Region-specific Patterns Research Articles

R2* mapping for brain iron: associations with cognition in normal aging

Brain iron accumulates during aging and has been associated with neurodegenerative disorders including Alzheimer's disease. Magnetic resonance (MR)–based R2* mapping enables the in vivo detection of iron content in brain tissue. We investigated if during normal brain aging iron load relates to cognitive impairment in region-specific patterns in a community-dwelling cohort of 336 healthy, middle aged, and older adults from the Austrian Stroke Prevention Family Study. MR imaging and R2* mapping in the basal ganglia and neocortex were done at 3T. Comprehensive neuropsychological testing assessed memory, executive function, and psychomotor speed. We found the highest iron concentration in the globus pallidus, and pallidal and putaminal iron was significantly and inversely associated with cognitive performance in all cognitive domains, except memory. These associations were iron load dependent. Vascular brain lesions and brain volume did not mediate the relationship between iron and cognitive performance. We conclude that higher R2*-determined iron in the basal ganglia correlates with cognitive impairment during brain aging independent of concomitant brain abnormalities. The prognostic significance of this finding needs to be determined.

Cell-Autonomous Repression of Shh by Transcription Factor Pax6 Regulates Diencephalic Patterning by Controlling the Central Diencephalic Organizer

SummaryDuring development, region-specific patterns of regulatory gene expression are controlled by signaling centers that release morphogens providing positional information to surrounding cells. Regulation of signaling centers themselves is therefore critical. The size and the influence of a Shh-producing forebrain organizer, the zona limitans intrathalamica (ZLI), are limited by Pax6. By studying mouse chimeras, we find that Pax6 acts cell autonomously to block Shh expression in cells around the ZLI. Immunoprecipitation and luciferase assays indicate that Pax6 can bind the Shh promoter and repress its function. An analysis of chimeras suggests that many of the regional gene expression pattern defects that occur in Pax6−/− diencephalic cells result from a non-cell-autonomous position-dependent defect of local intercellular signaling. Blocking Shh signaling in Pax6−/− mutants reverses major diencephalic patterning defects. We conclude that Pax6’s cell-autonomous repression of Shh expression around the ZLI is critical for many aspects of normal diencephalic patterning.

Microglial phenotypes and toll-like receptor 2 in the substantia nigra and hippocampus of incidental Lewy body disease cases and Parkinson's disease patients.

Next to α-synuclein deposition, microglial activation is a prominent pathological feature in the substantia nigra (SN) of Parkinson’s disease (PD) patients. Little is known, however, about the different phenotypes of microglia and how they change during disease progression, in the SN or in another brain region, like the hippocampus (HC), which is implicated in dementia and depression, important non-motor symptoms in PD.We studied phenotypes and activation of microglia in the SN and HC of established PD patients (Braak PD stage 4–6), matched controls (Braak PD stage 0) and of incidental Lewy Body disease (iLBD) cases (Braak PD stage 1–3) that are considered a prodromal state of PD. As recent experimental studies suggested that toll-like receptor 2 (TLR2) mediates α-synuclein triggered microglial activation, we also studied whether TLR2 expression is indeed related to pathology in iLBD and PD patients.A clear α-synuclein pathology-related increase in amoeboid microglia was present in the HC and SN in PD. Also, morphologically primed/reactive microglial cells, and a profound increase in microglial TLR2 expression were apparent in iLBD, but not PD, cases, indicative of an early activational response to PD pathology. Moreover, TLR2 was differentially expressed between the SN and HC, consistent with a region-specific pattern of microglial activation.In conclusion, the regional changes in microglial phenotype and TLR2 expression in primed/reactive microglia in the SN and HC of iLBD cases indicate that TLR2 may play a prominent role in the microglial-mediated responses that could be important for PD progression.

PARP1 activation/expression modulates regional-specific neuronal and glial responses to seizure in a hemodynamic-independent manner.

