Blog

Magnetic Resonance Elastography

The elastic properties of human tissues have been evaluated in a clinical setting by palpation. Although this procedure has often helped clinical diagnosis, it is a subjective procedure and cannot be quantified.

More recently a quantifiable technique has been developed using imaging technologies such as  MRI, Ultrasound, Optical Imaging and so forth, whereby the degree of elasticity can be observed has hard data after administering vibrations to the tissue.

For the brain, the preferred technology has been MRI . Vibrations of 60 Hz have been applied at the base of the brain and elastic properties then measured. We can envision a wide range of applications of this technique for the brain, including but not limited to: Alzheimer’s disease, Brain Tumours, Multiple Sclerosis, and Stroke. The vibratory frequency used seems to be safe and unable to produce damage such as the rupture of brain vessels.

In my opinion this technique can be very useful for the differential diagnosis of brain disorders in conjunction with the already known anatomical information that  MRI can provide.

This is a good paper on the subject:

Mariappan YK, etc al. Magnetic Resonance Elastography: A Review. Clinical Anatomy, 2010, 23: 497-11.

 
Adolfo Cotter, MD

Nov 28/2010

Imaging Genetics

Imaging genetics has been focused so far in imaging the phenotype. Most of the research done has been related to human behavior.  The phenotype constitutes the biological basis of the clinical manifestation of the specific gene. For example, we could image brain circuitry by using MRI in order to understand the biological basis of schizophrenia and its relation to the genotype. After the circuit has been understood, we can perform statistical analysis between these findings and the clinical manifestations. We have to understand that phenotype is also related to non-genetic factors such as: diet, age, smoking habits, sleep, medications, etc. We have to include those as covariates when we perform”the statistical analysis.

In my opinion imaging genetics might include not only phenotype imaging but also genetic imaging itself such as with MRI Spectroscopy.   Other areas besides behavior will most likely be explored in the future 

This is a good article related to this topic:

Bigos KL, Weinberg DR. Imaging Genetics- days of future and””past.  NeuroImage. 2010; 53:  804-809.

Adolfo Cotter, MD

Oct 21/2010

Mapping the Mind

As I mentioned on previous blog entries, I believe the brain and the mind overlap to some degree but also there should be a free brain area without mind and a free mind area without brain. Because our medications act on the brain but not on the mind itself, our knowledge of this interface is most useful to treat psychological and psychiatric conditions, in my opinion.

The Allen Brain Science Institute has identified over 20,000 genes responsible of brain activity and has created an atlas. Having this important knowledge, the next step would be to understand the effect and the functioning of these genes. Imaging studies such as fMRI and  MRI Spectroscopy could help understand these cellular processes by evaluating brain function and brain chemistry.

The NIH has started working on the Human Connectome Project looking for brain circuitry. In my opinion, understanding the brain circuitry related to mental processes and states as well as the cellular mechanisms involved, will help us develop drugs that will target more specifically mental activity with less side effects. Also, if we apply Pharmacogenomics to psychiatric medications, we will be able to more efficiently treat psychiatric conditions.

An interesting paper related to this topic is the following:

Jones, AR, etal, Mapping The Mind, Scientific American Mind, September/October 2010, pp 57 – 63.

Adolfo Cotter, MD

Oct 14/2010

Measures of Cortical Brain Thickness

Anatomical MRI measures of cortical brain thickness have been recently evaluated. In normal aging there is a decrease in cortical thickness, which presents an anterior-posterior gradient, being more prominent in Frontal and Parietal than in Temporal and Occipital lobes. There are regional differences between both sexes. In Alzheimer’s disease the reduction in cortical thickness is significantly greater. The sensitivity of AD diagnosis by measurements of cortical thickness is close to 90%, which is higher than with other anatomical measures. In early AD the regions affected are usually medial temporal lobe regions, such as: the hippocampus and entorhinal cortices.

In my opinion, if we combine these anatomical MRI measures with functional ones such as with PET or SPECT, we should obtain higher sensitivity values approaching 100%. This is because anatomical and functional measures are usually synergistic.

The following is a good paper related to this subject:

Thambisetty M, etal., Longitudinal changes in cortical thickness associated with normal aging, NeuroImage, 52 (2010) 1215-1223.

Adolfo Cotter, MD

Aug 16/2010

Nanoantibodies

Nanoantibodies also known as nanobodies, have advantage over full size antibodies that they are more stable, aggregate less, and they can penetrate very small locations. There are currently attempts to make them cross the blood brain barrier ( BBB ). An idea that I suggest is to bind a nanobody to a nanoparticle, so the nanoparticle can help them cross the BBB. I think this is doable and I invite interested scientists to try it.

They also show very good specificity, which can be useful to treat cancer for example. One of the problems with chemotherapy for cancer is its lack of specificity, and in consequence it shows many side effects. Other therapeutic applications that look promising are: Alzheimer’s disease by targeting amyloid plaques, and Parkinson’s disease by targeting alpha-synuclein. 

