An in vivo ultrahigh field 14.1 T (1) H-MRS study on 6-OHDA and α-synuclein-based rat models of Parkinson's disease: GABA as an early disease marker.

The detection of Parkinson's disease (PD) in its preclinical stages prior to outright neurodegeneration is essential to the development of neuroprotective therapies and could reduce the number of misdiagnosed patients. However, early diagnosis is currently hampered by lack of reliable biomarkers. (1) H magnetic resonance spectroscopy (MRS) offers a noninvasive measure of brain metabolite levels that allows the identification of such potential biomarkers. This study aimed at using MRS on an ultrahigh field 14.1 T magnet to explore the striatal metabolic changes occurring in two different rat models of the disease. Rats lesioned by the injection of 6-hydroxydopamine (6-OHDA) in the medial-forebrain bundle were used to model a complete nigrostriatal lesion while a genetic model based on the nigral injection of an adeno-associated viral (AAV) vector coding for the human α-synuclein was used to model a progressive neurodegeneration and dopaminergic neuron dysfunction, thereby replicating conditions closer to early pathological stages of PD. MRS measurements in the striatum of the 6-OHDA rats revealed significant decreases in glutamate and N-acetyl-aspartate levels and a significant increase in GABA level in the ipsilateral hemisphere compared with the contralateral one, while the αSyn overexpressing rats showed a significant increase in the GABA striatal level only. Therefore, we conclude that MRS measurements of striatal GABA levels could allow for the detection of early nigrostriatal defects prior to outright neurodegeneration and, as such, offers great potential as a sensitive biomarker of presymptomatic PD.

Comment on recent modeling studies of astrocyte-neuron metabolic interactions.

Recent years have seen a surge in mathematical modeling of the various aspects of neuron-astrocyte interactions, and the field of brain energy metabolism is no exception in that regard. Despite the advent of biophysical models in the field, the long-lasting debate on the role of lactate in brain energy metabolism is still unresolved. Quite the contrary, it has been ported to the world of differential equations. Here, we summarize the present state of this discussion from the modeler's point of view and bring some crucial points to the attention of the non-mathematically proficient reader.

Primate adult brain cell autotransplantation produces behavioral and biological recovery in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonian St. Kitts monkeys.

The potential for "replacement cells" to restore function in Parkinson's disease has been widely reported over the past 3 decades, rejuvenating the central nervous system rather than just relieving symptoms. Most such experiments have used fetal or embryonic sources that may induce immunological rejection and generate ethical concerns. Autologous sources, in which the cells to be implanted are derived from recipients' own cells after reprogramming to stem cells, direct genetic modifications, or epigenetic modifications in culture, could eliminate many of these problems. In a previous study on autologous brain cell transplantation, we demonstrated that adult monkey brain cells, obtained from cortical biopsies and kept in culture for 7 weeks, exhibited potential as a method of brain repair after low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) caused dopaminergic cell death. The present study exposed monkeys to higher MPTP doses to produce significant parkinsonism and behavioral impairments. Cerebral cortical cells were biopsied from the animals, held in culture for 7 weeks to create an autologous neural cell "ecosystem" and reimplanted bilaterally into the striatum of the same six donor monkeys. These cells expressed neuroectodermal and progenitor markers such as nestin, doublecortin, GFAP, neurofilament, and vimentin. Five to six months after reimplantation, histological analysis with the dye PKH67 and unbiased stereology showed that reimplanted cells survived, migrated bilaterally throughout the striatum, and seemed to exert a neurorestorative effect. More tyrosine hydroxylase-immunoreactive neurons and significant behavioral improvement followed reimplantation of cultured autologous neural cells as a result of unknown trophic factors released by the grafts. J. Comp. Neurol. 522:2729-2740, 2014. © 2014 Wiley Periodicals, Inc.

The complete amino acid sequence for brain beta spectrin (beta fodrin): relationship to globin sequences.

The amino acid sequence of mouse brain beta spectrin (beta fodrin), deduced from the nucleotide sequence of complementary DNA clones, reveals that this non-erythroid beta spectrin comprises 2363 residues, with a molecular weight of 274,449 Da. Brain beta spectrin contains three structural domains and we suggest the position of several functional domains including f-actin, synapsin I, ankyrin and spectrin self association sites. Analysis of deduced amino acid sequences indicated striking homology and similar structural characteristics of brain beta spectrin repeats beta 11 and beta 12 to globins. In vitro analysis has demonstrated that heme is capable of specific attachment to brain spectrin, suggesting possible new functions in electron transfer, oxygen binding, nitric oxide binding or heme scavenging.

