Characterization of ten white matter tracts in a representative sample of Cuban population

Background: The diffusion tensor imaging technique (DTI) combined with tractography methods, has achieved the tridimensional reconstruction of white matter tracts in the brain. It allows their characterization in vivo in a non-invasive way. However, one of the largest sources of variability originates from the location of regions of interest, is therefore necessary schemes which make it possible to establish a protocol to be insensitive to variations in drawing thereof. The purpose of this paper is to stablish a reliable protocol to reconstruct ten prominent tracts of white matter and characterize them according to volume, fractional anisotropy and mean diffusivity. Also we explored the relationship among these factors with gender and hemispheric symmetry. Methods: This study aims to characterize ten prominent tracts of white matter in a representative sample of Cuban population using this technique, including 84 healthy subjects. Diffusion tensors and subsequently fractional anisotropy and mean diffusivity maps were calculated from each subject's DTI scans. The trajectory of ten brain tracts was estimated by using deterministic tractography methods of fiber tracking. In such tracts, the volume, the FA and MD were calculated, creating a reference for their study in the Cuban population. The interactions between these variables with age, cerebral hemispheres and gender factors were explored using Repeated Measure Analysis of Variance. Results: The volume values showed that a most part of tracts have bigger volume in left hemisphere. Also, the data showed bigger values of MD for males than females in all the tracts, an inverse behavior than FA values. Conclusions: This work showed that is possible reconstruct white matter tracts using a unique region of interest scheme defined from standard to native space. Also, this study indicates differing developmental trajectories in white matter for males and females and the importance of taking gender into account in developmental DTI studies and in underlie gender-related cognitive differences

Lipids and lipoxidation in human brain aging. Mitochondrial ATP-synthase as a key lipoxidation target

The human brain is a target of the aging process like other cell systems of the human body. Specific regions of the human brain exhibit differential vulnerabilities to the aging process. Yet the underlying mechanisms that sustain the preservation or deterioration of neurons and cerebral functions are unknown. In this review, we focus attention on the role of lipids and the importance of the cross-regionally different vulnerabilities in human brain aging. In particular, we first consider a brief approach to the lipidomics of human brain, the relationship between lipids and lipoxidative damage, the role of lipids in human brain aging, and the specific targets of lipoxidative damage in human brain and during aging. It is proposed that the restricted set of modified proteins and the functional categories involved may be considered putative collaborative factors contributing to neuronal aging, and that mitochondrial ATP synthase is a key lipoxidative target in human brain aging

Altered gene transcription linked to astrocytes and oligodendrocytes in frontal cortex in Creutzfeldt-Jakob disease

Targeted expression of genes coding for proteins specific to astrocytes, oligodendrocytes and myelin was performed in frontal cortex area 8 of Creutzfeldt-Jakob disease methionine/methionine and valine/valine (CJD MM1 and VV2, respectively) compared with controls. GFAP (glial fibrillary acidic protein) mRNA was up-regulated whereas SLC1A2 (solute carrier family 1 member 2, coding for glutamate transporter 1: GLT1), AQ4 (aquaporin 4), MPC1 (mitochondrial pyruvate carrier 1) and UCP5 (mitochondrial uncoupled protein 5) mRNAs were significantly down-regulated in CJD MM1 and CJD VV2, and GJA1 (connexin 43) in CJD VV2. OLIG1 and OLIG2 (oligodendocyte transcription factor 1 and 2, respectively), SOX10 (SRY-Box10) and oligodendroglial precursor cell (OPC) marker NG2 (neuronal/glial antigen) 2 were preserved, but GALC (coding for galactosylceramidase), SLC2A1 (solute carrier family 2 member 1: glucose transporter member 1: GLUT1) and MCT1 (monocarboxylic acid transporter 1) mRNA expression levels were significantly reduced in CJD MM1 and CJD VV2. Expression levels of most genes linked to myelin were not altered in the cerebral cortex in CJD. Immunohistochemistry to selected proteins disclosed individual variations but GFAP, Olig-2, AQ4 and GLUT1 correlated with mRNA levels, whereas GLT1 was subjected to individual variations. However, MPC1, UCP5 and MCT1 decrease was more closely related to the respective reduced neuronal immunostaining. These observations support the idea that molecular deficits linked to energy metabolism and solute transport in astrocytes and oligodendrocytes, in addition to neurons, are relevant in the pathogenesis of cortical lesions in CJD

Redox proteomic profiling of neuroketal-adducted proteins in human brain: regional vulnerability at middle age increases in the elderly

