Cerebral Palsy

Increased oxidative damage is a prominent and early feature in Alzheimer disease (AD). We previously crossed AD transgenic (APPsw) model mice with alpha-tocopherol transfer protein knockout (Ttpa-/-) mice in which lipid peroxidation in the brain was significantly increased. The resulting double-mutant (Ttpa-/-APPsw) mice showed increased amyloid beta (Abeta) deposits in the brain, which was ameliorated with alpha-tocopherol (alpha-Toc) supplementation. To investigate the mechanism of the increased Abeta accumulation, we here studied generation, degradation, aggregation and efflux of Abeta in the mice. The clearance of intracerebrally microinjected [125I]Abeta1-40 from brain was decreased in Ttpa-/- mice to be compared with wild-type mice, whereas the generation of Abeta was not increased in Ttpa-/-APPsw mice. The activity of an Abeta-degrading enzyme, neprilysin did not decrease, but the expression level of insulin-degrading enzyme (IDE) was markedly decreased in Ttpa-/- mouse brain. In contrast, Abeta aggregation was accelerated in Ttpa-/- mouse brains compared with wild-type ones, and well-known molecules involved in Abeta transport from brain to blood, low-density lipoprotein receptor-related protein-1 (LRP-1) and p-glycoprotein, were upregulated in the small vascular fraction of Ttpa-/- mouse brains. Moreover, disappearance of intravenously administered [125I]Abeta1-40 was decreased in Ttpa-/- mice with reduced translocation of LRP-1 in the hepatocytes. These results suggest that lipid peroxidation due to depletion of alpha-Toc impairs Abeta clearances from the brain and from the blood, possibly causing increased Abeta accumulation in Ttpa-/-APPsw mouse brain and plasma.

The primary progressive aphasias (PPA) are paradigmatic disorders of language network breakdown associated with focal degeneration of the left cerebral hemisphere. Here we addressed brain correlates of PPA in a detailed neuroanatomical analysis of the third canonical syndrome of PPA, logopenic/phonological aphasia (LPA), in relation to the more widely studied clinico-anatomical syndromes of semantic dementia (SD) and progressive nonfluent aphasia (PNFA). 32 PPA patients (9 SD, 14 PNFA, 9 LPA) and 18 cognitively-normal controls had volumetric brain MRI with regional volumetry, cortical thickness, grey and white matter voxel-based morphometry analyses. 5/9 patients with LPA had cerebrospinal fluid biomarkers consistent with Alzheimer (AD) pathology (AD-PPA) and 2/9 patients had progranulin (GRN) mutations (GRN-PPA). The LPA group had tissue loss in a widespread left hemisphere network. Compared with PNFA and SD, the LPA group had more extensive involvement of grey matter in posterior temporal and parietal cortices and and long association white matter tracts. Overlapping but distinct networks were involved in the AD-PPA and GRN-PPA subgroups, with more anterior temporal lobe involvement in GRN-PPA. The importance of these findings are threefold: firstly, the clinico-anatomical entity of LPA has a profile of brain damage that is complementary to the network-based disorders of SD and PNFA; secondly, the core phonological processing deficit in LPA is likely to arise from temporo-parietal junction damage but disease spread occurs through the dorsal language network (and in GRN-PPA, also the ventral language network); and finally, GRN mutations provide a specific molecular substrate for language network dysfunction.