Poly(ADP-ribose) polymerase-1 (PARP1) plays a regulatory role in apoptosis, necrosis and other cellular processes after injury. Status epilepticus (SE) induces neuronal and astroglial death that show regional-specific patterns in the rat hippocampus and piriform cortex (PC). Thus, we investigated whether PARP1 regulates the differential neuronal/glial responses to pilocarpine (PILO)-induced SE in the distinct brain regions. In the present study, both CA1 and CA3 neurons showed PARP1 hyperactivation-dependent neuronal death pathway, whereas PC neurons exhibited PARP1 degradation-mediated neurodegeneration following SE. PARP1 degradation was also observed in astrocytes within the molecular layer of the dentate gyrus. PARP1 induction was detected in CA1–3-reactive astrocytes, as well as in reactive microglia within the PC. Although PARP1 inhibitors attenuated CA1–3 neuronal death and reactive gliosis in the CA1 region, they deteriorated the astroglial death in the molecular layer of the dentate gyrus and in the stratum lucidum of the CA3 region. Ex vivo study showed the similar regional and cellular patterns of PARP1 activation/degradation. Taken together, our findings suggest that the cellular-specific PARP1 activation/degradation may distinctly involve regional-specific neuronal damage, astroglial death and reactive gliosis in response to SE independently of hemodynamics.

Analysis of spontaneous MEG activity in mild cognitive impairment and Alzheimer's disease using Jensen's divergence.

The aim of this study was to analyze the changes that mild cognitive impairment (MCI) and Alzheimer's disease (AD) elicit in brain dynamics. For this task, the spontaneous magnetoencephalographic (MEG) activity from 36 AD patients, 18 MCI subjects and 24 healthy controls was analyzed. A disequilibrium measure, Jensen's divergence, was used to estimate the irregularity of neural dynamics. Results revealed that AD patients displayed significant changes (p<;0.05) in the patterns of irregularity in comparison with MCI subjects and healthy controls. Slight differences between MCI subjects and elderly controls were also found. Our results suggest that AD progression is accompanied by region-specific patterns of abnormalities in the neural activity.

Country-specific dietary patterns and associations with socioeconomic status in European children: the IDEFICSstudy.

Children from lower socioeconomic status (SES) may be at higher risk of unhealthy eating. We described country-specific dietary patterns among children aged 2-9 years from eight European countries participating in the IDEFICS study and assessed the association of dietary patterns with an additive SES indicator. Children aged 2-9 years from eight European countries were recruited in 2007-2008. Principal component analysis was applied to identify dietary country-specific patterns. Linear regression analyses were applied to assess their association with SES. Two to fourdietary patterns were identified in the participating regions. The existence of a 'processed' pattern was found in the eight regions. Also, a 'healthy' pattern was identified in seven of the eight regions. In addition, region-specific patterns were identified, reflecting the existing gastronomic and cultural differences in Europe. The 'processed' pattern was significantly inversely associated with the SES additive indicator in all countries except Sweden, whereasthe 'healthy' pattern was positively associated with SES in the Belgian, Estonian, German and Hungarian regions, but was not significant in the Italian, Spanish and Swedish regions. A 'processed' pattern and a 'healthy' pattern were found in most of the participating countries in the IDEFICS study, with comparable food itemprofiles. The results showed a strong inverse association of SES with the 'processed' pattern, suggesting that children of parents with lower SES may be at higher risk of unhealthy eating. Therefore, special focus should be given to parents and their children from lower SES levels when developing healthy eating promotion strategies.

Unravelling the complex MRI pattern in glutaric aciduria type I using statistical models-a cohort study in 180 patients.

