The aim of this study was to analyze whether polymorphisms for the null alleles of Glutathione S-Transferase Mu-1 (GSTM1), Glutathione S-Transferase Theta-1 (GSTT1), and a low-activity genetic variation of epoxide hydrolase exon three (EPHX*3) affect the risk of developing polyneuropathy. The enzymes of these genes are important in the metabolism of toxic compounds. Seventy-nine patients with cryptogenic polyneuropathy (equivalent to chronic idiopathic axonal neuropathy) and 398 controls were tested for the genetic polymorphism. Medical records were reviewed to collect data regarding clinical findings at diagnosis, and exposure data was collected via questionnaires. The odds ratios (ORs) for the null forms of GSTM1 and GSTT1 and the normal activity YY form of EPHX*3 were close to one except GSTT1, which reached 1.86. The highest risk of polyneuropathy was found in smokers with GSTT1 null, who had a 3.7 times increased risk. Interactions between genes were analyzed and confirmed the increased OR for GSTT1, which was strongest if the patients had the low-activity HH form of EPHX*3 (OR 2.37). Our hypothesis is that the GSTT1 null polymorphism may be related to an impaired metabolism of toxic substances that could lead to nerve damage in the peripheral nervous system.
Chronic idiopathic axonal neuropathy; Glutathione S-Transferase; epoxide hydrolase; smoking; solvents
Handedness has been found to be associated with structural and functional cerebral differences. Left handedness and mixed handedness also appear to be associated with an elevated risk of some developmental and immunological disorders that may contribute to pathological processes developing in ageing. Inconsistent reports show that left handedness may be more prevalent in early-onset as well as late-onset Alzheimer's disease, but might also be associated with slower decline. Such inconsistencies may be due to handedness being usually modeled as a binary construct while substantial evidence suggests it to be a continuous trait. The aim of this study was to investigate the relationship between brain structures known to be implicated in pathological ageing and strength and direction of handedness. The association between handedness and hippocampal and amygdalar atrophy was investigated in 327 cognitively healthy older individuals. Handedness was measured with the Edinburgh Inventory. Two measures were computed from this index, one reflecting the direction (left = 0/right = 1) and the other the degree of handedness (ranging from 0 to 1). Hippocampal and amygdalar volumes were manually traced on scans acquired 4 years apart. Regression analyses were used to assess the relationship between strength and direction of handedness and incident hippocampal and amygdalar atrophy. Analyses showed that strength but not direction of handedness was a significant predictor of hippocampal (Left: beta = 0.118, P = 0.013; Right: beta = 0.116, P = 0.010) and amygdalar (Right: beta = 0.105, P = 0.040) atrophy. The present findings suggest that mixed but not left handedness is associated with greater hippocampal and amygdalar atrophy. This effect may be due to genetic, environmental, or behavioural differences that will need further investigation in future studies.
Amygdala; hippocampus; laterality; longitudinal; MRI
The detrimental effects of hypoxic damage to central nervous system lead to energy depletion, free radical formation, lipid peroxidation (LPO), and increased calcium. We hypothesized that in vitro tacrolimus (FK-506) and cyclosporine A (CsA) could be protective against hypoxic damage in spinal cord. Dorsal columns were isolated from the spinal cord of adult rats and injured by exposure to hypoxic condition for 1 h, and treated with FK-506 (0.1 μM) and CsA (0.1 μM). After injury, reperfusion was carried out for 2 h. Tissues were collected, processed for biochemical assays, and 2,3,5-triphenyltetrazolium chloride (TTC) staining. Spinal cord hypoxia caused a significant decrease (P < 0.001) in mitochondrial ATP (30.64%) and tissue reduced glutathione (GSH) (60.14%) content. Conversely, a significant increase (P < 0.001) in tissue LPO level (57.77%) and myeloperoxidase (MPO) activity (461.24%) was observed in hypoxic group. Mitochondrial swelling was also significantly increased in hypoxic group (90.0%). Treatment with either FK-506 or CsA showed that significant neuroprotective effects (P < 0.05–0.01) were measured in various parameters in hypoxic groups. FK-506 and CsA treatment showed increase in ATP by 11.19% and 16.14% while GSH content increased by 66.46% and 77.32%, respectively. Conversely, LPO content decreased by 18.97% and 24.06% and MPO level by 42.86% and 18.66% after FK-506 and CsA treatment. Calcium uptake was also decreased in mitochondria as exhibited by the increase in absorbance by 11.19% after FK-506 treatment. TTC staining also showed increased viability after FK-506 and CsA treatment. In conclusion, present study demonstrates the neuroprotective effect of FK-506 and CsA treatment against spinal cord hypoxia induced damage is mediated via their antioxidant actions.