Due to the heterogeneous nature of most brain injuries, the contributions of gray and white matter involvement to motor deficits and recovery potential remain obscure. We tested the hypothesis that duration of hand motor impairment and recovery of skilled arm and hand motor function depends on the volume of gray and white matter damage of the frontal lobe. Lesions of the primary motor cortex (M1), M1+ lateral premotor cortex (LPMC), M1+ LPMC+ supplementary motor cortex (M2) or multi-focal lesions affecting motor areas and medial prefrontal cortex were evaluated in rhesus monkeys. Fine hand motor function was quantitatively assessed pre-lesion and for 3-12 months post-lesion using two motor tests. White and gray matter lesion volumes were determined using histological and quantitative methods. Regression analyses showed that duration of fine hand motor impairment was strongly correlated (R(2)> 0.8) with the volume of gray and white matter lesions, with white matter lesion volume being the primary predictor of impairment duration. Level of recovery of fine hand motor skill was also well correlated (R(2)> 0.5) with gray and white matter lesion volume. In some monkeys post-lesion skill exceeded pre-lesion skill in one or both motor tasks demonstrating that continued post-injury task practice can improve motor performance after localized loss of frontal motor cortex. These findings will assist in interpreting acute motor deficits, predicting the time course and expected level of functional recovery, and designing therapeutic strategies in patients with localized frontal lobe injury or neurosurgical resection.

ABSTRACT: BACKGROUND: In animal models, ischemia reperfusion (IR) injury triggers membrane lipid degradation and accumulation of lipoxidative exacerbations in neurovascular unit, leading to blood brain barrier (BBB) damage and neurologic deficits. In this study, we investigated whether impeding membrane lipid breakdown by inhibiting secretory phospholipase A2 (sPLA2) activity reduces BBB leakage, leading to neuroprotection and functional recovery. METHODS: Focal cerebral IR injury was induced by middle cerebral artery occlusion (MCAO) in adult male rats. A sPLA2 inhibitor, 7,7-dimethyleicosadienoic acid (DEDA), was administered following IR injury. DEDA-treated animals were compared with vehicle-treated in terms of BBB leakage, edema, infarct volume, and neurological deficit. Membrane lipid degradation and the expression/activity of sPLA2 were also assessed. The role of one of the sPLA2 products, arachidonic acid (AA), on the morphology of the differentiated neuronal cell PC12 was examined by light microscopy. RESULTS: Treatment with DEDA after IR injury not only reduced BBB leakage but also decreased infarct volume and improved neurologic function. The treatment attenuated both the activity of sPLA2 and the levels of sPLA2-derived oxidized products. The metabolites of lipid oxidation/peroxidation, including the protein carbonyl, were reduced as well. The treatment also restored the levels of glutathione, indicating attenuation of oxidative stress. In vitro treatment of PC12 cells with DEDA did not restore the AA-mediated inhibition of neurite formation and the levels of glutathione, indicating that effect of DEDA is up stream to AA release. CONCLUSIONS: sPLA2-derived oxidative products contribute to significant neurovascular damage, and treatment with sPLA2 inhibitor DEDA ameliorates secondary injury by reducing exacerbations from lipoxidative stress.