Brain structure in movement disorders: a neuroimaging perspective.

Purpose of review: An overview of recent advances in structural neuroimaging and their impact on movement disorders research is presented. Recent findings: Novel developments in computational neuroanatomy and improvements in magnetic resonance image quality have brought further insight into the pathophysiology of movement disorders. Sophisticated automated techniques allow for sensitive and reliable in-vivo differentiation of phenotype/genotype related traits and their interaction even at presymptomatic stages of disease. Summary: Voxel-based morphometry consistently demonstrates well defined patterns of brain structure changes in movement disorders. Advanced stages of idiopathic Parkinson's disease are characterized by grey matter volume decreases in basal ganglia. Depending on the presence of cognitive impairment, volume changes are reported in widespread cortical and limbic areas. Atypical Parkinsonian syndromes still pose a challenge for accurate morphometry-based classification, especially in early stages of disease progression. Essential tremor has been mainly associated with thalamic and cerebellar changes. Studies on preclinical Huntington's disease show progressive loss of tissue in the caudate and cortical thinning related to distinct motor and cognitive phenotypes. Basal ganglia volume in primary dystonia reveals an interaction between genotype and phenotype such that brain structure changes are modulated by the presence of symptoms under the influence of genetic factors. Tics in Tourette's syndrome correlate with brain structure changes in limbic, motor and associative fronto-striato-parietal circuits. Computational neuroanatomy provides useful tools for in-vivo assessment of brain structure in movement disorders, allowing for accurate classification in early clinical stages as well as for monitoring therapy effects and/or disease progression.

Time constant of the cerebral arterial bed in normal subjects.

The time constant of cerebral arterial bed (in brief time constant) is a product of brain arterial compliance (C(a)) and resistance (CVR). We tested the hypothesis that in normal subjects, changes in end-tidal CO(2) (EtCO(2)) affect the value of the time constant. C(a) and CVR were estimated using mathematical transformations of arterial pressure (ABP) and transcranial Doppler (TCD) cerebral blood flow velocity waveforms. Responses of the time constant to controlled changes in EtCO(2) were compared in 34 young volunteers. Hypercapnia shortened the time constant (0.22 s [0.17, 0.26] vs. 0.16 s [0.13, 0.20]; p = 0.000001), while hypocapnia lengthened the time constant (0.22 s [0.17, 0.26] vs. 0.23 s [0.19, 0.32]; p < 0.0032). The time constant was negatively correlated with changes in EtCO(2) (R(partial) = -0.68, p < 0.000001). This was associated with a decrease in CVR when EtCO(2) increased (R(partial) = -0.80, p < 0.000001) and C(a) remained independent of changes in EtCO(2). C(a) was negatively correlated with mean ABP (R(partial) = -0.68, p < 0.000001). In summary, the time constant shortens with increasing EtCO(2). Its potential role in cerebrovascular investigations needs further studies.

Brain lactate metabolism in humans with subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Lactate is central for the regulation of brain metabolism and is an alternative substrate to glucose after injury. Brain lactate metabolism in patients with subarachnoid hemorrhage has not been fully elucidated. METHODS: Thirty-one subarachnoid hemorrhage patients monitored with cerebral microdialysis (CMD) and brain oxygen (PbtO(2)) were studied. Samples with elevated CMD lactate (>4 mmol/L) were matched to PbtO(2) and CMD pyruvate and categorized as hypoxic (PbtO(2) <20 mm Hg) versus nonhypoxic and hyperglycolytic (CMD pyruvate >119 μmol/L) versus nonhyperglycolytic. RESULTS: Median per patient samples with elevated CMD lactate was 54% (interquartile range, 11%-80%). Lactate elevations were more often attributable to cerebral hyperglycolysis (78%; interquartile range, 5%-98%) than brain hypoxia (11%; interquartile range, 4%-75%). Mortality was associated with increased percentage of samples with elevated lactate and brain hypoxia (28% [interquartile range 9%-95%] in nonsurvivors versus 9% [interquartile range 3%-17%] in survivors; P=0.02) and lower percentage of elevated lactate and cerebral hyperglycolysis (13% [interquartile range, 1%-87%] versus 88% [interquartile range, 27%-99%]; P=0.07). Cerebral hyperglycolytic lactate production predicted good 6-month outcome (odds ratio for modified Rankin Scale score, 0-3 1.49; CI, 1.08-2.05; P=0.016), whereas increased lactate with brain hypoxia was associated with a reduced likelihood of good outcome (OR, 0.78; CI, 0.59-1.03; P=0.08). CONCLUSIONS: Brain lactate is frequently elevated in subarachnoid hemorrhage patients, predominantly because of hyperglycolysis rather than hypoxia. A pattern of increased cerebral hyperglycolytic lactate was associated with good long-term recovery. Our data suggest that lactate may be used as an aerobic substrate by the injured human brain.

