Vitamin D has been called the “miracle vitamin” by many health experts due to mounting discoveries of its significance in promoting health and fighting numerous diseases, including cancer, heart disease, and diabetes. It may also be therapeutic for neurodegenerative diseases, which may be relevant to Huntington’s disease (HD). This particular vitamin is found in many food sources, including milk, eggs, and fish, and it can also be produced by the skin through sunlight exposure. While vitamin D is widely known for its role in maintaining strong and healthy bones by helping the body absorb calcium, it is much more than a bone-protecting vitamin. Research for the past few decades has shed light on the protective effects of vitamin D on immune and neural cells and has implicated a deficiency of vitamin D as a risk factor for various brain diseases. This article will focus primarily on a form of vitamin D called vitamin D3, also known as cholecalciferol, and how the vitamin may be protective against neurodegenerative diseases such as HD.
What is vitamin D?^
The term “vitamin D” actually refers to a group of fat-soluble vitamins. There are five different forms of vitamin D, but the two major forms are vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). Vitamin D2 is produced by plants, while vitamin D3 is produced by the skin of animals in response to sunlight (UV light) exposure. UV light reacts with an enzyme called 7-dehydrocholesterol to create pre-vitamin D, which rearranges its structure to form vitamin D3. An enzyme then converts vitamin D3 into a compound called calcitriol, which is the active form of vitamin D that is responsible for the numerous health benefits.
What is its mechanism of action?^
After its conversion from Vitamin D3, calcitriol exerts its effects on the body by binding to and activating vitamin D receptors (VDRs), which are located in the nuclei of target cells. Once activated, VDRs can function as transcription factors that bind to cellular DNA and control gene expression, ultimately triggering a biological response.
The major physiological role of vitamin D is to facilitate the intestinal absorption of calcium, by stimulating the expression of proteins involved in calcium transport. Vitamin D also plays a crucial role in providing the proper balance of minerals necessary for bone growth and function. However, it turns out that VDRs are present in the cells of most organs in the body, suggesting that there is wide diversity in the types of responses that vitamin D3 can promote.
Vitamin D3 and the brain^
Initially it was believed that only the liver and kidneys contained the enzyme responsible for producing calcitriol from vitamin D3. It is now known that many tissues, including the brain, contain this enzyme. In addition, VDRs are widely present throughout the brain, implicating vitamin D3 as a contributor to a variety of neural processes. Several of these processes are thought to be neuroprotective.
Studies have indicated that calcitriol may possess antioxidant properties and also strengthens the role of existing antioxidants in the body. For instance, Garcion et al. (1997) demonstrated that calcitriol acts similarly to traditional antioxidant nutrients by inhibiting an enzyme called inducible nitric oxide synthase (iNOS), which is overactive in patients with Alzheimer’s and Parkinson’s disease. Baas et al. (2000) showed that calcitriol increases levels of glutathione, a natural antioxidant which protects oligodendrocytes, which are brain cells that provide support and insulation for neurons.
Calcitriol can also protect neurons by producing neurotrophins, including neurotrophin-3 (NT-3), glial cell derived neurotrophic factor (GDNF), and nerve growth factor (NGF) that promote the survival of neurons in aging and with neurological injury. As shown in studies by Naveilhan et al. (1993) and Neveu et al. (1994), calcitriol increases levels of GDNF and NT-3. NT-3 protects nerve transmission and synaptic plasticity, and GDNF influences the survival and differentiation of dopamine-producing cells. In animal models of Parkinson’s disease, treatment with calcitriol increased GDNF levels and reduced oxidative stress (Wang et al., 2001). On the other hand, in newborn rodents, depleting vitamin D3 while they were in their mother’s uterus reduced levels of GDNF and NGF and caused damaging structural brain changes (Becker et al., 2005). (To read more about neurotrophins, click here.)
Vitamin D3 and neurodegenerative disorders^
While there has not been much research focused on its potential role in HD, vitamin D3 deficiency has been implicated as serving a role in a number of neurodegenerative disorders.