ATP; hypoxia; mitochondrial swelling; neuroprotection; spinal cord
We demonstrate for the first time the ability to determine in vivo and in utero the transitions between the main stages of white matter (WM) maturation in normal human fetuses using magnetic resonance diffusion tensor imaging (DTI) tractography. Biophysical characteristics of water motion are used as an indirect probe to evaluate progression of the tissue matrix organization in cortico-spinal tracts (CSTs), optic radiations (OR), and corpus callosum (CC) in 17 normal human fetuses explored between 23 and 38 weeks of gestation (GW) and selected strictly on minimal motion artifacts. Nonlinear polynomial (third order) curve fittings of normalized longitudinal and radial water diffusivities (Z-scores) as a function of age identify three different phases of maturation with specific dynamics for each WM bundle type. These phases may correspond to distinct cellular events such as axonal organization, myelination gliosis, and myelination, previously reported by other groups on post-mortem fetuses using immunostaining methods. According to the DTI parameter dynamics, we suggest that myelination (phase 3) appears early in the CSTs, followed by the OR and by the CC, respectively. DTI tractography provides access to a better understanding of fetal WM maturation.
Corpus callosum; corticospinal tracts; diffusion tractography; fetal development; human; in utero; visual pathways; white matter maturation
The possible effect of antihypertensive therapy on Alzheimer's disease (AD) has been studied, and angiotensin II receptor blockers (ARBs) have been suggested to exert an effect on cognitive decline. The purpose of this study is to clarify the functional effects of telmisartan, a long-acting ARB, on AD brain using prospective longitudinal 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) studies. For this purpose, brain glucose metabolism of four hypertensive patients with AD was examined with FDG-PET before and after administration of telmisartan. Studied subjects underwent three FDG-PET studies at intervals of 12 weeks. Antihypertensive treatment except for telmisartan was started after the first FDG-PET and continued for 24 weeks. Then 40–80 mg of telmisartan was added after the second FDG-PET and continued for 12 weeks.Glucose metabolism was significantly decreased during the first 12 weeks without telmisartan use at an area (−10, 21, −22, x, y, z; Z = 3.56) caudal to the left rectal gyrus and the olfactory sulcus corresponding to the left olfactory tract. In contrast, the introduction of telmisartan during the following 12 weeks preserved glucose metabolism at areas (5, 19, −20, x, y, z; Z = 3.09; 6, 19, −22, x, y, z; Z = 2.88) caudal to the bilateral rectal gyri and olfactory sulci corresponding to the bilateral olfactory tracts. No areas showed decreased glucose metabolism after the introduction of telmisartan. In AD, amyloid-β deposition is observed in the anterior olfactory nucleus (AON) of the olfactory tract. Glucose metabolism in AON may be progressively decreased and preserved by telmisartan.