Primate adult brain cell autotransplantation, a pilot study in asymptomatic MPTP-treated monkeys.

Autologous brain cell transplantation might be useful for repairing lesions and restoring function of the central nervous system. We have demonstrated that adult monkey brain cells, obtained from cortical biopsy and kept in culture for a few weeks, exhibit neural progenitor characteristics that make them useful for brain repair. Following MPTP treatment, primates were dopamine depleted but asymptomatic. Autologous cultured cells were reimplanted into the right caudate nucleus of the donor monkey. Four months after reimplantation, histological analysis by stereology and TH immunolabeling showed that the reimplanted cells successfully survived, bilaterally migrated in the whole striatum, and seemed to have a neuroprotection effect over time. These results may add a new strategy to the field of brain neuroprotection or regeneration and could possibly lead to future clinical applications.

Mobile phone use and brain tumors in children and adolescents: a multicenter case-control study.

Background It has been hypothesized that children and adolescents might be more vulnerable to possible health effects from mobile phone exposure than adults. We investigated whether mobile phone use is associated with brain tumor risk among children and adolescents. Methods CEFALO is a multicenter case-control study conducted in Denmark, Sweden, Norway, and Switzerland that includes all children and adolescents aged 7-19 years who were diagnosed with a brain tumor between 2004 and 2008. We conducted interviews, in person, with 352 case patients (participation rate: 83%) and 646 control subjects (participation rate: 71%) and their parents. Control subjects were randomly selected from population registries and matched by age, sex, and geographical region. We asked about mobile phone use and included mobile phone operator records when available. Odds ratios (ORs) for brain tumor risk and 95% confidence intervals (CIs) were calculated using conditional logistic regression models. Results Regular users of mobile phones were not statistically significantly more likely to have been diagnosed with brain tumors compared with nonusers (OR = 1.36; 95% CI = 0.92 to 2.02). Children who started to use mobile phones at least 5 years ago were not at increased risk compared with those who had never regularly used mobile phones (OR = 1.26, 95% CI = 0.70 to 2.28). In a subset of study participants for whom operator recorded data were available, brain tumor risk was related to the time elapsed since the mobile phone subscription was started but not to amount of use. No increased risk of brain tumors was observed for brain areas receiving the highest amount of exposure. Conclusion The absence of an exposure-response relationship either in terms of the amount of mobile phone use or by localization of the brain tumor argues against a causal association.

Synchronizability of EEG-Based Functional Networks in Early Alzheimer's Disease.

Recently graph theory and complex networks have been widely used as a mean to model functionality of the brain. Among different neuroimaging techniques available for constructing the brain functional networks, electroencephalography (EEG) with its high temporal resolution is a useful instrument of the analysis of functional interdependencies between different brain regions. Alzheimer's disease (AD) is a neurodegenerative disease, which leads to substantial cognitive decline, and eventually, dementia in aged people. To achieve a deeper insight into the behavior of functional cerebral networks in AD, here we study their synchronizability in 17 newly diagnosed AD patients compared to 17 healthy control subjects at no-task, eyes-closed condition. The cross-correlation of artifact-free EEGs was used to construct brain functional networks. The extracted networks were then tested for their synchronization properties by calculating the eigenratio of the Laplacian matrix of the connection graph, i.e., the largest eigenvalue divided by the second smallest one. In AD patients, we found an increase in the eigenratio, i.e., a decrease in the synchronizability of brain networks across delta, alpha, beta, and gamma EEG frequencies within the wide range of network costs. The finding indicates the destruction of functional brain networks in early AD.

Rupture of a concealed aneurysm after intravenous thrombolysis of a thrombus in the parent middle cerebral artery.

BACKGROUND: Management of ischemic stroke in the presence of aneurysmal brain disease is controversial. Recent retrospective evidence suggests that in selected patients, intravenous thrombolysis (IVT) remains a safe approach for reperfusion. METHODS: We document a case of post-thrombolysis aneurysmal rupture. Supported by additional scientific literature we postulate that acute aneurysmal thrombosis leading to stroke in the culprit artery may be an ominous sign of rupture and should be considered separately from fortuitously discovered distant aneurysmal disease. RESULTS: A 71-year-old female presented with an acute right middle cerebral artery stroke syndrome. IVT allowed vessel reperfusion and revealed a previously concealed, juxtaposed non-giant M1 segment saccular aneurysm. Secondary aneurysmal rupture ensued. The aneurysm was secured by surgical clipping. Postoperative course was uneventful. CONCLUSIONS: This case shows that despite reports of thrombolysis safety in the presence of brain aneurysms, thrombolysis remains potentially hazardous and hints toward an increased risk when the stroke arises on the parent vessel itself.