Glutaric aciduria type I (GA-I) is a cerebral organic aciduria caused by inherited deficiency of glutaryl-CoA dehydrogenase and is characterized biochemically by an accumulation of putatively neurotoxic dicarboxylic metabolites. The majority of untreated patients develops a complex movement disorder with predominant dystonia during age 3-36months. Magnetic resonance imaging (MRI) studies have demonstrated striatal and extrastriatal abnormalities. The major aim of this study was to elucidate the complex neuroradiological pattern of patients with GA-I and to associate the MRI findings with the severity of predominant neurological symptoms. In 180 patients, detailed information about the neurological presentation and brain region-specific MRI abnormalities were obtained via a standardized questionnaire. Patients with a movement disorder had more often MRI abnormalities in putamen, caudate, cortex, ventricles and external CSF spaces than patients without or with minor neurological symptoms. Putaminal MRI changes and strongly dilated ventricles were identified as the most reliable predictors of a movement disorder. In contrast, abnormalities in globus pallidus were not clearly associated with a movement disorder. Caudate and putamen as well as cortex, ventricles and external CSF spaces clearly collocalized on a two-dimensional map demonstrating statistical similarity and suggesting the same underlying pathomechanism. This study demonstrates that complex statistical methods are useful to decipher the age-dependent and region-specific MRI patterns of rare neurometabolic diseases and that these methods are helpful to elucidate the clinical relevance of specific MRI findings.

Global Ecosystem Response Types Derived from the Standardized Precipitation Evapotranspiration Index and FPAR3g Series

Observing trends in global ecosystem dynamics is an important first step, but attributing these trends to climate variability represents a further step in understanding Earth system changes. In the present study, we classified global Ecosystem Response Types (ERTs) based on common spatio-temporal patterns in time-series of Standardized Precipitation Evapotranspiration Index (SPEI) and FPAR3g anomalies (1982–2011) by using an extended Principal Component Analysis. The ERTs represent region specific spatio-temporal patterns of ecosystems responding to drought or ecosystems with decreasing severity in drought events as well as ecosystems where drought was not a dominant factor in a 30-year period. Highest explanatory values in the SPEI12-FPAR3g anomalies and strongest SPEI12-FPAR3g correlations were seen in the ERTs of Australia and South America whereas lowest explanatory value and lowest correlations were observed in Asia and North America. These ERTs complement traditional pixel based methods by enabling the combined assessment of the location, timing, duration, frequency and severity of climatic and vegetation anomalies with the joint assessment of wetting and drying climatic conditions. The ERTs produced here thus have potential in supporting global change studies by mapping reference conditions of long term ecosystem changes.

Phylogeography ofPeromyscus schmidlyi: an endemic of the Sierra Madre Occidental, Mexico

Peromyscus schmidlyi is an endemic rodent from the forested highlands of the Sierra Madre Occidental (SMO) in Mexico. Using 2 genetic markers (cytochrome-b and D-loop) we explored the possible relationship between a recently proposed division of pine–oak forests of the SMO into specific regional communities and patterns of genetic and morphometric variation in P. schmidlyi. We found no genetic structure or significant relationships between either marker and ecological or morphometric variation. Phylogenetic and haplotypic network analyses revealed no geographically structured clusters; phylogenetic trees were shallow and networks were star-shaped. No signal of selection was detected for either marker at the local level. All available evidence suggests that the current distribution of P. schmidlyi is the result of dispersal into the SMO followed by rapid population expansion throughout the area in the late Pleistocene, following the glacial cooling of the SMO highlands.