For instance, there is compelling evidence that low levels of vitamin D3 are a risk factor for multiple sclerosis (MS), a disease in which the immune system attacks the central nervous system and causes demyelination and axon degeneration. The prevalence of MS is linked with decreasing exposure to solar UV radiation, and a study by Munger et al. suggests that high circulating levels of vitamin D3 correspond to a lower risk of MS.
There is also evidence that vitamin D3 deficiency is relevant for Parkinson’s disease and Alzheimer’s disease. The greatest number of VDRs are found in the substantia nigra, the portion of the brain that primarily degenerates in Parkinson’s disease and can also be affected in HD. Treating substantia nigra neurons with vitamin D3 protects them from Parkinson-like insults (Shinpo et al., 2000). In Alzheimer’s disease, a condition characterized by dementia and neuron loss in the hippocampus, some evidence suggests that there may be a vitamin D3 deficiency early in the disease (Landfield et al., 1991), and, in aging rats, treating with calcitriol reduced hippocampus shrinkage and prevented decreases in neuron density (Landfield and Cadwallader-Neal, 1998). Although more extensive research into this area is needed, these results suggest that vitamin D3 could have a potential role in the prevention of neurodegenerative disorders.
Despite the many exciting findings about this “miracle vitamin” over the years, determining the many health benefits of vitamin D3 is still an active area of research. While the extent to which vitamin D3 contributes to neural processes is not clearly understood, there is currently much evidence to support a neuroprotective role for vitamin D3 in the brain, as well as promising evidence that it may have preventative effects against neurodegenerative disorders.
Baas, D et al. “Rat oligodendrocytes express the vitamin D(3) receptor and respond to 1,25-dihydroxyvitamin D(3).” Glia 31.1 (2000): 59–68. Print.
Becker, Axel et al. “Transient prenatal vitamin D deficiency is associated with subtle alterations in learning and memory functions in adult rats.” Behavioural brain research 161.2 (2005): 306–312.
Garcion, E et al. “1,25-Dihydroxyvitamin D3 inhibits the expression of inducible nitric oxide synthase in rat central nervous system during experimental allergic encephalomyelitis.” Brain research. Molecular brain research 45.2 (1997): 255–267. Print.
Landfield, P W et al. “Phosphate/calcium alterations in the first stages of Alzheimer’s disease: implications for etiology and pathogenesis.” Journal of the neurological sciences 106.2 (1991): 221–229. Print.
Landfield, P W, and L Cadwallader-Neal. “Long-term treatment with calcitriol (1,25(OH)2 vit D3) retards a biomarker of hippocampal aging in rats.” Neurobiology of aging 19.5 (1998): 469–477. Print.
Naveilhan, P et al. “Expression of 25(OH) vitamin D3 24-hydroxylase gene in glial cells.” Neuroreport 5.3 (1993): 255–257. Print.
Neveu, I et al. “1,25-dihydroxyvitamin D3 regulates NT-3, NT-4 but not BDNF mRNA in astrocytes.” Neuroreport 6.1 (1994): 124–126. Print.
Shinpo, Kazuyoshi et al. “Effect of 1,25-dihydroxyvitamin D3 on Cultured Mesencephalic Dopaminergic Neurons to the Combined Toxicity Caused by L-buthionine Sulfoximine and 1-methyl-4-phenylpyridine.” Journal of Neuroscience Research 62.3 (2000): 374–382. Web. 7 Apr. 2013.
Wang, J Y et al. “Vitamin D(3) attenuates 6-hydroxydopamine-induced neurotoxicity in rats.” Brain research 904.1 (2001): 67–75. Print.
J. Nguyen 2013 More
Neuroimaging refers to techniques that produce images of the brain without requiring surgery, incision of the skin, or any direct contact with the inside of the body. Because these technologies enable noninvasive visualization of the structure and functionality of the brain, neuroimaging has become a powerful tool for both research and medical diagnosis. Although still relatively young, the field of neuroimaging has rapidly advanced over the years due to breakthroughs in technology and computational methods. Applications of neuroimaging techniques have likewise become far-reaching.