Absence of residual Hodgkin's disease demonstrated by PET/CT in a deceased organ donor.

With the current limited availability of organs for transplantation, it is important to consider marginal donor candidates, including survivors of potentially curable malignancies such as lymphoma. The absence of refractory/recurrent residual disease at the time of brain death can be difficult to establish. Therefore, it is critical to have objective data to decide whether to proceed or not with organ procurement and transplantation. We report a unique situation in which (18)F-fluorodeoxyglucose positron emission tomography (PET) was used to rule out Hodgkin's lymphoma recurrence in a 33-year-old, heart-beating, brain-dead, potential donor with a past history of Hodgkin's disease and a persistent mediastinal mass. PET showed no significant uptake in the mass, allowing organ donation and transplantation to occur. We present a new means of evaluating potential brain-dead donors with a past history of some lymphoma, whereby PET may help transplant physicians by optimizing donation safety while rationalizing the inclusion of marginal donors.

Brain metastasis: opportunity for drug development?

PURPOSE OF REVIEW: Brain metastases are a common clinical problem, and only limited treatment options exist. We review recent advances in medical brain metastasis research with a focus on the most common tumor types associated with secondary brain colonization: melanoma, breast cancer and lung cancer. We speculate on opportunities for drug development in patients with brain metastases, both as a treatment of established disease and as an adjuvant and prophylactic strategy. RECENT FINDINGS: BRAF inhibitors and the immunomodulatory anticytotoxic T-lymphocyte-associated antigen 4 antibody ipilimumab have shown clinically meaningful activity in melanoma patients with brain metastases. In breast cancer, current studies on drug treatment of brain metastases are mainly focusing on human epidermal growth factor receptor 2 targeting agents such as lapatinib. Emerging data seem to implicate a potential role of targeted agents including antiangiogenic compounds, pazopanib, and epithelial growth factor receptor inhibitors for prevention of brain metastasis formation in breast cancer or nonsmall cell lung cancer. SUMMARY: Novel drugs are beginning to enter clinical practice for selected patients with brain metastases. The promising findings from recent studies may fuel more research on brain metastases and their optimal drug treatment.

RNA interference against aquaporin-4 decreases the apparent diffusion coefficient in the normal brain

Aim: Diffusion weighted magnetic resonance imaging (MRI) is now widely used in human brain diagnosis.1 To date molecular mechanisms underlying changes in Apparent Diffusion Coefficient (ADC) signals remain poorly understood. AQP4, localized to astrocytes, is one of the most highly expressed cerebral AQPs.2 AQP4 is involved in water movement within the cell membrane of cultured astrocytes.3 We hypothesize that AQP4 contributes to water diffusion and underlying ADC values in normal brain. Methods: We used an RNA interference (RNAi) protocol in vivo, to acutely knockdown expression of AQP4 in rat brain and to determine whether this was associated with changes in brain ADC values using MRI protocols as previously described.4 RNAi was performed using specific small interference RNA (siRNA) against AQP4 (siAQP4) and a non-targeted-siRNA (siGLO) as a control. The specificity and efficiency of the siAQP4 were first tested in vitro in astrocyte and hippocampal slice cultures. In vivo, siRNAs were injected into the rat cortex 3d prior to MRI acquisition and AQP4 was assessed by western blot (n=4) and immunohistochemistry (n=6). Histology was performed on adjacent slices. Results: siAQP4 application on primary astrocyte cultures induced a 76% decrease in AQP4 expression after 4 days. In hippocampal slice cultures; we also found a significant decrease in AQP4 expression in astrocytes after siAQP4. In vivo, injection of non-targeted siRNA (siGLO) tagged with CY3 allowed us to show that GFAP positive cells (astrocytes) were positively stained with CY3-siGLO, showing efficient transfection. Western blot and immunohistochemical analysis showed that siAQP4 induced a ~30% decrease in AQP4 expression without modification of tissue properties or cell death. After siAQP4 treatment, a significant decrease in ADC values (~50%) were observed without altered of T2 values. Conclusions: Together these results suggest that AQP4 reduces water diffusion through the astrocytic plasma membrane and decreases ADC values. Our findings demonstrate for the first time that astrocytic AQP4 contributes significantly to brain water diffusion and ADC values in normal brain. These results open new avenues to interpretation of ADC values under normal physiological conditions and in acute and chronic brain injuries.