MP11-10 BEST PRACTICES IN SHOCKWAVE LITHOTRIPSY: ADOPTION OF GUIDELINES IN CLINICAL PRACTICE

You have accessJournal of UrologyGeneral & Epidemiological Trends & Socioeconomics: Practice Patterns, Cost Effectiveness II1 Apr 2014MP11-10 BEST PRACTICES IN SHOCKWAVE LITHOTRIPSY: ADOPTION OF GUIDELINES IN CLINICAL PRACTICE Robert Brown, Shubha De, Carl Sarkissian, and Manoj Monga Robert BrownRobert Brown More articles by this author , Shubha DeShubha De More articles by this author , Carl SarkissianCarl Sarkissian More articles by this author , and Manoj MongaManoj Monga More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.425AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Evidence based treatment guidelines for extracorporeal shockwave lithotripsy (SWL) have been developed to improve outcomes and minimize adverse affects. In this study we aim to evaluate regional differences in adaptation of best practice recommendations for SWL across four distinct geographical regions. METHODS A retrospective study was performed using a prospective database maintained by a mobile lithotripsy provider (Fortec Medical, Ohio). SWL cases performed in Ohio, Northern Illinois/Southern Wisconsin, Florida, and New York were included. Treatment parameters evaluated included treatment rate, use of a power ramp-up protocol, use of a pretreatment pause after the initial 100 shocks, ancillary procedures and need for retreatment. Regional and physician specific patterns were examined. Statistical analyses using chi square and ANOVA was performed with a significance of p<0.05. RESULTS Data from 2240 SWL procedures were included in the study. The mean patient age was 54.7, mean BMI was 29.9, and 52.5% were male. Overall adaptation of power ramp-up protocols and treatment rates were high while use of pause was lower (Table 1). Ancillary procedures were performed in 34% of patients with 8.3% of patients receiving stents for stones <1cm. Comparing regions, Florida had the lowest use of ramp up (83%, p<0.001) but had highest use of a pause (98%, p<0.001) while all other regions had less than 80% rate of pause. Both Florida and Ohio were more likely to implement a slow SW rate (95%, p<0.001). New York had the highest retreatment rate (14.7%, p<0.001). Florida performed the most ancillary procedures (43%, p<0.001) and placed the highest percentage of stents for stone burden less than 1 cm (11%, p<0.001). CONCLUSIONS The recommendations for slower SW rates and power ramp protocols have reached high penetration in urologic practices, however the more recent recommendation for a pause after the initial 100 shocks has been less uniformly implemented. Inconsistencies in regional adaptation of best practices may identify opportunities for further education. Table 1. Treatment choices and outcome Ohio WI/IL Florida New York Total p-value Variables 844 429 715 252 2240 Ramp-up, N (%) 817 (96.8) 426 (99.3) 595 (83.2) 250 (99.2) 2088 (93.2) < 0.001 Pause, N (%) 581 (68.8) 342 (79.7) 701 (98.0) 61 (24.2) 1685 (75.2) < 0.001 Rate<120, N (%) 807 (95.6) 372 (86.7) 684 (95.7) 212 (84.1) 2075 (92.6) < 0.001 Retreatment, N (%) 20 (2.4) 7 (1.6) 32 (4.5) 37 (14.7) 96 (4.3) < 0.001 All analysis was done by Chi-squared test © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e99 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Robert Brown More articles by this author Shubha De More articles by this author Carl Sarkissian More articles by this author Manoj Monga More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Serotonin induces depolarization in lateral amygdala neurons by activation of TRPC-like current and inhibition of GIRK current depending on 5-HT2C receptor

Regional differences are known in the serotonin-induced modulation of neuronal activity within the amygdala. This in vitro study in rats focuses on analyzing the ionic mechanism underlying serotonin-induced depolarization in the lateral amygdala. Serotonin depolarized membrane potential by 5 mV, which is underlain by a serotonin-induced inward current at rest with a characteristic reversal potential of −105 mV. From pharmacological experiments, the 5-HT2C subtype was singled out as the receptor subtype involved. Under blockade of K+ channels by Ba2+, 5-HT induced an inward current with no reversal at the range between −50 and −130 mV, which was identified as a TRPC-like current. This current was blocked by the specific phosphatidylinositol 3-kinse (PI3-kinase) inhibitor LY294002, pointing to its dependence on PI3-kinase. The Ba2+-sensitive component, obtained by subtraction, showed a strong outward rectification and the reversal potential of K+, indicating that this component results from a serotonin-induced inhibition of G-protein coupled inwardly rectifying K+ channel (GIRK) current. By wortmannin, an inhibitor of both PI3-kinase and PI4-kinase, a serotonin-induced phosphatidylinositol 4,5-bisphosphate (PIP2) depletion was revealed to underlie GIRK inhibition. Thus, the serotonin-induced current turned out to be caused by a combined occurrence of GIRK inhibition and PI3-kinase-dependent TRPC-like current. With serotonergic modulation, all these mechanisms should be recruited in lateral amygdala principal neurons and likely contribute to generation of region-specific neuronal activity patterns within the amygdala, which may at least partly implement its required role in fear and anxiety.