Alzheimer's disease (AD); angiotensin II receptor blocker (ARB); telmisartan; 18F-fluorodeoxyglucose positron emission tomography (FDG-PET); anterior olfactory nucleus
Alzheimer disease (AD) is an increasingly prevalent neurodegenerative condition and a looming socioeconomic threat. A biomarker for the disease could make the process of diagnosis easier and more accurate, and accelerate drug discovery. The current work describes a method for scoring brain images that is inspired by fundamental principles from information retrieval (IR), a branch of computer science that includes the development of Internet search engines. For this research, a dataset of 254 baseline 18-F fluorodeoxyglucose positron emission tomography (FDG-PET) scans was obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI). For a given contrast, a subset of scans (nine of every 10) was used to compute a residual vector that typified the difference, at each voxel, between the two groups being contrasted. Scans that were not used for computing the residual vector (the remaining one of 10 scans) were then compared to the residual vector using a cosine similarity metric. This process was repeated sequentially, each time generating cosine similarity scores on 10% of the FDG-PET scans for each contrast. Statistical analysis revealed that the scores were significant predictors of functional decline as measured by the Functional Activities Questionnaire (FAQ). When logistic regression models that incorporated these scores were evaluated with leave-one-out cross-validation, cognitively normal controls were discerned from AD with sensitivity and specificity of 94.4% and 84.8%, respectively. Patients who converted from mild cognitive impairment (MCI) to AD were discerned from MCI nonconverters with sensitivity and specificity of 89.7% and 62.9%, respectively, when FAQ scores were brought into the model. Residual vectors are easy to compute and provide a simple method for scoring the similarity between an FDG-PET scan and sets of examples from a given diagnostic group. The method is readily generalizable to any imaging modality. Further interdisciplinary work between IR and clinical neuroscience is warranted.
ADNI; Alzheimer disease; Bioinformatics; Mild cognitive impairment; PET scan
Although prominent personality theories postulate orthogonality between traits of positive emotionality (PEM) and negative emotionality (NEM), empirical evidence often demonstrates the opposite indicating a negative relationship. Therefore, it is not surprising that dopaminergic (DA) gene loci have been related to traits of positive and of NEM. The present genetic association study investigates the influence of two functional DA gene polymorphisms on Sadness as defined by the Affective Neuroscience Personality Scales (ANPS) in healthy Caucasians (n = 1041). We observed a significant interaction effect between the 10-repeat (10R) allele of the dopamine transporter (DAT1) gene and the methionine (Met) allele of the catechol-O-methyltransferase (COMT) Val158Met polymorphism (F(1,1018) = 11.11; P < 0.001). Carriers of the 9R/9R and the Val/Val genotype showed dramatically reduced Sadness scores in comparison to the other three genotype configurations. Both the 9R/9R and the Val/Val genotypes characterized by reduced transporter density and high dopamine catabolism, respectively, have been separately related to personality traits of PEM and externalizing behavior in the past. The present findings indicate that gene variations of the DA system previously associated with PEM are at the same time protective against high NEM and can therefore constitute a resilience factor against depression.
ANPS; COMT Val158Met; DAT1 VNTR; Dopamine; Negative emotionality; Sadness
A new subtype of autoimmune encephalitis associated with antibodies against GABAB receptor was recently identified. Although immune-mediated functional abnormalities are suggested for the pathogenesis, functional brain imaging such as perfusion SPECT has not been documented. A 62-year-old woman with anti-GABAB receptor associated encephalitis underwent 123I-IMP SPECT in the beginning and after methylprednisolone pulse therapy. Three-dimensional stereotactic surface projection analysis was used to evaluate the cortical distribution of perfusion abnormality. The patient presented with clinical features of subacute limbic encephalitis. Antibodies to GABAB receptor were identified in her serum and cerebrospinal fluid (CSF), but no tumor was detected. Despite normal magnetic resonance imaging (MRI) findings, the first SPECT revealed hypoperfusion of the frontal, parietal and medial temporal lobes, as well as thalamus, and cerebellum. These areas are known to contain high levels of GABAB receptors. In contrast, the SPECT revealed hyperperfusion in the motor strip and left temporal lobe, which are areas related to some of the patient's symptoms, including seizures, orolingual dyskinesia, and Wernicke aphasia. After treatment with pulses of methylprednisolone, the neuropsychiatric symptoms resolved and the SPECT findings showed substantial improvement in most of these regions. In conclusion, the findings suggest that immunotherapy improved the cortical dysfunction mediated by GABAB receptor antibodies.
