Mapping the effects of age on brain iron, myelination, and macromolecules – with data!

The structure, function, and connectivity of the brain changes considerably as we age1–4. Recent advances in MRI physics and neuroimaging have led to the development of new techniques which allow researchers to map quantitative parameters sensitive to key histological brain factors such as iron and myelination5–7. These quantitative techniques reveal the microstructure of the brain by leveraging our knowledge about how different tissue types respond to specialized MRI-sequences, in a fashion similar to diffusion-tensor imaging, combined with biophysical modelling. Here at the Wellcome Trust Centre for Neuroimaging, our physicists and methods specialists have teamed up to push these methods to their limit, delivering sub-millimetre, whole-brain acquisition techniques that can be completed in less than 30 minutes. By combining advanced biophysical modelling with specialized image co-registration, segmentation, and normalization routines in a process known as ‘voxel-based quantification’ (VBQ), these methods allow us to image key markers of histological brain factors. Here is a quick description of the method from a primer at our centre’s website:

Anatomical MR imaging has not only become a cornerstone in clinical diagnosis but also in neuroscience research. The great majority of anatomical studies rely on T1-weighted images for morphometric analysis of local gray matter volume using voxel-based morphometry (VBM). VBM provides insight into macroscopic volume changes that may highlight differences between groups; be associated with pathology or be indicative of plasticity. A complimentary approach that has sensitivity to tissue microstructure is high resolution quantitative imaging. Whereas in T1-weighted images the signal intensity is in arbitrary units and cannot be compared across sites or even scanning sessions, quantitative imaging can provide neuroimaging biomarkers for myelination, water and iron levels that are absolute measures comparable across imaging sites and time points.

These biomarkers are particularly important for understanding aging, development, and neurodegeneration throughout the lifespan. Iron in particular is critical for the healthy development and maintenance of neurons, where it is used to drive ATP in glial support cells to create and maintain the myelin sheaths that are critical for neural function. Nutritional iron deficiency during foetal, childhood, or even adolescent development is linked to impaired memory and learning, and altered hippocampal function and structure8,9. Although iron homeostasis in the brain is hugely complex and poorly understood, we know that run-away iron in the brain is a key factor in degenerative diseases like Alzheimer’s and Parkinson’s10–16. Data from both neuroimaging and post-mortem studies indicate that brain iron increases throughout the lifespan, particular in structures rich in neuromelanin such as the basal ganglia, caudate, and hippocampus. In Alzheimer’s and Parkinson’s for example, it is thought that runaway iron in these structures eventually overwhelms the glial systems responsible for chelating (processing) iron, and as iron becomes neurotoxic at excessive levels, leading to a runaway chain of neural atrophy throughout the brain. Although we don’t know how this process begins (scientist believe factors including stress and disease-related neuroinflammation, normal aging processes, and genetics all probably contribute), understanding how iron and myelination change over the lifespan is a crucial step towards understanding these diseases. Furthermore, because VBQ provides quantitative markers, data can be pooled and compared across research centres.

Recently I’ve been doing a lot of work with VBQ, examining for example how individual differences in metacognition and empathy relate to brain microstructure. One thing we were interested in doing with our data was examining if we could follow-up on previous work from our centre showing wide-spread age-related changes in iron and myelination. This was a pretty easy analysis to do using our 59 subjects, so I quickly put together a standard multiple regression model including age, gender, and total intracranial volume. Below are the maps for magnetization transfer (MT),  longitudinal  relaxation  rate (R1),  and  effective  transverse relaxation rate (R2*), which measure brain macromolecules/water, myelination, and iron respectively (click each image to see explore the map in neurovault!). All maps are FWE-cluster corrected, adjusting for non-sphericity, at a p < 0.001 inclusion threshold.

 

Effect of aging on MT
Effect of aging on MT

You can see that there is increased MT throughout the brain, particularly in the amygdala, post central gyrus, thalamus, and other midbrain and prefrontal areas. MT (roughly) measures water in the brain, and is mostly sensitive to myelination and macromolecules such as microglia and astrocytes. Interestingly our findings here contrast to Callaghan et al (2014), who found decreases in myelination whereas we find increases. This is probably explained by differences in our samples.