How Brain Circuits Adapt to Changes in Sensory Experience

The cerebral cortex, the outer portion of the brain, consists of a layered structure of neural tissue that contains the cell bodies of neurons and plays a key role in perception and cognition. Although cortical circuits throughout the brain share similarities, the patterns of connections among neurons in different brain regions can vary widely. Yet, relatively little is known about how region-specific wiring patterns relate to information processing in the brain. Specific neuronal connections can respond in independent and sometimes opposite ways to changes in sensory input. In a study published in PLOS Biology, Dennis Katzel and Gero Miesenbock of the University of Oxford investigated how wiring patterns in the brains of adult mice adapt to changes in sensory input. They found that distinct connections in neural networks responded in different ways to sensory changes, allowing neurons to continue to function optimally. The findings reveal a remarkable level of adaptability in cortical circuits of the adult brain. To examine how brain circuits adapt to changes in sensory experience, the researchers used optogenetic mapping, a technique that combines genetics and optics to precisely control the activity of individual neurons. Katzel and Miesenbock inserted channelrhodopsin, a light-sensitive receptor protein originally found in algae, into neurons, making them sensitive to activation by light of specific wavelengths. This allowed them to control the activity of these neurons and study their wiring patterns and function. The researchers first examined how neural circuits would change in response to sensory deprivation. They trimmed the whiskers of adult mice to deprive the animals of tactile sensation for two to three weeks, and then prepared slices from barrel cortex, a brain region involved in processing tactile information from the whiskers. The researchers stimulated neurons in barrel cortex and then recorded light-evoked neural activity to map out neuronal connections. They found that sensory deprivation caused an overall reduction in inhibitory neural activity in cortical circuits, consistent with previous findings in brain regions that process visual information. But this new study paints a more refined picture. Different neuronal connections responded in different ways to sensory deprivation. Neurons in layer 5 of barrel cortex stopped sending inhibitory signals to neurons in layer 2/3, making layer 2/3 neurons more excitable. This change may be an autoregulatory adaptation, because the lack of tactile signals from the whiskers had caused a sharp decrease in excitatory neural activity in barrel cortex. The release from inhibition could prevent a total shutdown of neural function, allowing neurons in layer 2/3 to continue to process even weak tactile signals in the wake of sensory deprivation. On the other hand, neurons in layer 1 sent more inhibitory signals to neurons in layer 2/3 in response to sensory deprivation. Because layer 1 neurons carry information from higher brain regions involved in complex perceptual and cognitive processes, this adaptation could reflect top-down suppression of unusual activity in layer 2/3 neurons, which were no longer responding normally after sensory deprivation. Moreover, these changes in cortical wiring patterns were entirely reversible. In a different experiment, the researchers trimmed the whiskers of adult mice for several weeks and then allowed the whiskers to regrow for four to five weeks before preparing the brain slices. The return to normal sensory stimulation restored the original level of inhibitory signals from neurons in layers 1 and 5 to neurons in layer 2/3. This finding suggests that changes in sensory stimulation do not destroy the underlying physical structure of neuronal connections, but rather modify the patterns of communication between neurons in cortical circuits. Taken together, the findings suggest that specific neuronal connections can respond in independent and sometimes opposite ways to changes in sensory input. Surprisingly, these reversible changes occur in adulthood, well past the time window during which neuronal connections are thought to adapt to environmental fluctuations. The ability of wiring motifs to change in sophisticated ways could reflect a self-regulating mechanism that ensures optimal neural function in cortical circuits despite changes in sensory experience. Katzel D, Miesenbock G (2014) Experience-Dependent Rewiring of Specific Inhibitory Connections in Adult Neocortex. doi:10.1371/journal.pbio.1001798