This article will cover three of the most common techniques in neuroimaging: computerized tomography (CT), functional magnetic resonance imaging (fMRI), and positron emission tomography (PET). You will likely come across at least one of these techniques while reading about Huntington’s disease (HD) news and research. For each technique, the article will discuss its working mechanism, its pros and cons, and its relevance to HD.
Computerized tomography (CT)
Computerized tomography (CT) is a medical imaging procedure that uses x-rays to generate detailed pictures of structures inside the body. It has become a valuable tool for medical diagnosis and for planning, guiding, and monitoring therapy.
A CT scan of a human brain. (Source: Aaron G. Filler, MD, PhD)
How CT works
A CT scan uses X-rays positioned at different angles to create cross-sectional images of the brain. During a CT scan, a movable X-ray source is rotated around the patient’s head. Detectors record information about the intensity of the rays transmitted through the head at each angle, which is sort of like taking a series of two-dimensional snapshots. The computer then uses an algorithm to combine all the individual snapshots from different axes of rotation of the source together and to reconstruct them into a 3-D, cross-sectional image. By allowing doctors and researchers to view the full volume of the head, CT scans can provide much more information about the brain than traditional X-ray scans, which only offer a two-dimensional representation of the brain.
Advantages and Disadvantages of CT
CT scans are painless, fast, and cost-effective. CT can image bone, blood vessels, and soft tissue simultaneously and provides very detailed images of many types of tissue. There are, however, several risks associated with the use of CT. The main risks, according to the US Food and Drug Administration, are:
- An increased lifetime risk of cancer due to x-ray radiation exposure
- Possible allergic reactions or kidney failure due to contrast agent, or “dye” that may be used in some cases to improve visualization
- The need for additional follow-up tests after receiving abnormal test results or to monitor the effect of a treatment on disease
You and your physician should decide whether or not the benefits of getting the added information from a CT scan outweigh the possible risks.
CT and Huntington’s disease
CT cannot by itself be used to diagnose HD, since other disorders or conditions can result in similar anatomical change in the brain; often it is used along with family history and medical records in order to provide a more detailed diagnosis. (The same is true of MRI scans, which will be discussed in the upcoming section.) Doctors use CT (or MRI) to evaluate a patient with HD by checking for characteristic degeneration in the brain and ruling out other possible disorders. A CT scan for a patient in the early stages of HD may appear normal, but a CT scan for a patient in advanced stages of the disease can often reveal significant degeneration – specifically, reduction in volume of certain regions of the basal ganglia.
Functional Magnetic Resonance Imaging (fMRI)
Functional magnetic resonance imaging (fMRI) is a specialized form of MRI that indirectly provides information on brain activity by measuring changes in blood flow in the brain.
An fMRI scan of a human brain. (Public domain)
How MRI works
A traditional MRI scanner contains a very strong electromagnet, which generates a strong magnetic field inside the scanner. When turned on, this causes randomly spinning protons, or positively charged particles, in the brain (in this case hydrogen protons from water molecules) to align themselves with the direction of the field. (Think of how a compass needle at rest is aligned with the Earth’s magnetic field, which is why it always points north.) However, the protons still spin while in alignment in the field, and the axis of their spin isn’t perfectly parallel to the direction of the field – rather, the protons behave like wobbling tops. The rate at which the protons wobble is called resonance.
We can also think of resonance as the ability of a system to absorb energy delivered at a particular frequency. To illustrate this concept, imagine that you are pushing a small child on a playground swing. If you push the child too quickly or too slowly, the child won’t rise very high. But if you give the child enough pushes at just the right frequency, the child will rise to the maximum height attainable due to the energy you have provided by pushing. This frequency is called the resonant frequency of the swing, which is the rate at which the swing will naturally oscillate. The swing absorbs the most energy when it is pushed at exactly this frequency. Similarly, protons placed in a strong magnetic field will efficiently absorb energy when the energy is delivered at a particular resonant frequency, namely the rate of “wobbling.” In the case of MRI, radio waves provide the “push” necessary to move the protons.
