationship with brain structure in myotonic dystrophy type 1

Studies have shown relationships between white matter abnormalities and cognitive dysfunction in myotonic dystrophy type 1 (DM1), but comprehensive analysis of potential structure–function relationships are lacking. Fifty adult‐onset DM1 individuals (33 female) and 68 unaffected adults (45 female) completed the Wechsler Adult Intelligence Scale‐IV (WAIS‐IV) to determine the levels and patterns of intellectual functioning. Neuroimages were acquired with a 3T scanner and were processed with BrainsTools. Regional brain volumes (regions of interest, ROIs) were adjusted for inter‐scanner variation and intracranial volume. Linear regression models were conducted to assess if group by ROI interaction terms significantly predicted WAIS‐IV composite scores. Models were adjusted for age and sex. The DM1 group had lower Perceptual Reasoning Index (PRI), Working Memory Index (WMI), and Processing Speed Index (PSI) scores than the unaffected group (PRI t₍₁₁₃₎ = ?3.28, p = 0.0014; WMI t₍₁₁₄₎ = ?3.49, p = 0.0007; PSI t₍₁₁₄₎ = ?2.98, p = 0.0035). The group by hippocampus interaction term was significant for both PRI and PSI (PRI (t₍₁₁₁₎ = ?2.82, p = 0.0057; PSI (t₍₁₁₂₎ = ?2.87, p = 0.0049)). There was an inverse association between hippocampal volume and both PRI and PSI in the DM1 group (the higher the volume, the lower the intelligence quotient scores), but no such association was observed in the unaffected group. Enlarged hippocampal volume may underlie some aspects of cognitive dysfunction in adult‐onset DM1, suggesting that increased volume of the hippocampus may be pathological.     

Rat models of dementia based on reductions in regional glucose metabolism,cerebral blood flow and cytochrome oxidase activity

Summary. Three models are described in rats which attempt to mimic morphological and behavioural pathology of Alzheimers dementia; intracerebroventricular injection of streptozotocin (STZ), permanent bilateral carotid artery occlusion (2VO) and brain mitochondrial cytochrome oxidase inhibition by sodium azide. Learning and memory are impaired within 4 weeks in all models. This probably involves a reduction in cortical and/or hippocampal cholinergic neurotransmission. STZ causes microglial activation and specific damage to myelinated tracts in the fornix through generation of oxidative stress, thereby disrupting connections between the septum and hippocampus. 2VO results in damage to myelin and CA1 cells in hippocampus and in abnormal processing of APP to -amyloid. It is not known if microglial activation and neuronal damage occur after sodium azide administration. Memory and learning can be improved in the STZ and 2VO models by estradiol, melatonin and cholinesterase inhibitors. Antioxidants and neuroprotective agents may also decrease memory deficits by preventing inflammation and neurodegeneration.     

PETCO2监测过度通气水平对脑外伤患者脑血流、脑代谢和脑灌注的影响

目的 探讨呼吸末二氧化碳分压(PETCO2)监测下过度通气水平对颅脑外伤患者术中脑血流、脑代谢和脑灌注的影响.方法 选择东营鸿港医院神经外科自2009年1月至2012年6月急诊行脑外伤开颅去骨瓣减压血肿清除术的患者70例,按随机数字表法分为A、B2组,每组35例,A组患者PETCO2控制在20～25 mm Hg之间,动脉血二氧化碳分压(PaCO2)维持在22～25 mm Hg之间,B组患者PETCO2控制在25～30 mm Hg之间,PaCO2维持在30～45 mm Hg之间,比较手术开始去骨瓣前2组患者血气分析结果、平均动脉压、颅内压、脑氧分压、脑灌注压和脑氧供需平衡以及代谢产物神经元特异性稀醇化酶(NSE)、葡萄糖、乳酸的变化.结果 手术开始去骨瓣前A组患者的PaCO2水平、平均动脉压、颅内压、NSE、葡萄糖和乳酸水平显著低于B组,差异有统计学意义(P＜0.05);2组患者脑氧分压和脑灌注压、动脉血氧含量(CaO2)、静脉血氧含量(CjvO2)和脑氧摄取率(CERO2)比较差异无统计学意义(P＞0.05).结论 术中将PETCO2控制在20～25 mm Hg之间,能有效维持患者脑血流灌注和脑氧供需平衡,降低病理性代谢产物水平,值得临床重视.     