autoimmune; limbic encephalitis; GABA; SPECT; cerebral perfusion; cerebral cortex
Phosphoinositide-3-kinase, class III (PIK3C3) is a member of the phosphoinosite-3-kinases family, involved in cell signaling, membrane trafficking, and neurodevelopment. Previous studies have indeed shown an association between PIK3C3 gene variants and both bipolar disorder (BD) and schizophrenia (SZ). Brain-derived neurotrophic factor (BDNF) is a neurodevelopmental factor, which can regulate the PI3K signaling pathway. Associations have been reported between BDNF gene polymorphisms and affective and psychotic disorders. The aim of the present study was to replicate an association between PIK3C3 and BDNF gene variants in SZ and BD and a putative epistasis between the two genes. Patients meeting the DSM-IV criteria of BD and SZ were included in this study (98 BD and 79 SZ) as well as 158 healthy controls. Blood DNA was extracted and genotyping was performed either by the polymerase chain reaction (PCR) technique followed by enzymatic digestion or by the high-resolution melt (HRM) method. Genotype and haplotype association was assessed with the UNPHASED statistical program.The results showed one nominal association with BD (P < 0.02) and two risk haplotypes in both SZ (P < 0.001) and BP (P < 0.0005), which survived multiple testing correction. A modest interaction between a BDNF variant and PI3KC3 polymorphism was observed (P < 0.04).These preliminary results confirm the genetic association of PI3K gene variants with both SZ and BD, and support the hypothesis that SZ and BD share a genetic background.
BDNF gene; bipolar disorder; genetic overlaps; PIK3C3 gene; schizophrenia; SNPs
Mutations in the L1 gene cause severe brain malformations and mental retardation. We investigated the potential roles of L1 in the regulation of choline acetyltransferase (ChAT) and in the development of septal cholinergic neurons, which are known to project to the hippocampus and play key roles in cognitive functions. Using stereological approaches, we detected significantly fewer ChAT-positive cholinergic neurons in the medial septum and vertical limb of the diagonal band of Broca (MS/VDB) of 2-week-old L1-deficient mice compared to wild-type littermates (1644 ± 137 vs. 2051 ± 165, P = 0.038). ChAT protein levels in the septum were 53% lower in 2-week-old L1-deficient mice compared to wild-type littermates. ChAT activity in the septum was significantly reduced in L1-deficient mice compared to wild-type littermates at 1 (34%) and 2 (40%) weeks of age. In vitro, increasing doses of L1-Fc induced ChAT activity in septal neurons with a significant linear trend (*P = 0.0065). At 4 weeks of age in the septum and at all time points investigated in the caudate-putamen (CPu), the number of ChAT-positive neurons and the levels of ChAT activity were not statistically different between L1-deficient mice and wild-type littermates. The total number of cells positive for the neuronal nuclear antigen (NeuN) in the MS/VDB and CPu was not statistically different in L1-deficient mice compared to wild-type littermates, and comparable expression of the cell cycle marker Ki67 was observed. Our results indicate that L1 is required for the timely maturation of septal cholinergic neurons and that L1 promotes the expression and activity of ChAT in septal neurons.