During a process called excitation, the MRI scanner emits energy in the form of radio waves at precisely the resonant frequency of protons. These radio waves knock the protons out of alignment, causing them to flip and spin on their opposite ends. In order to flip over, the protons have to absorb some energy from the radio waves. When the radio signal is turned off, the protons flip back around to their original alignment, and in the process release the energy they have absorbed. This released energy is called the MR (magnetic resonance) signal and can be measured by electromagnetic detectors around the subject. A computer receives the MR signals as mathematical data and compiles them into an image.
Although fMRI uses the same principles as MRI, there is one important distinction. MRI (often called structural MRI) reveals brain anatomy, while fMRI reveals brain function, often in the form of neural activity. For this reason, fMRI is very useful for neuroscience and clinical research, while MRI is traditionally used for clinical characterization in the same manner as CT scans.
However, fMRI doesn’t reveal neural activity directly. Recall that when neurons are active, they fire action potentials and send messages in the form of neurotransmitters to other neurons. (To read more about this, click here.) While other imaging methods such as EEG (electroencephalography) can measure this activity directly, they often come with severe limitations such as poor spatial resolution. Instead, fMRI studies neural activity indirectly by measuring the BOLD (Blood Oxygenation Level Dependent) signal. This method is based on the fact that hemoglobin carrying a bound oxygen molecule (oxyhemoglobin) in the bloodstream emits a different MR signal than oxygen-depleted hemoglobin (deoxyhemoglobin). When parts of the brain become active, such as when a person is carrying out a cognitive task, they use up more oxygen than relatively inactive parts of the brain. You might think that this would result in a relative decrease in the level of oxygen in the active areas compared to the inactive areas, but actually the reverse happens! Because oxygen is being depleted, the brain compensates for the loss by increasing the flow of oxygenated blood to the active area. There is a slight overcompensation, which causes an increased oxyhemoglobin to deoxyhemoglobin ratio. As this ratio increases, the BOLD signal gets stronger. Essentially the BOLD signal measures the ratio of oxyhemoglobin to deoxyhemoglobin in the brain, which enables researches to indirectly gauge neural activity: higher neural activity = higher oxyhemoglobin to deoxyhemoglobin ratio = stronger BOLD signal.
Advantages and Disadvantages of fMRI and MRI
MRI and fMRI both involve no radiation, and there are no known side effects caused by the magnetic fields and radio waves. The main risk with MRI is that the presence of metal in the body (such as pacemakers or other implants) can be a safety hazard. fMRI is also relatively inexpensive, non-invasive, widely available, and provides excellent spatial resolution and good temporal resolution. Largely because of these factors, fMRI has come to predominate in the field of neuroimaging research.
fMRI and Huntington’s Disease
Use of fMRI or MRI scans in HD patients sometimes requires sedation since both techniques require remaining extremely still and the results can be ruined by small movements. It is thought that fMRI can potentially be used as an indicator, or imaging biomarker, of early neuronal dysfunction in individuals before the onset of HD (a stage called pre-HD). A 2004 study conducted with pre-HD patients demonstrated that fMRI could detect abnormalities in brain activity more than 12 years before the estimated onset of motor systems (Paulsen et al). fMRI was also able to distinguish differences between patients closer to estimated onset and patients further away from estimated onset. These results suggest that fMRI may be useful for tracking changes in neural function during the early stages of pre-HD, and could improve the prediction of when HD manifests in an individual. The study also suggests that fMRI can be helpful in determining the optimal time frame of treatments aimed at slowing down the progression of HD. However, further research is required to determine whether the potential of fMRI technology will be realized.
Positron Emission Tomography (PET)
Positron emission tomography is a technique that uses radioactively labeled molecules (called tracers) that are injected into the bloodstream and taken up by active neurons. PET studies blood flow and metabolic activity in the brain and helps visualize biochemical changes that take place. Essentially, PET indicates how well the brain is functioning.