In-vivo measurements of regional acetylcholine esterase activity in degenerative dementia: comparison with blood flow and glucose metabolism

Summary. Memory and attention are cognitive functions that depend heavily on the cholinergic system. Local activity of acetylcholine esterase (AChE) is an indicator of its integrity. Using a recently developed tracer for positron emission tomography (PET), C-11-labeled N-methyl-4-piperidyl-acetate (C-11-MP4A), we measured regional AChE activity in 4 non-demented subjects, 4 patients with dementia of Alzheimer type (DAT) and 1 patient with senile dementia of Lewy body type (SDLT), and compared the findings with measurements of blood flow (CBF) and glucose metabolism (CMRGlc). Initial tracer extraction was closely related to CBF. AChE activity was reduced significantly in all brain regions in demented subjects, whereas reduction of CMRGlc and CBF was more limited to temporo-parietal association areas. AChE activity in SDLT was in the lower range of values in DAT. Our results indicate that, compared to non-demented controls, there is a global reduction of cortical AChE activity in dementia. Received November 13, 1999; accepted May 15, 2000     

大骨瓣减压对不同年龄重型颅脑创伤患者脑血流量及脑代谢的影响

目的 探讨大骨瓣减压对不同年龄重型颅脑创伤患者脑血流量及脑代谢的影响.方法 将71例重型颅脑创伤患者分为＜30岁组、30～50岁组和＞50岁组.每组又分为治疗组和对照组,大骨瓣减压手术前后行桡动脉和颈内静脉血气分析及血糖、血乳酸、血红蛋白监测,计算动脉-颈内静脉血糖差、颈内静脉-动脉乳酸差以及脑氧摄取率,TCD测定脑血流量.结果 术后第1天开始,≤50岁治疗组患者的脑血流量和脑氧摄取率均明显大于对照组;＞50岁治疗组患者的脑血流量明显高于对照组,脑氧摄取率明显低于对照组(P＜0.05).术后第3天开始,≤50岁治疗组患者的动脉-颈内静脉血糖差明显高于对照组,颈内静脉-动脉乳酸差明显低于对照组;＞50岁治疗组患者的动脉-颈内静脉血糖差明显低于对照组(P＜0.05),颈内静脉-动脉乳酸差明显高于对照组(P＜0.05).结论 大骨瓣减压能增加50岁以下重型颅脑创伤患者的脑血流量和脑氧代谢,能增加50岁以上患者的脑血流量并降低脑氧代谢.

Abstract：

Objective To explore the effects of decompressive craniectomy on cerebral blood flow volume and brain metabolism in different aged patients with severe traumatic brain injury.Method 71 cases were divided into three groups according age:group A( ＜30 years) ,group B(30 ～50 years) ,group C ( ＞ 50 years).Each group was divided into decompressive craniectomy ( DC ) treatment group and control group.Monitor dynamically blood gas analysis, glucose, lactic acid, hemoglobin in radial artery and internal jugular venous bulb, accounting the cerebral oxygen extraction ( CEO2 ) and the D - values of glucose and lactic acid respectively between radial artery and internal jugular venous bulb.Color doppler ultrasonography was used to determine the cerebral blood flow volume(CBFV).Results From the 1 st to 7th day, the CBFV and CEO2 of DC group were significantly greater than control group in group A and group B.The CBFV was significantly greater than control group while the CEO2 was lower than control group in group C ( P ＜ 0.05 ).From third day, the D - values of glucose of DC group was significantly higher than control group while the D - values of lactic acid was lower than control group in group A and group B, the D - values of glucose of DC group was significantly lower than control group while the D - values of lactic acid was higher than control group in group C( P ＜ 0.05 ).Conclusions Decompression craniectomy can increase the CBFV and brain oxygen metabolism in STBI patients before age 50 and increase the CBFV in patients after age 50 whereas decrease the brain oxygeon metabolism.     

Comparative analysis of regional brain blood flow and glucose metabolism in focal cerebrovascular disease measured by dynamic positron emission tomography of fluorine-18-labelled tracers

Summary Regional cerebral blood flow (rCBF) and glucose metabolism (rCMRglc) were measured in 44 patients with various kinds of focal vascular brain lesions, using multislice positron emission tomography (PET). Haemodynamic data were obtained by a recently developed, non-invasive clearance method utilizing (¹⁸F)-methyl fluoride as a diffusible, gaseous indicator. Shortly after completion of each flow study, rCMRglc was dynamically determined by standard procedures using 2(¹⁸F)-fluorodeoxyglucose. While blood flow and glucose consumption in the structurally damaged area were often uncoupled during the acute phase, metabolism-to-flow ratios were markedly less scattered at later stages of cerebrovascular disease. Individual maximum-likelihood cluster analysis of brain regions revealed remarkable similarity between deactivation patterns of rCBF and rCMRglc, with Tanimoto coefficients averaging 0.56. This similarity was inversely related to the residual rCMRglc of the lesion. These findings are in line with results obtained by PET of other tracers, suggesting that the pair of methods provides valuable and somewhat complementary information on brain function and mechanisms of cerebral vascular disease.