 

Effect of aging on R1
Effect of aging on R1

R1 shows much more restricted effects, with increased R1 only in the left post-central gyrus, at least in this sample. This is in contrast to Callaghan et al2  who found extensive negative MT & R1 effects, but that was in a much larger sample and with a much wider age-related variation (19-75, mean = 45). Interestingly, Martina and colleagues actually reported widespread decreases in R1, whereas we find no decreases and instead slight increases in both MT and R1. This may imply a U-shaped response of myelin to aging, which would fit with previous structural studies.

Our iron-sensitive map (R2*) somewhat reproduces their effects however, with significant increases in the hippocampus, posterior cingulate, caudate, and other dopamine-rich midbrain structures:

 

Effect of aging on R2*
Effect of aging on R2*

Wow! What really strikes me about this is that we can find age-related increases in a very young sample of mostly UCL students. Iron is already accumulating in the range from 18-39. For comparison, here are the key findings from Martina’s paper:

 

1-s2.0-S0197458014002000-gr2
From Callaghan et al, 2014. Increasing iron in green, decreasing myelin in red.

 

The age effects in left hippocampus are particularly interesting as we found iron and myelination in this area related to these participant’s metacognitive ability, while controlling for age. Could this early life iron accumulation be a predictive biomarker for the possibility to develop neurodegenerative disease later in life? I think so. Large sample prospective imaging could really open up this question; does anyone know if UK Biobank will collect this kind of data? UK biobank will eventually contain ~200k scans with full medical workups and follow-ups. In a discussion with Karla Miller on facebook she mentioned there may be some low-resolution R2* images in that data. It could really be a big step forward to ask whether the first time-point predicts clinical outcome; ultimately early-life iron accumulation could be a key biomarker for neuro-degeneration.

 


References

  1. Gogtay, N. & Thompson, P. M. Mapping gray matter development: implications for typical development and vulnerability to psychopathology. Brain Cogn. 72, 6–15 (2010).
  2. Callaghan, M. F. et al. Widespread age-related differences in the human brain microstructure revealed by quantitative magnetic resonance imaging. Neurobiol. Aging 35, 1862–1872 (2014).
  3. Sala-Llonch, R., Bartrés-Faz, D. & Junqué, C. Reorganization of brain networks in aging: a review of functional connectivity studies. Front. Psychol. 6, 663 (2015).
  4. Sugiura, M. Functional neuroimaging of normal aging: Declining brain, adapting brain. Ageing Res. Rev. (2016). doi:10.1016/j.arr.2016.02.006
  5. Weiskopf, N., Mohammadi, S., Lutti, A. & Callaghan, M. F. Advances in MRI-based computational neuroanatomy: from morphometry to in-vivo histology. Curr. Opin. Neurol. 28, 313–322 (2015).
  6. Callaghan, M. F., Helms, G., Lutti, A., Mohammadi, S. & Weiskopf, N. A general linear relaxometry model of R1 using imaging data. Magn. Reson. Med. 73, 1309–1314 (2015).
  7. Mohammadi, S. et al. Whole-Brain In-vivo Measurements of the Axonal G-Ratio in a Group of 37 Healthy Volunteers. Front. Neurosci. 9, (2015).
  8. Carlson, E. S. et al. Iron Is Essential for Neuron Development and Memory Function in Mouse Hippocampus. J. Nutr. 139, 672–679 (2009).
  9. Georgieff, M. K. The role of iron in neurodevelopment: fetal iron deficiency and the developing hippocampus. Biochem. Soc. Trans. 36, 1267–1271 (2008).
  10. Castellani, R. J. et al. Iron: The Redox-active Center of Oxidative Stress in Alzheimer Disease. Neurochem. Res. 32, 1640–1645 (2007).
  11. Bartzokis, G. Alzheimer’s disease as homeostatic responses to age-related myelin breakdown. Neurobiol. Aging 32, 1341–1371 (2011).
  12. Gouw, A. A. et al. Heterogeneity of white matter hyperintensities in Alzheimer’s disease: post-mortem quantitative MRI and neuropathology. Brain 131, 3286–3298 (2008).
  13. Bartzokis, G. et al. MRI evaluation of brain iron in earlier- and later-onset Parkinson’s disease and normal subjects. Magn. Reson. Imaging 17, 213–222 (1999).
  14. Berg, D. et al. Brain iron pathways and their relevance to Parkinson’s disease. J. Neurochem. 79, 225–236 (2001).
  15. Dexter, D. T. et al. Increased Nigral Iron Content and Alterations in Other Metal Ions Occurring in Brain in Parkinson’s Disease. J. Neurochem. 52, 1830–1836 (1989).
  16. Jellinger, P. D. K., Paulus, W., Grundke-Iqbal, I., Riederer, P. & Youdim, M. B. H. Brain iron and ferritin in Parkinson’s and Alzheimer’s diseases. J. Neural Transm. – Park. Dis. Dement. Sect. 2, 327–340 (1990).