They also seem useful for molecular imaging as a probe for PET or SPECT. They seem to show a good uptake. A good paper in the topic is the following:

Dmitrov DS, Engineered CH2 domains (nanoantibodies), MAbs 2009 Vol 1 Issue 1 26-28

Adolfo Cotter, MD

Aug 08/2010

Longevity and Genomics

Methylation/demethylation of DNA  and/or histones, acethylation/deacethylation of histones and shortening of telomeres appear to be some of the epigenetic factors controlling gene expression over time. The epigenetic control mechanism is affected by the environment and seems to become progressively relaxed or disrupted as we age. Because of this disruption illnesses of aging can appear, including cancer. In fact, aging is one of the highest risk factors for cancer. Because cancer involves an uncontrolled cell replication, senescence of replication might appear as a compensatory mechanism. This seems to be at least partially mediated through changes in telomeres.

In a previous blog entry I mentioned that life events can change gene expression. The mechanism could be the one explained here. Because of this interaction with the environment, in my opinion, it seems that the control mechanism might respond to drug manipulations or specific changes in the environment. By doing this we could hope to delay or even stop the aging process and its consequences. One of the difficulties for doing this is the heterogeneity in different cells. There seems not to be a uniform response to epigenetic manipulations, and each cell seems to behave differently. A good paper in this topic is the following:

Gravina Silvia, etal, Epigenetic factors in aging and longevity, Pflugers Arch- Eur J Physiol 2010 459: 247-258

Adolfo Cotter, MD

Jul 26/2010

Selective Plane Illumination Microscopy

This new technique has the advantage of visualizing in vivo tissues, in real time and at very high resolution. It can visualize cellular events that have fluorescence. It is technically very similar to fluorescence microscopy, but the beam of light comes from the side, thereby generating a selective plane illumination that is captured by a widefield microscope. It shows high tissue penetration, high sensitivity, low bleaching, and especially fast acquisition times. This is particularly useful for long studies. One significant drawback so far is that this technique has difficulties with large structures.

In my opinion Selective Plane Illumination Microscopy is particularly useful in time-consuming studies and presents an advantage over MSOT in those cases. Also, it can potentially quantify cellular events. The following is a good paper on the topic:

Huisken J, etal., Selective plane illumination microscopy techniques in developmental biology, Development 136, 2009, 1963-1975

Adolfo Cotter, MD

Jul 14/2010

Nanoparticles (NPs)

Nanotechnology has made possible the production of Nanoparticles. NPs can be made of different materials such as ceramics, carbon and various metals. It also can take different shapes. They can be used in imaging and also to transport drugs. They can be widely used in imaging but in the case of Brain Imaging, its main use is to facilitate the passage of a tracer or drug across the blood brain barrier BBB. The basic mechanism of action is that the NPs bind to a receptor at the surface of the cell and the whole structure (NPs+tracer or NPs+drug) is transported by endocytosis and then released to the brain. NPs can be also targeted to specific molecules. In the case of tumors there is an extra advantage since the vascular leakage is higher and the lymphatic drainage is impaired, which promotes accumulation of the NPs.

In my opinion, Nanoparticles are a new technology with great promise, since imaging and drug delivery to the brain has long been hampered by the problem of BBB impermeability. Many drugs and tracers with great potential usefulness have had to be discarded in the past because they were unable to reach their target due to BBB impermeability. Hopefully this will no longer be a problem when using NPs in many instances. The following is a good paper on the topic:

Provenzale, JM etal., Uses of Nanoparticles for Central Nervous System  

Imaging and Therapy, Am J Neuroradiol 2009 Aug 30(7) 1293-301.

Adolfo Cotter, MD

Jul 05/2010

Multispectral Optoacustic Tomography (MSOT)

MSOT uses the photoacoustic principle I explained in a previous blog entry. With this technique one is able to visualize in vivo cellular events with high sensitivity, at a resolution of 100 micrometers. It has a big advantage of being able to visualize physiology and anatomy at the same time without combining two different technologies. It is also a portable technique. It can be used for molecular imaging, biomarkers, and it allows the use of contrast agents. It is currently used in small animal imaging and it can be very helpful in studies of drug development.

Its usefulness is however limited by its inability to penetrate tissue as well some other older technologies such as PET.

In my opinion this is new and revolutionary technology because of its high resolution and the ability to evaluate in vivo processes. It will be very useful in evaluating the mechanism of action of a drug, side effects of a drug in detail, pharmacodynamics, etc.

A good paper in this topic is-

Ntziachristos, V etal. Molecular Imaging by means of Mutispectral Optoacustic Tomography (MSOT); Chem Rev 2010, 110, 2783-2794

Adolfo Cotter, MD

Jun 27/2010

Microscopic Diffusion Tensor Imaging

Resolution is always a limitation when detailed analysis of the brain anatomy is needed. A partial solution for this problem is the use of Microscopic Diffusion Tensor Imaging.

Diffusion Tensor Imaging (DTI) is an MRI technique that displays the white matter tracts by using the diffusion of water as a technique. The applicability of this technique can be to build a detailed anatomical atlas of brain connectivity or the analysis of brain connectivity in pathological states. In my opinion, we would be able at some point to characterize some brain diseases by connectivity abnormalities, and DTI can be a test for those conditions. The problem I see is lack of resolution, and this can be overcome by the use of microscopy. On the other hand microscopic DTI uses in vitro specimens, so the microscopic test would be used for research applications and possible as a test used in autopsy. Microscopy increases resolution, but scanning time although long, it is being shortened by acquisition and processing techniques, such as- dynamic image acquisition and automated registration. Here is a good paper on this topic:

Jiang Yi, Microscopic diffusion tensor imaging of the mouse brain, NeuroImage, 50, 465-471.

Adolfo Cotter, MD

Jun 17/2010