To the Editor: It is important to recognize significant metabolic patterns like crossed cerebellar diaschisis (CCD) in oncology patients undergoing fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography ((18)FFDG- PET/CT) scans. CCD is a known complication of stroke both in acute and chronic phases. It occurs due to interruption of the cortico-ponto cerebellar tracts, leading to depression of regional neuronal metabolism and blood flow resulting in hypoperfusion and hypometabolism on cerebral perfusion and metabolism studies, respectively. As an example, we present a 55 years old case of papillary serous cystadenocarcinoma of the right ovary, referred to us for a (18)F-FDG-PET/CT study following completion of treatment to rule out the possibility of residual and/or metastatic disease. She had been treated with total abdominal hysterectomy, bilateral salpingo-ophrectomy and infra-colic omentectomy followed by 6 cycles of carboplatin and paclitaxel based chemotherapy. She was a known hypertensive, taking regular antihypertensive medication. The (18)F-FDG-PET/CT scan was done approximately 60min following the intravenous injection of 370MBq of (18)F-FDG. The patient was positioned supine with hands down on a whole body Full Ring PET/CT camera (Discovery STE16-GE, USA camera). Initial scout was obtained to localize acquisition from the vertex to mid thigh. A low dose CT of this area was done for attenuation correction and co-registration, followed by the usual 3D PET emission scan at 2min/bed osition for 7 bed positions. Images were reconstructed using a 3D VUE algorithm, which is similar to reconstructive algorithms, used by GE healthcare and viewed on the Xeleris workstation (GE) using the volumetric protocol. Visual evaluation of the maximum intensity projection (MIP) image revealed physiological tracer distribution in the body but on changing the window for brain evaluation, relatively decreased (18)F-FDG uptake was noted in the right cerebellar hemisphere. Evaluation of transaxial slices of the brain revealed reduced (18)F-FDG uptake in the left basal ganglia region and diffusely decreased (18)FFDG uptake in the right cerebellar hemisphere. Correlative CT revealed a hypo-dense lesion in the left basal ganglia, left internal capsule and left peri-ventricular region suggestive of an ischemic aetiology, while the cerebellar hemispheres did not reveal any structural abnormality. A detailed history revealed that she had suffered a left middle cerebral artery infarct 8 years ago with paresis of right side of the body and deviation of the face toward left. The left basal ganglia hypometabolism was thus the result of the ischemic episode while the right cerebellar hypometabolism represented crossed cerebellar diaschisis. Diaschisis (from Greek words: dia = throughout and skizo = split, meaning <<shocked throughout>>) is a sudden loss of function in a portion of the brain connected to but at a distance of a damaged area. The site of the originally damaged area and of the diaschisis are connected to each other by neurons. The term diaschisis was coined by von Monakow in 1914. Nowadays, CCD is considered to be a result of depression of regional neuronal metabolism and cerebral blood flow caused by dysfunction in an anatomically separate but functionally related neuronal region. Many connections between the cerebral hemispheres and the cerebellum exist with the cortico-ponto-cerebellar being the most numerous and accounting for 40 times all other afferent sources combined. The first order neurons arrive in the ipsilateral pons to synapse with the second order neurons before they cross to the contra-lateral cerebellar hemisphere via the middle cerebellar peduncle. Injury at any point can result in decreased metabolism of the contra-lateral cerebellar hemisphere. Interruption of these tracts can occur from a range of injuries including tumour (especially malignant frontal lobe tumours that extend onto the parietal lobe), stroke, gliosis, epilepsy or trauma, with supra-tentorial ischemic strokes after middle carotid artery occlusion being the most common aetiology. CCD can also be seen in patients with final infarcts and also in patients with initial hypo-perfusion recovering without morphologic sequelae. In the acute phase (i.e. within 3h of stroke), CCD indicates impaired tissue function due to penumbral flow (defined by CBF values below 20mL/100g min(-1)) and is reversible. Later than 24h after stroke, persisting CCD becomes a surrogate marker of tissue damage, independent of cortical (re)perfusion. Baron et al. in 1980, first described CCD in a positron emission tomography (PET) study and demonstrated matched reduction in cerebral blood flow and oxygen extraction fraction, in the contra-lateral cerebellum in patients with supratentorial ischemic stroke. Although the number of patients is small in series already published and the incidence of CCD on PET in acute stroke is unclear, several series of mixed chronicity of stroke have reported frequency of CCD after stroke greater than 60% and a little lower as detected by the perfusion weighted magnetic resonance imaging. CCD has been demonstrated on (18)F-FDG-PET up to 20 years after a cerebro-vascular accident indicating the irreversibility of the lesion once the acute phase is over. This (18)F FDG-PET/CT study showed abnormal findings reflecting glucose hypometabolism due to CCD, eight years after the stroke episode.