Effects of natal origin on localized distributions of Chinook salmon, Oncorhynchus tshawytscha, in the marine waters of Puget Sound, Washington

The inland marine waters of Puget Sound, Washington, and the Strait of Georgia and associated waters of British Columbia (the Salish Sea) have long been recognized as alternative rearing habitat to the continental shelf for Chinook and coho salmon. Recent analyses have indicated that these fish (termed residents) comprise a substantial fraction of the Chinook salmon populations originating from Puget Sound rivers. However, the extent to which these resident salmon remain within their natal region or move within Puget Sound has not been studied. Analysis of two decades of coded-wire tagging data revealed several clear patterns. First, the salmon showed spatial distributions that varied systematically with area of origin. In general, they were caught in the vicinity of their origin, indicating limited net movement during several years at large; however this pattern was not universal. Second, recovery distributions were highly influenced by marine age and showed region specific spatial patterns, with the largest differences between the youngest (marine age 1) and oldest (marine age 4) individuals.

Differential Entrainment and Learning-Related Dynamics of Spike and Local Field Potential Activity in the Sensorimotor and Associative Striatum

Parallel cortico-basal ganglia loops are thought to have distinct but interacting functions in motor learning and habit formation. In rats, the striatal projection neuron populations (MSNs) in the dorsolateral and dorsomedial striatum, respectively corresponding to sensorimotor and associative regions of the striatum, exhibit contrasting dynamics as rats acquire T-maze tasks (Thorn et al., 2010). Here, we asked whether these patterns could be related to the activity of local interneuron populations in the striatum and to the local field potential activity recorded simultaneously in the corresponding regions. We found that dorsolateral and dorsomedial striatal fast-spiking interneurons exhibited task-specific and training-related dynamics consistent with those of corresponding MSN populations. Moreover, both MSNs and interneuron populations in both regions became entrained to theta-band (5-12 Hz) frequencies during task acquisition. However, the predominant entrainment frequencies were different for the sensorimotor and associative zones. Dorsolateral striatal neurons became entrained mid-task to oscillations centered ∼ 5 Hz, whereas simultaneously recorded neurons in the dorsomedial region became entrained to higher frequency (∼ 10 Hz) rhythms. These region-specific patterns of entrainment evolved dynamically with the development of region-specific patterns of interneuron and MSN activity, indicating that, with learning, these two striatal regions can develop different frequency-modulated circuit activities in parallel. We suggest that such differential entrainment of sensorimotor and associative neuronal populations, acquired through learning, could be critical for coordinating information flow throughout each trans-striatal network while simultaneously enabling nearby components of the separate networks to operate independently.

Spatiotemporal variability of winter wheat phenology in response to weather and climate variability in China

Weather and climate variability are predicted to impact food security by altering crop growth, phenology, and yield processes. Adaptation measures are critical for reducing future vulnerability of crop production to warming weather and climate variability. It is therefore vital to investigate the shifts in crop phenological processes in response to weather/climate variability. This study analyzes the trends in the dates of winter wheat (Triticum aestivum L.) phenology in relation to average temperature of different growth stage and the adaptation of the crop to weather/climate variability in China. The results suggest that the phenological phases of winter wheat have specific regional patterns in China. There are also significant shifts in the dates of winter wheat phenology and the duration of the growth stages in the investigated 30-year period of 1980–2009. While the date of sowing winter wheat delays, the dates of post-winter phenological phases (e.g., heading and maturity dates) advances in most areas of China. Detailed analysis shows that the changes in the phenological phases of winter wheat are strongly related to temperature trends. Temporal trends in phenological phases of winter wheat are similar in characteristics to corresponding trends in temperature. Although warming weather and climate variability is the main driver of the changes in winter wheat phenology, temperature is lower than before in most of the investigated stations during the period from heading to maturity—mainly the grain-filling stage. This is mainly due to the early heading and maturity dates, which in turn not only prolong growth stages but also enhance productivity of winter wheat. This could be a vital adaptation strategy of winter wheat to warming weather with beneficial effects in terms of productivity.

