Archive for the ‘Middle temporal gyrus’ Category

A column of the cortex
Image by Ethan Hein via Flickr

Here’s a new addition to a rapidly growing list of findings for the valine-to-methionine substitution in the COMT gene (rs4680).  The paper, “Effects of the Val158Met catechol-O-methyltransferase polymorphism on cortical structure in children and adolescents” by Shaw and colleagues at the NIMH [doi:10.1038/mp.2008.121] finds that when genotype was used as a regressor for cortical thickness measures in children (8-14 years of age) significant associations were found in the right inferior frontal gyrus and the right superior/middle temporal gyrus (in both areas, the met/met group had thicker cortex).  The team notes that the findings in the frontal cortex were expected – as many others have found associations of COMT with this brain area using other imaging modalities.  However, the temporal lobe finds are something new.  No speculations on the mechanisms/implications are provided by the researchers on this new finding, but known interconnectivities of these two brain regions exist – perhaps supporting aspects of language, memory and/or other cognitive processes?

Perhaps the findings provide a clue to an important role that genes may play in the development of cognitive function.

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The hydrophobic cell membrane prevents charged...
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Few genes have been studies as intensely as apolipoprotein E (APOE).  In particular, one of its variants, the epsilon-4 allele has been especially scrutinized because it is correlated with an earlier onset (about 10 years earlier than average) of Alzheimer’s Disease.  Among the many roles of APOE – its just a tiny cholesterol binding protein – are those as participant in synaptic plasticity, early neural development, damage-response and other processes – all of which share the need for the synthesis and movement of neuronal membranes (see the fluid mosaic model) and their component parts – such as cholesterol.   Hence, whenever neural membranes are being synthesized (plasticity & development) or damaged (overstimulation and other sources of oxidative damage) the tiny APOE is there to help with its membrane stabilizing cholesterol molecule in hand. Over the course of a lifetime, routine damage to neuronal membranes adds up (particularly in the hippocampus where constant storage-recall memory functions place enormous demands on synaptic plasticity systems), and individuals (such as epsilon-4 carriers) may simply show more wear-and-tear because their version of APOE is not as optimal as the other forms (epsilon-2 and -3).

apoeWith this etiological model in mind, perhaps you would like to take better care of you cell membranes (much like your car mechanic implores to change your car’s spark plugs and oil to keep the engine clean on the inside).  Moreover, perhaps you would like to do-so especially if you knew that your APOE system was less optimal than average.  Indeed, results from the recent REVEAL study suggest that folks who are in their 50’s are not unduly distressed to make this genetic inquiry and find out their genotypic status at this APOE polymorphism – even though those who discovered that they were epsion-4 carriers reported more negative feelings, understandably.  Still, with a number of education and intervention strategies available, an optimistic outlook can prevail.

Furthermore, there are ever newer diagnostic strategies that can improve the rather weak predictive power of the genetic test.  For example, cognitive assessments that measure hippocampal-dependent aspects of memory or visual orienting have been shown to be valid predictors of subsequent dementia – even moreso in populations that carry the APOE epsilon-4 allele.  Other forms of neuroimaging that directly measure the structure and function of the hippocampus also have tremendous sensitivity (here for a broad review of imaging-genetics of AD) and can, in principle, provide a more predictive view into one’s distant future.

On the very cutting edge of this imaging-genetic crystal ball technology, lies a recent paper entitled, “Distinct patterns of brain activity in young carriers of the APOE-e4 allele” by Fillippini and colleagues [doi: 10.1073/pnas.0811879106].  Here, the research team asks whether individuals in their late 20’s show structural/functional brain differences that are related to APOE genotype.  They employ various forms of imaging analysis such as a comparison of brain activity when subjects were performing a novel vs. familiar memory task and also an analysis of so-called resting state networks – which reflect a form of temporal coherence (brain areas that oscillate in-sync with each other when subjects are lying still and doing nothing in the scanner).  For the analysis of the memory task, the team found that APOEe4 carriers showed more activation in the hippocampus as well as other brain regions like the anterior midbrain and cerebellum.  When the team analysed a particular resting state network – the default mode network – they found differences in the medial temporal lobe (containing head of the hippocampus and amygdala) as well as the medial prefronal cortex.  According to the paper, none of these differences could be explained by differences in the structure or resting perfusion of the young-adult brains in the study.

Wow, these results seem to suggest that decades before any mild cognitive impairments are observable, there are already subtle differences in the physiology of the APOEe4 brain – all of which could be detected using the data obtained in 6 minutes of rest. 6 minutes of rest and spit in a cup – what does the future hold?

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PhotoImage via Wikipedia Like most parents, I enjoy watching my children develop and marvel at the many similarities they bear to myself and my wife. The reshuffling of physical and behavioral features is always a topic of discussion and is the definitive icebreaker during uncomfortable silences with the inlaws. In some cases, the children are blessed with the better traits, but in other cases, there’s no option but to cringe when, “Look – wow, he really has your nose – hmmm”, is muttered. Most interesting, is the unfolding of patterns of behavior that unfold slowly with age. Differences in temperament and personality can instill great pride in parents but also can be a grating source of friction. One of my F1’s has recently taken to sessions of shrill, spine rattling, screaming which I hope will pass soon.

Why ? Many parents ask. “Have WE been raising him/her to do this ? – surely that’s what the neighbors must think”. “Is it something in the family ? I heard Aunt Marie was a bit of a screamer as a child – hmmm.”

In one of several of their landmark studies on the genetic regulation of pediatric brain development, Jay Giedd and colleagues, now provide in their recent paper, “Variance Decomposition of MRI-Based Covariance Maps Using Genetically-Informative Samples and Structural Equation Modeling”, a core framework on the relative contribution of genes vs. environment for the developing cortex. The paper is part of an ongoing longitudinal study of pediatric brain development at the Child Psychiatry branch at NIMH. Some 600 children participated – including identical twins, fraternal twins, siblings and singleton children.

The team used an analytical approach known as MACAAC (Mapping Anatomical Correlations Across the Cerebral Cortex) to ask how much does the variation in a single part of the brain co-vary with other parts ? Then the team used structural equation modeling to explore how much this co-variation might differ across identical twins vs. fraternal vs. siblings vs. age-matched singleton children. In locations where there is an high genetic contribution to co-variation in cortical thickness, identical twins should co-vary more tightly than fraternal twins or siblings etc. In this way, the team were able to parse out the relative influence of genes vs. environment to the developing brain.

In general terms, the team reports that a single genetic factor accounts for the majority of variation in cortical thickness, which they note may be consistent with a major mechanism of development of cortical layers involving the migration of neurons along radial glia. Genetic co-variances across separate locations in the brain were highest in the frontal cortex, middle temporal gyrus and left supramarginal gyrus. Interestingly, when environmental covariations were observed, they were usually restricted to just one hemisphere, while genetic covariations were often observed bilaterally.

Figure 5 of this paper is really incredible, it shows which areas of the cortex are more influenced by genes vs. environment. If I can just find the areas involved in screaming, the next time one of my neighbors looks askance at my F1, I’ll be able to explain.

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