Different perfusion defects reflect neurological damage characteristics of different kinds of dementia. Our aim was to investigate the role of brain single photon emission tomography (SPET) with semiquantitative analysis of Brodmann areas in dementia, by technetium-99m – hexamethyl-propylenamine- oxime ((99m)Tc-HMPAO) brain SPET with semiquantitative analysis of Brodmann areas in patients with Alzheimer’s disease (AD), frontotemporal dementia (FTD) and mild cognitive impairment (MCI). We studied 75 patients, 25 with AD (NiNCDS ADRDA criteria), 25 with FTD (Lund and Manchester criteria), 25 with MCI (EADC criteria). After i.v. injection of 740MBq of (99m)Tc-HMPAO, each patient underwent brain SPET. A software application was used able to map the SPET brain image to a stereotaxic atlas (Talairach), providing an affine co-registration by blocks of data defined in the Talairach space. A normal database calculating voxel by voxel the mean and the standard deviation of the measured values was built. Functional SPET data of 3D regions of interest (ROI) of predefined Brodmann’s area templates were compared with those of a database of healthy subjects of the same age and gender. Mean values obtained in the Brodmann area ROI in the different groups of patients studied were evaluated. Our results showed that different Brodmann areas were significantly impaired in the different categories of dementia subjects. Both areas 37 (temporal gyrus) and 39 (angular gyrus) of AD patients (mean+/-SD: 37L= -1.6+/-1.0; 37R= -1.5+/-1.1; 39L= -2.3+/-1.3; 39R= -1.9+/-1.2) showed significant hypoperfusion (P<0.05) versus MCI (37L= -0.9 +/-0.7; 37R= -1.1+/-0.9; 39L= -1.4+/-1.1; 39R= -1.6+/-1.6.) and FTD (37L= -1.1+/-0.8; 37R= -1.0+/-0.9; 39L= -1.4+/-1.0; 39R= -1.2+/-1.2) subjects. AD patients showed significantly (P<0.01) decreased perfusion in areas 40 (supramarginal gyrus) (40L= -2.6+/-1.0; 40R= -2.3+/-1.1) with respect to MCI patients (40L= -1.8+/-0.9; 40R= -1.7+/-1.2). Finally, FTD patients showed significant hypoperfusion (P<0.05) in both areas 47 (frontal association cortex) (47L= -1.8+/-0.8; 47R= -1.1+/-0.8) in comparison with MCI subjects (47L= -1.2+/-0.9; 47R= -0.9+/-0.9). In conclusion, our results suggest that semiquantitative analysis of single Brodmann areas identify frontal area hypoperfusion in FTD patients and also parietal and temporal impairment in AD patients. In MCI patients, no hypoperfusion pattern is identified.

Summary Purpose: Early life status epilepticus (SE) could enhance the vulnerability of the immature brain to a second SE in adulthood (two-hit seizure model). Naloxone has been proved to possess inflammation inhibitory effects in nervous system. This study was designed to evaluate the dose-dependent protective effects of naloxone in kainic acid (KA)-induced two-hit seizure model. Methods: After KA-induced SE at postnatal day 15 (P15), Sprague-Dawley rats were infused with either saline or different doses (1.92, 3.84, 5.76, and 7.68 mg/kg) of naloxone continuously for 12 h. De novo synthesis of cytokines (interleukin-1beta [IL-1beta], S100B) was assessed by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) at 12 h after P15 SE. Glial activation states were analyzed by western blotting of glial markers (glial fibrillary acidic protein [GFAP], S100B, Iba1) both at 12 h after P15 SE and at P45. After a second SE at P45, cognitive deteriorations were evaluated by Morris water tests and neuron injuries were evaluated by TdT-mediated dUTP nick end labeling (TUNEL) assays. Results: Naloxone reduced IL-1beta synthesis and microglial activation most potently at a dose of 3.84 mg/kg. Attenuation of S100B synthesis and astrocyte activation were achieved most dramatically by naloxone at a dose of 5.76 mg/kg, which is equal to the most powerful dose in ameliorating cognitive injuries and neuron apoptosis after second SE. Conclusions: Naloxone treatment immediately after early life SE could dose-dependently reduce cytokine production, glial activation, and further lower the vulnerability of immature brains to a second hit in adulthood.