Caudate-putamen; cell adhesion molecule L1; choline acetyltransferase; cholinergic neurons; L1-deficient mice; medial septum; stereology; striatum; vertical limb of diagonal band of Broca
Abnormal eye contact is a core symptom of autism spectrum disorders (ASD), though little is understood of the neural bases of gaze processing in ASD. Competing hypotheses suggest that individuals with ASD avoid eye contact due to the anxiety-provoking nature of direct eye gaze or that eye-gaze cues hold less interest or significance to children with ASD. The current study examined the effects of gaze direction on neural processing of emotional faces in typically developing (TD) children and those with ASD. While undergoing functional magnetic resonance imaging (fMRI), 16 high-functioning children and adolescents with ASD and 16 TD controls viewed a series of faces depicting emotional expressions with either direct or averted gaze. Children in both groups showed significant activity in visual-processing regions for both direct and averted gaze trials. However, there was a significant group by gaze interaction such that only TD children showed reliably greater activity in ventrolateral prefrontal cortex for direct versus averted gaze. The ASD group showed no difference between direct and averted gaze in response to faces conveying negative emotions. These results highlight the key role of eye gaze in signaling communicative intent and suggest altered processing of the emotional significance of direct gaze in children with ASD.
Autism; facial expression; functional magnetic resonance imaging; gaze; developmental neuroimaging
Unilateral and bilateral subthalamic nucleus deep brain stimulation (STN DBS) in Parkinson's disease (PD) result in weight gain in the initial postoperative months, but little is known about the changes in weight following unilateral and staged bilateral STN DBS over longer time intervals. A case–control comparison evaluated weight changes over 2 years in 43 consecutive unilateral STN DBS patients, among whom 25 elected to undergo staged bilateral STN DBS, and 21 age-matched and disease severity matched PD controls without DBS. Regression analyses incorporating age, gender, and baseline weight in case or control were conducted to assess weight changes 2 years after the initial unilateral surgery. Unilateral STN DBS and staged bilateral STN DBS patients gained 3.9 ± 2.0 kg and 5.6 ± 2.1 kg versus their preoperative baseline weight (P < 0.001, respectively) while PD controls without DBS lost 0.8 ± 1.1 kg. Although bilateral STN DBS patients gained 1.7 kg more than unilateral STN DBS patients at 2 years, this difference was not statistically significant (P = 0.885). Although there was a trend toward greater weight gain in staged bilateral STN DBS patients versus unilateral patients, we found no evidence for an equivalent or synergistic increase in body weight following placement of the second DBS electrode.
Bilateral; deep brain stimulation; Parkinson's disease; subthalamic; unilateral; weight
Focusing gaze on a target helps stabilize upright posture. We investigated how this visual stabilization can be affected by observing a target presented under different gaze and viewing angles. In a series of 10-second trials, participants (N = 20, 29.3 ± 9 years of age) stood on a force plate and fixed their gaze on a figure presented on a screen at a distance of 1 m. The figure changed position (gaze angle: eye level (0°), 25° up or down), vertical body orientation (viewing angle: at eye level but rotated 25° as if leaning toward or away from the participant), or both (gaze and viewing angle: 25° up or down with the rotation equivalent of a natural visual perspective). Amplitude of participants’ sagittal displacement, surface area, and angular position of the center of gravity (COG) were compared. Results showed decreased COG velocity and amplitude for up and down gaze angles. Changes in viewing angles resulted in altered body alignment and increased amplitude of COG displacement. No significant changes in postural stability were observed when both gaze and viewing angles were altered. Results suggest that both the gaze angle and viewing perspective may be essential variables of the visuomotor system modulating postural responses.