 

In defence of preregistration

Psychbrief has a great rebuttal to a recent paper arguing against pre-registration. Go read it!

PsychBrief

This post is a response to “Pre-Registration of Analysis of Experiments is Dangerous for Science” by Mel Slater (2016). Preregistration is stating what you’re going to do and how you’re going to do it before you collect data (for more detail, read this). Slater gives a few examples of hypothetical (but highly plausible) experiments and explains why preregistering the analyses of the studies (not preregistration of the studies themselves) would not have worked. I will reply to his comments and attempt to show why he is wrong.

Slater describes an experiment where they are conducting a between groups experimental design, with 2 conditions (experimental & control), 1 response variable, and no covariates. You find the expected result but it’s not exactly as you predicted. It turns out the result is totally explained by the gender of the participants (a variable you weren’t initially analysing but was balanced by chance). So…

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Neurovault: a must-use tool for every neuroimaging paper!

Something that has long irked me about cognitive neuroscience is the way we share our data. I still remember the very first time I opened a brain imaging paper and was struck dumbfounded by the practice of listing activation results in endless p-value tables and selective 2D snapshots. How could anyone make sense of data this way? Now having several years experience creating such papers, I am only more dumbfounded that we continue to present our data in this way. What purpose can be served by taking a beautiful 3-dimensional result and filtering it through an awkward foci ‘photoshoot’? While there are some standards you can use to improve the 2D presentation of 3D brain maps, for example showing only peak activation and including glass-brains, this is an imperfect solution – ultimately the best way to assess the topology of a result is by directly examining the full 3D result.

Just imagine how improved every fMRI paper would be, if instead of a 20+ row table and selective snapshot, results were displayed in a simple 3D viewing widget right in the paper? Readers could assess the underlying effects at whatever statistical threshold they feel is most appropriate, and PDF versions could be printed at a particular coordinate and threshold specified by the author. Reviewers and readers alike could get a much fuller idea of the data, and meta-analysis would be vastly improved by the extensive uploading of well-categorized contrast images. More-over, all this can be easily achieved while excluding worries about privacy and intellectual property, using only group-level contrast images, which are inherently without identifying features and contain only those effects included in the published manuscript!

Now imagine my surprise when I learned that thanks to Chris Gorgolewksi and colleagues, all of this is already possible! Chris pioneered the development of neurovault.org, an extremely easy to use data sharing site backed by the International Neuroinformatics Coordinating Facility. To use it, researchers simply need to create a new ‘collection’ for their study and then upload whatever images they like. Within about 15 minutes I was able to upload both the T- and contrast-images from my group level analysis, complete with as little or as much meta-data as I felt like including. Collections can be easily linked to paper DOIs and marked as in-review, published, etc. Collections and entries can be edited or added to at any time, and the facilities allow quick documentation of imaging data at any desired level, from entire raw imaging datasets to condition-specific group contrast images. Better still, neurovault seamlessly displays these images on a 3D MNI standard brain with flexible options for thresholding, and through a hookup to neurosynth.org can even seamlessly find meta-analytic feature loadings for your images! Check out these t-map display and feature loadings for the stimulus intensity contrast for my upcoming somatosensory oddball paper, which correctly identified the modality of stimulation!

T-map in the neurovault viewer.
T-map in the neurovault viewer.
Decoded features for my contrast image.
Decoded features for my contrast image, with accurate detection of stimulation modality!

Neurovault.org doesn’t yet support embedding the viewer, but it is easy to imagine that with collaboration from publishers, future versions could be embedded directly within HTML full-text for imaging papers. For now, the site provides the perfect solution for researchers looking to make their data available to others and to more fully present their results, simply by providing supplementary links either to the neurovault collection or directly to individual viewer results. This is a tool that everyone in cognitive neuroscience should be using – I fully intend to do so in all future papers!