Protein lipoxidation was assessed in the parietal cortex (PC), frontal cortex (FC), and cingulate gyrus (CG) in middle-aged and old-aged individuals with no clinical manifestations of cognitive impairment, in order to increase understanding of regional brain vulnerability to oxidative damage during aging. Twenty-five lipoxidized proteins were identified in all the three regions although with regional specificities, by using redox proteomics to detect target proteins of neuroketals (NKT) adduction. The number of cases with NKT-adducted proteins was higher in old-aged individuals but most oxidized proteins were already present in middle-aged individuals. Differences in vulnerability to oxidation were dependent on the sub-cellular localization, secondary structure, and external exposition of certain amino acids. Lipoxidized proteins included those involved in energy metabolism, cytoskeleton, proteostasis, neurotransmission and O2/CO2, and heme metabolism. Total NKT and soluble oligomer levels were estimated employing slot-blot, and these were compared between age groups. Oligomers increased with age in PC and FC; NKT significantly increased with age in FC, whereas total NKT and oligomer levels were not modified in CG, thus highlighting differences in brain regional vulnerability with age. Oligomers significantly correlated with NKT levels in the three cortical regions, suggesting that protein NKT adduction parallels soluble oligomer formation

Lipid profile in human frontal cortex is sustained throught healthy adult lifde span to decay at advanced ages

Fatty acids are key components in the structural diversity of lipids and play a strategic role in the functional properties of lipids which determine the structural and functional integrity of neural cell membranes, the generation of lipid signaling mediators, and the chemical reactivity of acyl chains. The present study analyzes the profile of lipid fatty acid composition of membranes of human frontal cortex area 8 in individuals ranging from 40 to 90 years old. Different components involved in polyunsaturated fatty acid biosynthesis pathways, as well as adaptive defense mechanisms involved in the lipid-mediated modulation of inflammation, are also assessed. Our results show that the lipid profile in human frontal cortex is basically preserved through the adult life span to decay at advanced ages, which is accompanied by an adaptive proactive anti-inflammatory response possibly geared to ensuring cell survival and function

Sixty years old is the breakpoint of human frontal cortex aging

Human brain aging is the physiological process which underlies as cause of cognitive decline in the elderly and the main risk factor for neurodegenerative diseases such as Alzheimer's disease. Human neurons are functional throughout a healthy adult lifespan, yet the mechanisms that maintain function and protect against neurodegenerative processes during aging are unknown. Here we show that protein oxidative and glycoxidative damage significantly increases during human brain aging, with a breakpoint at 60 years old. This trajectory is coincident with a decrease in the content of the mitochondrial respiratory chain complex I to IV. We suggest that the deterioration in oxidative stress homeostasis during aging induces an adaptive response of stress resistance mechanisms based on the sustained expression of REST, and increased or decreased expression of Akt and mTOR, respectively, over the adult lifespan in order to preserve cell neural survival and function

Specific metabolomics adaptations define a differential regional vulnerability in the adult human cerebral cortex

Brain neurons offer diverse responses to stresses and detrimental factors during development and aging, and as a result of both neurodegenerative and neuropsychiatric disorders. This multiplicity of responses can be ascribed to the great diversity among neuronal populations. Here we have determined the metabolomic profile of three healthy adult human brain regions¿entorhinal cortex, hippocampus, and frontal cortex¿using mass spectrometry-based technologies. Our results show the existence of a lessened energy demand, mitochondrial stress, and lower one-carbon metabolism (particularly restricted to the methionine cycle) specifically in frontal cortex. These findings, along with the better antioxidant capacity and lower mTOR signaling also seen in frontal cortex, suggest that this brain region is especially resistant to stress compared to the entorhinal cortex and hippocampus, which are more vulnerable regions. Globally, our results show the presence of specific metabolomics adaptations in three mature, healthy human brain regions, confirming the existence of cross-regional differences in cell vulnerability in the human cerebral cortex. Keywords: energy metabolism, mammalian target of rapamycin (mTOR), metabolomics, methionine cycle, mitochondrial stress, nucleotide metabolism, one-carbon metabolism, selective neuronal vulnerabilit

Daño oxidativo y regulación redox en el envejecimiento cerebral: vulnerabilidad regional