Eye movements; postural control; visual perception
Dopamine (DA) agonists are widely used as primary treatments for Parkinson's disease. However, they do not prevent progressive degeneration of dopaminergic neurons, the central pathology of the disease. In this study, we found that subcutaneous injection of a cytokine mixture containing granulocyte macrophage colony-stimulating factor and interleukin-3 (IL-3) markedly suppressed dopaminergic neurodegeneration in 6-hydroxydopamine-lesioned rats, an animal model of Parkinson's disease. The cytokine mixture suppressed the decrease of DA content in the striatum, and ameliorated motor function in the lesioned rats. In response to the cytokine injection, dopaminergic neurons in the substantia nigra pars compacta increased expression of the antiapoptotic protein Bcl-xL. Microglial activation in the pars compacta was evident in both the saline- and cytokine-injected rats. However, the cytokine mixture suppressed expression of the proinflammatory cytokines IL-1β and tumor necrosis factors α, and upregulated the neuroprotective factors insulin-like growth factor-1 and hepatocyte growth factor. Similar responses were observed in cultured microglia. Detailed morphometric analyses revealed that NG2 proteoglycan-expressing glial cells increased in the cytokine-injected rats, while astrocytic activation with increased expression of antioxidative factors was evident only in the saline-injected rats. Thus, the present findings show that the cytokine mixture was markedly effective in suppressing neurodegeneration. Its neuroprotective effects may be mediated by increased expression of Bcl-xL in dopaminergic neurons, and the activation of beneficial actions of microglia that promote neuronal survival. Furthermore, this cytokine mixture may have indirect actions on NG2 proteoglycan-expressing glia, whose role may be implicated in neuronal survival.
Astrocyte; dopamine; HGF; 6-hydroxydopamine; neuroinflammation; NG2 glia
Drug abuse robs individuals of their jobs, their families, and their free will as they succumb to addiction; but may cost even more: a life of disability or even life lost due to stroke. Many illicit drugs have been linked to major cardiovascular events and other comorbidities, including cocaine, amphetamines, ecstasy, heroin, phencyclidine, lysergic acid diethylamide, and marijuana. This review focuses on available epidemiological data, mechanisms of action, particularly those leading to cerebrovascular events, and it is based on papers published in English in PubMed during 1950 through February 2011. Each drug's unique interactions with the brain and vasculature predispose even young, healthy people to ischemic or hemorrhagic stroke. Cocaine and amphetamines have the strongest association with stroke. However, the level of evidence firmly linking other drugs to stroke pathogenesis is weak. Large epidemiological studies and systematic evaluation of each drug's action on the brain and cardiovascular system are needed to reveal the full impact of drug use on the population.
Acute ischemic stroke; illicit drugs; intracerebral hemorrhage; subarachnoid hemorrhage; substance abuse
An eye-of-the-tiger sign is previously known to have one-to-one correlation with pantothenate kinase-associated neurodegeneration (PKAN). Reviewing the literature on this subject, the correlation between eye-of-the-tiger sign and PKAN seems to show an interesting hypothesis that differs from conventional conclusion. We analyze the published papers in an attempt to reflect this trend and illustrate our points with findings in a 39-year-old man. His brain magnetic resonance imaging study shows typical eye-of-the-tiger sign suggestive of PKAN. Genetic analyses revealed no mutations in pantothenate kinase 2.
Neurodegeneration with brain iron accumulation; pantothenate kinase-associated neurodegeneration; pantothenate kinase 2; eye-of-the-tiger sign; PKAN; NBIA; Hallervorden-Spatz syndrome
Isolated central nervous system (CNS) vasculitis is a rare and complicated disorder. Patients typically present with nonspecific neurologic symptoms such as headache and encephalopathy, and have variable progression and severity of the disease. Challenges to definitive diagnosis include the limitations of currently available diagnostic modalities with high likelihood of false-positive or false-negative findings. Imaging, serologic, and cerebrospinal fluid (CSF) evaluation, and even angiography can fail to establish the diagnosis. Often, brain biopsy is required. In order to illustrate these challenges, we report the case of a patient who presented with subacute cognitive decline and was ultimately diagnosed with isolated CNS eosinophilic vasculitis. Initial work-up included CSF and serologic analyses, magnetic resonance imaging (MRI), and cerebral angiography, but definitive diagnosis required brain biopsy. Immunosuppressive therapy resulted in clinical improvement and stabilization. To our knowledge, only one other case of isolated CNS eosinophilic vasculitis has been reported in the literature. We discuss the importance of a high index of clinical suspicion in cases of progressive nonspecific neurologic symptoms.
Vasculitis; hypereosinophilic syndrome; primary angiitis of the central nervous system; memory; aphasia