A post-processing pipeline to reconstruct the developing fetal brain using low-resolution MRI

Introduction. Development of the fetal brain surfacewith concomitant gyrification is one of the majormaturational processes of the human brain. Firstdelineated by postmortem studies or by ultrasound, MRIhas recently become a powerful tool for studying in vivothe structural correlates of brain maturation. However,the quantitative measurement of fetal brain developmentis a major challenge because of the movement of the fetusinside the amniotic cavity, the poor spatial resolution,the partial volume effect and the changing appearance ofthe developing brain. Today extensive efforts are made todeal with the âeurooepost-acquisitionâeuro reconstruction ofhigh-resolution 3D fetal volumes based on severalacquisitions with lower resolution (Rousseau, F., 2006;Jiang, S., 2007). We here propose a framework devoted tothe segmentation of the basal ganglia, the gray-whitetissue segmentation, and in turn the 3D corticalreconstruction of the fetal brain. Method. Prenatal MRimaging was performed with a 1-T system (GE MedicalSystems, Milwaukee) using single shot fast spin echo(ssFSE) sequences in fetuses aged from 29 to 32gestational weeks (slice thickness 5.4mm, in planespatial resolution 1.09mm). For each fetus, 6 axialvolumes shifted by 1 mm were acquired (about 1 min pervolume). First, each volume is manually segmented toextract fetal brain from surrounding fetal and maternaltissues. Inhomogeneity intensity correction and linearintensity normalization are then performed. A highspatial resolution image of isotropic voxel size of 1.09mm is created for each fetus as previously published byothers (Rousseau, F., 2006). B-splines are used for thescattered data interpolation (Lee, 1997). Then, basalganglia segmentation is performed on this superreconstructed volume using active contour framework witha Level Set implementation (Bach Cuadra, M., 2010). Oncebasal ganglia are removed from the image, brain tissuesegmentation is performed (Bach Cuadra, M., 2009). Theresulting white matter image is then binarized andfurther given as an input in the Freesurfer software(http://surfer.nmr.mgh.harvard.edu/) to provide accuratethree-dimensional reconstructions of the fetal brain.Results. High-resolution images of the cerebral fetalbrain, as obtained from the low-resolution acquired MRI,are presented for 4 subjects of age ranging from 29 to 32GA. An example is depicted in Figure 1. Accuracy in theautomated basal ganglia segmentation is compared withmanual segmentation using measurement of Dice similarity(DSI), with values above 0.7 considering to be a verygood agreement. In our sample we observed DSI valuesbetween 0.785 and 0.856. We further show the results ofgray-white matter segmentation overlaid on thehigh-resolution gray-scale images. The results arevisually checked for accuracy using the same principlesas commonly accepted in adult neuroimaging. Preliminary3D cortical reconstructions of the fetal brain are shownin Figure 2. Conclusion. We hereby present a completepipeline for the automated extraction of accuratethree-dimensional cortical surface of the fetal brain.These results are preliminary but promising, with theultimate goal to provide âeurooemovieâeuro of the normal gyraldevelopment. In turn, a precise knowledge of the normalfetal brain development will allow the quantification ofsubtle and early but clinically relevant deviations.Moreover, a precise understanding of the gyraldevelopment process may help to build hypotheses tounderstand the pathogenesis of several neurodevelopmentalconditions in which gyrification have been shown to bealtered (e.g. schizophrenia, autismâeuro¦). References.Rousseau, F. (2006), 'Registration-Based Approach forReconstruction of High-Resolution In Utero Fetal MR Brainimages', IEEE Transactions on Medical Imaging, vol. 13,no. 9, pp. 1072-1081. Jiang, S. (2007), 'MRI of MovingSubjects Using Multislice Snapshot Images With VolumeReconstruction (SVR): Application to Fetal, Neonatal, andAdult Brain Studies', IEEE Transactions on MedicalImaging, vol. 26, no. 7, pp. 967-980. Lee, S. (1997),'Scattered data interpolation with multilevel B-splines',IEEE Transactions on Visualization and Computer Graphics,vol. 3, no. 3, pp. 228-244. Bach Cuadra, M. (2010),'Central and Cortical Gray Mater Segmentation of MagneticResonance Images of the Fetal Brain', ISMRM Conference.Bach Cuadra, M. (2009), 'Brain tissue segmentation offetal MR images', MICCAI.