[spa] El presente trabajo exploró el proceso de envejecimiento cerebral humano considerando la vulnerabilidad regional específica en cuanto a eventos de daño oxidativo, respuesta antioxidante, metabolismo energético y moléculas implicadas en la inflamación. Se emplearon muestras de tejido post mortem de 12 regiones cerebrales (corteza frontal, corteza parietal, giro cingulado, corteza temporal, corteza entorrinal, hipocampo, tálamo, caudado, putamen, corteza visual, sustancia nigra y vermis) provenientes de 18 sujetos sanos de mediana y avanzada edad (grupos de edad). Mediante proteómica redox se identificaron 30 proteínas específicas susceptibles de ser lipoxidadas por NKT con patrones respecto a la edad y regionales específicos. Su vulnerabilidad a la lipoxidación se relacionó con patrones proteicos de localización, estructurales y funcionales. Además, el nivel global de NKT correlacionó con el nivel de oligómeros solubles, detectados por slot-blot, en las regiones con mayor aumento de la lipoxidación con la edad de proteínas específicas. Empleando Western-blot y densitometría se detectaron los niveles globales de marcadores de lipoxidación (NKT y MDA), glicoxidación (CEL y CML), defensas antioxidantes (SOD1, SOD2, CAT, GPX4, TRX1 y Nrf2), metabolismo energético (subunidades de los complejos mitocondriales: CI al CV, VDAC), metabolismo lipídico e inflamación (COX-2, CYP2J2 y vía NF-κB: p65, p50 e IκBα); y se exploraron sus diferencias con la edad en cada región comparando estadísticamente sus niveles entre grupos de edad. La lipoxidación proteica global presentó cambios con la edad específicos tanto para la región cerebral como el marcador estudiado. Los niveles globales de NKT se modificaron con la edad en pocas regiones cerebrales en contraste los de MDA, siendo este último el marcador que mostró más acusadamente cambios con la edad en el cerebro. Existió mayormente un aumento de la lipoxidación con la edad en las regiones en que variaron sus niveles (excepto NKT en tálamo y MDA en las cortezas temporal y entorrinal). Los niveles de las enzimas COX-2 y CYP2J2 presentaron variaciones con la edad y regionales en el cerebro, siendo el aumento de COX-2 característico del envejecimiento. Corteza frontal, corteza temporal e hipocampo podrían ser regiones particularmente susceptibles a alteraciones inflamatorias con la edad que involucren el metabolismo lipídico. Los niveles globales de glicoxidación proteica tendieron a aumentar durante el envejecimiento con patrones regionales específicos, a excepción de una disminución en hipocampo del CML. Varias regiones mostraron aumentos con la edad de glicoxidación no coincidentes con los de lipoxidación; durante el envejecimiento el daño a proteínas por glicoxidación podría ser más relevante en estas regiones que la lipoxidación. Se detectó una amplia modulación con la edad región-específica del nivel de enzimas antioxidantes, y discreta del factor transcripcional Nrf2. Los niveles de VDAC disminuyeron con la edad en tres regiones cerebrales (corteza frontal, corteza entorrinal y sustancia nigra), sugiriendo una disminución en el número de mitocondrias. En general, existió una amplia variación con la edad y regional en los niveles de los complejos mitocondriales del I al IV y poca en el CV; indicando que la regulación del nivel de los mismos (CI al IV) se modifica ampliamente en el cerebro humano con la edad. Se detectaron pocas variaciones con la edad y en cuanto a regiones cerebrales en los niveles de los componentes de la vía de respuesta NF-κB explorados. Giro cingulado, caudado y putamen resultaron las regiones en las que más se modificaron los componentes de esta vía con la edad. Además, el conjunto de datos permitió, mediante análisis bioinformático, establecer un perfil de vulnerabilidad regional con el envejecimiento en el cerebro que refleja en parte la tendencia a la neurodegeneración, apoyando la relevancia de los procesos redox en el envejecimiento y la susceptibilidad a la neurodegeneración.[eng] The present work explored the process of human brain aging considering the specific regional vulnerability in terms of oxidative damage events, antioxidant response, energy metabolism and molecules involved in inflammation. Post mortem tissue samples from 12 brain regions (frontal cortex, parietal cortex, cingulate gyrus, temporal cortex, entorhinal cortex, hippocampus, thalamus, caudate, putamen, visual cortex, substantia nigra and vermis) were used, from 18 healthy subjects of middle and advanced age (age groups). By means of redox proteomics, specific proteins were identified as lipoxidized by NKT with particular age and regional patterns. Their vulnerability to lipoxidation was related to localization, structural and functional patterns. In addition, the overall level of NKT correlated with the level of soluble oligomers, detected by slot blot, in regions with high increase in the lipoxidation of specific proteins with age. By using Western blot and densitometry, the levels of lipoxidation (NKT and MDA), glycoxidation (CEL and CML), antioxidant defenses (SOD1, SOD2, CAT, GPX4, TRX1 and Nrf2), proteins involved in energy metabolism (subunits of mitochondrial complexes: CI to CV, VDAC) and lipid metabolism and inflammation (COX-2, CYP2J2 and NF-κB pathway: p65, p50 and IκBα) were explored in brain aging. In each brain region, their level modifications with age were tested by statistical comparison between age groups. The particular regional and age specific changes for these markers are reported and discussed throughout the work. In addition, the data set allowed to establish, by bioinformatic analysis, a regional vulnerability profile with aging in the brain which partly reflects the trend towards neurodegeneration, supporting the relevance of redox processes in brain aging and susceptibility to neurodegeneration