A PET scan of a human brain. (Public domain)
How PET works
The scanner consists of a ring of detectors that surround that subject. Detectors contain crystals that scintillate (give off light) in response to gamma rays, which are extremely high-energy rays of light. Each time a crystal in a detector absorbs a gamma ray is called an event. When two detectors exactly opposite from each other on the ring simultaneously detect a gamma ray, a computer hooked up to the scanner records this as a coincidence event. A coincidence event represents a line in space connecting those two detectors, and it is assumed that the source of the two gamma rays lies somewhere along that line. The computer records all of the coincidence events that occur during the imaging period and then reconstructs this data to produce cross-sectional images.
The tracer is usually a substance, such as a type of sugar like glucose, that can be broken down (metabolized) by cells in the body, and it is labeled with a radioactive isotope. There is minimal risk involved since the dose of radiation is low and the isotope is quickly eliminated from the body through urination. After it has been injected into the bloodstream, the isotope, which is very unstable, starts to decay, becoming less radioactive over time. In the process it emits a positron (a positively charged electron). When a positron collides with an electron, the two particles annihilate each other, producing two gamma rays with the same energy but traveling in opposite directions. These gamma rays leave the subject’s body and are sensed by two detectors positioned 180 degrees from each other on the scanner, which gets recorded as a coincidence event. A computer can determine where the gamma rays came from in the brain and generate a three-dimensional image.
As blood is more concentrated in activated brain areas than in inactivated ones, the scanner will detect more gamma rays coming from parts of the brain that are working harder. On a PET scan regions of the brain show up as different colors depending on the degree of activity in those regions. Yellow and red regions are “hot” and indicate high brain activity, while blue and black regions indicate little to no brain activity.
The brain function measured by a PET scan varies according to the type of radioisotope that is used. For instance, oxygen-15 is used to study oxygen metabolism in the brain. FDG, which is fluorine-18 attached to a glucose molecule, is used to study sugar metabolism in the brain. Many more radioisotopes exist, and which one is chosen for a specific PET scan depends on what type of brain function a researcher desires to study.
Advantages and Disadvantages of PET
PET, unlike other imaging tests, is able to detect irregularities in body function caused by disease, which often occur before anatomical changes become observable. The quality of a PET scan is not affected by small movements, so the subject does not have to remain as still for a PET scan as they would for a fMRI or MRI scan, both of which can be ruined by small movements.
A main setback to PET is that it affords relatively poor spatial resolution, so the images may not be very clear. Due to this, it is common for PET to be used together with CT or fMRI. In addition, the use of radiation, even in a small dose, always involves a slight risk.
PET and Huntington’s disease
PET scans are sometimes ordered by physicians as a follow-up to a CT or MRI scan in order to reveal any irregularities in brain processes. They can be used as part of a more detailed diagnosis for HD, as well as in research related to abnormalities in metabolism and progression of the disease. Nowadays PET scans are often combined with CT scans to provide images that pinpoint the location of abnormal activity within the brain; combined, these scans provide more accurate diagnoses than either performed alone.
CT, fMRI/MRI, and PET are three of the most popular techniques currently used for neuroimaging. Each method comes with its own advantages as well as its own risks and disadvantages. While neuroimaging is still a fairly new development in medicine and neuroscience, the discipline will likely continue expanding in the future, and will continue to provide valuable clinical applications and scientific insights about the brain.
Paulsen JS, Zimbelman JL, Hinton SC, Langbehn DR, Leveroni CL, Benjamin ML, Reynolds NC, Rao SM. fMRI biomarker of early neuronal dysfunction in presymptomatic Huntington’s Disease. AJNR Am J Neuroradiol. 2004 Nov-Dec;25(10):1715-21.