Background: Binge Drinking (BD) typically involves heavy drinking over a short time, followed by a period of abstinence, and is common among young people, especially university students. Animal studies have demonstrated that this type of alcohol consumption causes brain damage, especially in the nonmature brain. The aim of the present study was to determine how BD affects brain functioning in male and female university students, during the performance of a visual working memory task. Methods: Event-related potentials (ERPs) were recorded, with an extensive set of 32 scalp electrodes, in 95 first-year university students (age range 18 to 20 years), comprising 42 binge drinkers (BD) and 53 controls, in a visual “identical pairs” continuous performance task. Principal components analysis was used to identify and analyze the N2 (negative waveform with a latency around 200 to 300 ms related to attentional processes) and P3 (positive waveform with a latency around 300 to 600 ms related to working memory processes) components of the ERPs. Results: In the matching condition of the task, the N2 component in central and parietal regions was significantly larger in the BD than in the control group. In the control group, the P3 component was larger in the matching than in the nonmatching condition in the frontal, central, and parietal regions, whereas the BD group did not show any significant differences between conditions in any region. Conclusions: The results of this study confirm the presence of electrophysiological differences between young university student binge drinkers and controls during the execution of a visual task with a high working memory load. The larger N2 in the BD group suggests higher levels of attentional effort required by this group to perform the task adequately. The absence of any differences in the P3 component in the different conditions (matching and nonmatching stimuli) in the BD group suggests a deficiency in the electrophysiological differentiation between relevant and irrelevant information, which may reflect some impairment of working memory processes.

Background: While behavioral studies have established that prenatal alcohol exposure (PAE) can result in diminished arithmetic processing capability, the underlying neural correlates of this deficit are still unclear. The aim of the present study was to use functional magnetic resonance imaging to determine the effect of PAE on neuronal activation during a subtraction task. Methods: Participants were young adults from a low socio-economic status population who were identified prenatally; the sample consisted of healthy unexposed controls (n = 17) and PAE who were subdivided based on the presence (n = 19) or absence of physical dysmorphic signs (n = 18). Multiple regression analysis was used to determine extent of activation and percent signal change during arithmetic processing, using a letter-matching task as the baseline. Region of interest analysis of activation was performed in the native space and normalized for each individual to compensate for the considerable variability in head size observed in the alcohol-exposed population. Results: An exposure-dependent response was observed in task performance and neuronal activation. Dysmorphic PAE individuals showed significantly lower task-related performance and activation in regions known to be associated with arithmetic processing, including left superior and right inferior parietal regions and medial frontal gyrus, while the nondysmorphic PAE group was generally intermediate but not significantly different from the control group in task performance and activation. Conclusions: Results indicate that there is a range of effects of PAE on arithmetic processing and that the severity of this deficit may be dependent on degree of impairment demonstrated by the exposed individual. Evidence of physical dysmorphia may be indicative of functional damage to regions associated with arithmetic calculation, resulting in markedly impaired neuronal recruitment.

Abstract Congenital cytomegalovirus (CMV) infection occurs in 0.6-0.7% of all newborns and is the most prevalent infection-related cause of congenital neurological handicap. Vertical transmission occurs in around 30% of cases, but the fetus is not always affected. Symptomatic newborns at birth have a much higher risk of suffering severe neurological sequelae. Detection of specific IgG and IgM and IgG avidity seem to be the most reliable tests to identify a primary infection but interpretation in a clinical context may be difficult. If a seroconversion is documented or a fetal infection is suspected by ultrasound markers, an amniocentesis should be performed to confirm a vertical transmission. In the absence of a confirmed fetal infection with fetal structural anomalies, a pregnancy termination should be discouraged. Fetal prognosis is mainly correlated to the presence of brain damage. Despite promising results with the use of antiviral drugs and CMV hyperimmune globulin (HIG), results have to be interpreted with caution. Pregnant women should not be systematically tested for CMV during pregnancy. Managing CMV screening should be restricted to pregnancies where a primary infection is suspected or among women at high risk. The magnitude of congenital CMV disease and the value of interventions to prevent its transmission or to decrease the sequelae need to be established before implementing public health interventions. In this paper, aspects of CMV infection in the pregnant woman and her infant are reviewed.