Characterization of ten white matter tracts in a representative sample of Cuban population

Background: The diffusion tensor imaging technique (DTI) combined with tractography methods, has achieved the tridimensional reconstruction of white matter tracts in the brain. It allows their characterization in vivo in a non-invasive way. However, one of the largest sources of variability originates from the location of regions of interest, is therefore necessary schemes which make it possible to establish a protocol to be insensitive to variations in drawing thereof. The purpose of this paper is to stablish a reliable protocol to reconstruct ten prominent tracts of white matter and characterize them according to volume, fractional anisotropy and mean diffusivity. Also we explored the relationship among these factors with gender and hemispheric symmetry. Methods: This study aims to characterize ten prominent tracts of white matter in a representative sample of Cuban population using this technique, including 84 healthy subjects. Diffusion tensors and subsequently fractional anisotropy and mean diffusivity maps were calculated from each subject's DTI scans. The trajectory of ten brain tracts was estimated by using deterministic tractography methods of fiber tracking. In such tracts, the volume, the FA and MD were calculated, creating a reference for their study in the Cuban population. The interactions between these variables with age, cerebral hemispheres and gender factors were explored using Repeated Measure Analysis of Variance. Results: The volume values showed that a most part of tracts have bigger volume in left hemisphere. Also, the data showed bigger values of MD for males than females in all the tracts, an inverse behavior than FA values. Conclusions: This work showed that is possible reconstruct white matter tracts using a unique region of interest scheme defined from standard to native space. Also, this study indicates differing developmental trajectories in white matter for males and females and the importance of taking gender into account in developmental DTI studies and in underlie gender-related cognitive differences

Altered gene transcription linked to astrocytes and oligodendrocytes in frontal cortex in Creutzfeldt-Jakob disease

Targeted expression of genes coding for proteins specific to astrocytes, oligodendrocytes and myelin was performed in frontal cortex area 8 of Creutzfeldt-Jakob disease methionine/methionine and valine/valine (CJD MM1 and VV2, respectively) compared with controls. GFAP (glial fibrillary acidic protein) mRNA was up-regulated whereas SLC1A2 (solute carrier family 1 member 2, coding for glutamate transporter 1: GLT1), AQ4 (aquaporin 4), MPC1 (mitochondrial pyruvate carrier 1) and UCP5 (mitochondrial uncoupled protein 5) mRNAs were significantly down-regulated in CJD MM1 and CJD VV2, and GJA1 (connexin 43) in CJD VV2. OLIG1 and OLIG2 (oligodendocyte transcription factor 1 and 2, respectively), SOX10 (SRY-Box10) and oligodendroglial precursor cell (OPC) marker NG2 (neuronal/glial antigen) 2 were preserved, but GALC (coding for galactosylceramidase), SLC2A1 (solute carrier family 2 member 1: glucose transporter member 1: GLUT1) and MCT1 (monocarboxylic acid transporter 1) mRNA expression levels were significantly reduced in CJD MM1 and CJD VV2. Expression levels of most genes linked to myelin were not altered in the cerebral cortex in CJD. Immunohistochemistry to selected proteins disclosed individual variations but GFAP, Olig-2, AQ4 and GLUT1 correlated with mRNA levels, whereas GLT1 was subjected to individual variations. However, MPC1, UCP5 and MCT1 decrease was more closely related to the respective reduced neuronal immunostaining. These observations support the idea that molecular deficits linked to energy metabolism and solute transport in astrocytes and oligodendrocytes, in addition to neurons, are relevant in the pathogenesis of cortical lesions in CJD