Predictors and patterns of cigarette and smokeless tobacco use among adolescents in 32 countries, 2007-2011.

This study compared data from 32 countries to assess predictors and patterns of cigarette and smokeless tobacco (SLT) use among students aged 13-15 years old. Data from the 2007-2008 Global Youth Tobacco Surveys were analyzed for students aged 13-15 years in 31 countries located in all six World Health Organization regions. In addition, the 2011 National Youth Tobacco Survey was analyzed for U.S. students aged 13-15 years. Country-specific prevalence of current smoking, current SLT use, and concurrent use patterns were assessed. The national prevalence of current cigarette smoking among students aged 13-15 years ranged from 1.8% (Rwanda) to 32.9% (Latvia), whereas current SLT use ranged from 1.1% (Montenegro) to 14.4% (Lesotho). In the U.S. and most European countries surveyed, current smoking prevalence was significantly higher than SLT prevalence, in contrast to patterns observed in low- and middle-income countries. Also, in most of the surveyed countries outside of Europe and the United States, SLT use among girls was as common as their use of cigarettes, and not significantly different from use by boys. When compared with U.S. adolescents, the odds of SLT use were highest among African adolescents (adjusted odds ratio = 3.98; 95% CI: 2.19-7.24) followed by those in the Southeast Asian region (adjusted odds ratio = 2.76; 95% CI: 1.38-5.53). Region-specific patterns of tobacco use were noticed. Furthermore, it is alarming that in several low- and middle-income countries, the prevalence of SLT use among females did not differ from that among males, suggesting the possibility of a future shared burden of disease between both males and females.

Anterior brain glucose hypometabolism predates dementia in progranulin mutation carriers

In this prospective cohort study, we investigated cerebral glucose metabolism reductions on [(18)F]-fluorodeoxyglucose (FDG)-PET in progranulin (GRN) mutation carriers prior to frontotemporal dementia (FTD) onset. Nine mutation carriers (age 51.5 ± 13.5 years) and 11 noncarriers (age 52.7 ± 9.5 years) from 5 families with FTD due to GRN mutations underwent brain scanning with FDG-PET and MRI and clinical evaluation. Normalized FDG uptake values were calculated with reference to the pons. PET images were analyzed with regions of interest (ROI) and statistical parametric mapping (SPM) approaches. Compared with noncarriers, GRN mutation carriers had a lowered anterior-to-posterior (AP) ratio of FDG uptake (0.86 ± 0.09 vs 0.92 ± 0.05) and less left-right asymmetry, consistent with an overall pattern of right anterior cerebral hypometabolism. This pattern was observed regardless of whether they were deemed clinically symptomatic no dementia or asymptomatic. Individual ROIs with lowered FDG uptake included right anterior cingulate, insula, and gyrus rectus. SPM analysis supported and extended these findings, demonstrating abnormalities in the right and left medial frontal regions, right insular cortex, right precentral and middle frontal gyri, and right cerebellum. Right AP ratio was correlated with cognitive and clinical scores (modified Mini-Mental State Examination r = 0.74; Functional Rating Scale r = -0.73) but not age and years to estimated onset in mutation carriers. The frontotemporal lobar degenerative process associated with GRN mutations appears to begin many years prior to the average age at FTD onset (late 50s-early 60s). Right medial and ventral frontal cortex and insula may be affected in this process but the specific regional patterns associated with specific clinical variants remain to be elucidated.

Glucocorticoid receptor gene expression and promoter CpG modifications throughout the human brain

Glucocorticoids and the glucocorticoid (GR) and mineralocorticoid (MR) receptors have been implicated in many processes, particularly in negative feedback regulation of the hypothalamic-pituitary-adrenal axis. Epigenetically programmed GR alternative promoter usage underlies transcriptional control of GR levels, generation of GR 3′ splice variants, and the overall GC response in the brain. No detailed analysis of GR first exons or GR transcript variants throughout the human brain has been reported. Therefore we investigated post mortem tissues from 28 brain regions of 5 individuals. GR first exons were expressed throughout the healthy human brain with no region-specific usage patterns. First exon levels were highly inter-correlated suggesting that they are co-regulated. GR 3′ splice variants (GRα and GR-P) were equally distributed in all regions, and GRβ expression was always low. GR/MR ratios showed significant differences between the 28 tissues with the highest ratio in the pituitary gland. Modification levels of individual CpG dinucleotides, including 5-mC and 5-hmC, in promoters 1D, 1E, 1F, and 1H were low, and diffusely clustered; despite significant heterogeneity between the donors. In agreement with this clustering, sum modification levels rather than individual CpG modifications correlated with GR expression. Two-way ANOVA showed that this sum modification was both promoter and brain region specific, but that there was however no promoter*tissue interaction. The heterogeneity between donors may however hide such an interaction. In both promoters 1F and 1H modification levels correlated with GRα expression suggesting that 5-mC and 5-hmC play an important role in fine tuning GR expression levels throughout the brain.

Robust estimation of fractal measures for characterizing the structural complexity of the human brain: Optimization and reproducibility

High-resolution isotropic three-dimensional reconstructions of human brain gray and white matter structures can be characterized to quantify aspects of their shape, volume and topological complexity. In particular, methods based on fractal analysis have been applied in neuroimaging studies to quantify the structural complexity of the brain in both healthy and impaired conditions. The usefulness of such measures for characterizing individual differences in brain structure critically depends on their within-subject reproducibility in order to allow the robust detection of between-subject differences. This study analyzes key analytic parameters of three fractal-based methods that rely on the box-counting algorithm with the aim to maximize within-subject reproducibility of the fractal characterizations of different brain objects, including the pial surface, the cortical ribbon volume, the white matter volume and the gray matter/white matter boundary. Two separate datasets originating from different imaging centers were analyzed, comprising 50 subjects with three and 24 subjects with four successive scanning sessions per subject, respectively. The reproducibility of fractal measures was statistically assessed by computing their intra-class correlations. Results reveal differences between different fractal estimators and allow the identification of several parameters that are critical for high reproducibility. Highest reproducibility with intra-class correlations in the range of 0.9–0.95 is achieved with the correlation dimension. Further analyses of the fractal dimensions of parcellated cortical and subcortical gray matter regions suggest robustly estimated and region-specific patterns of individual variability. These results are valuable for defining appropriate parameter configurations when studying changes in fractal descriptors of human brain structure, for instance in studies of neurological diseases that do not allow repeated measurements or for disease-course longitudinal studies.

Influence of the topography of brain damage on depression and fatigue in patients with multiple sclerosis

Objectives: Involvement of selected central nervous system (CNS) regions has been associated with depression and fatigue in MS. We assessed whether specific regional patterns of lesion distribution and atrophy of the gray (GM) and white matter (WM) are associated with these symptoms in MS. Methods: Brain dual-echo and 3D T1-weighted images were acquired from 123 MS patients (69 depressed (D), 54 non-depressed (nD), 64 fatigued, 59 non-fatigued) and 90 controls. Lesion distribution, GM and WM atrophy were estimated using VBM and SPM8. Results: Gender, age, disease duration and conventional MRI characteristics did not differ between D-MS and nD-MS patients. Fatigued patients experienced higher EDSS and depression than non-fatigued ones. Lesion distribution and WM atrophy were not related to depression and fatigue. Atrophy of regions in the frontal, parietal and occipital lobes had a combined effect on depression and fatigue. Atrophy of the left middle frontal gyrus and right inferior frontal gyrus were selectively related to depression. No specific pattern of GM atrophy was found to be related to fatigue. Conclusions: Depression in MS is linked to atrophy of cortical regions located in the bilateral frontal lobes. A distributed pattern of GM atrophy contributes to the concomitant presence of depression and fatigue in these patients.