FAQ about getting CT scans
A more detailed explanation of how MRI works
Additional information about fMRI
FAQ about getting PET/CT scans
J. Nguyen 4.9.12 More
Recent research has spotlighted retinoic acid (RA) as an intriguing possibility for further exploration as a treatment for Huntington’s disease. Retinoic acid is derived from a compound that we know as Vitamin A, which is fat-soluble and primarily found in two forms: retinol and carotenoids. Retinoic acid is synthesized in the body from retinol, which is derived from a precursor found in animal foods such as milk and eggs. Once in the body, the precursor is converted to retinol, which then undergoes a series of reactions to form RA.
Retinoic acid is a biological molecule that regulates gene expression throughout the body and is crucial for cell differentiation and proliferation. These functions of RA have made it a useful treatment for skin diseases and cancer. In addition to the body, RA may regulate the expression of many proteins in the brain. Most proteins in the RA signaling pathway have been identified in the brain, including many that are adversely affected in HD. Nevertheless, little is currently known about where RA acts in the brain, what specific proteins it affects, or how its signaling relates to brain function, so much work still needs to be done to identify RA’s functions.
RA Signaling and Function
Some evidence suggests that RA may play a role in gene transcription and cell differentiation. RA binds to specialized receptors in the cell nucleus, where transcription takes place, and can activate a large number of molecules within the cell. These molecules include enzymes, transcription factors, and inflammatory agents (i.e. cytokines and cytokine receptors), all of which are important in regulating crucial biological functions. RA may, for instance, send a signal that causes stem cells to become neurons. In fact the compound has been used in research for years, as a differentiation agent that can produce many types of early neural cells. When RA is absent, its receptors can also act as gene repressors, turning off gene transcription and thus inhibiting certain functions.
RA was first recognized as a key mediator of early development. It forms a concentration gradient across developing embryonic tissues and thereby governs the pattern of gene expression. This pattern regulation promotes development of different parts of the body depending on what genes are switched on. This property of RA was demonstrated by an experiment conducted on tadpole embryos. In this experiment, researchers noticed that concentrations of RA were much higher in the posterior (back or tail) end of the tadpole embryo than in the anterior (front or head) end. They exposed the embryo to elevated RA, and as a result, certain structures in the anterior end (such as the brain) failed to develop properly. This finding implied that different parts of the embryo required different amounts of RA, and receiving more or less than the required amount interfered with vital developmental processes (Altaba & Jessell, 1991).
It was later discovered that RA acts in a similar fashion in the adult brain, in which gene transcription is also controlled through varying RA concentrations. Several important functions found to be regulated by the RA pathway include spatial learning, long-term potentiation (LTP), synaptic plasticity, and nerve regeneration.
Implications for HD
RA may play a role in motor disorders such as Parkinson’s disease (PD) and HD since it is involved in the function of the striatum, a brain structure involved in planning and execution of movement and that undergoes cell death in HD. RA promotes neuron formation and differentiation in the striatum, which receives RA from the substantia nigra, a midbrain structure that is also important for motor planning. Neurons in the substantia nigra express high levels of an enzyme that catalyzes RA synthesis. This enzyme travels along the neurons extending from the substantia nigra to the striatum, where it can help generate RA. In studies of HD transgenic mice, it was found that more than 20% of the genes in the striatum that showed diminished expression contained elements of the RA signaling pathway. This result could suggest that some type of defect in the RA pathway contributes to HD. Further research is needed to determine whether a defective RA pathway could relate to HD motor symptoms.
Several discoveries suggest that RA may be able to treat key pathological symptoms of HD, making it a candidate therapeutic for the disease. For instance, huntingtin aggregates, which form in the brains of HD patients, interfere with RA signaling. These aggregates disrupt the activity of a protein called PGC1-alpha, which in turn disturbs the protein PPAR-delta, which mediates cellular responses to RA. PPAR-delta function is significantly diminished in HD mouse models, implicating PPAR-delta in the pathology of the disease. (You can read more about this study here). Drugs that target the RA signaling pathway are currently on the market to treat tumors and cancers such as leukemia. Further investigation of RA and the RA signaling pathway could open the door to a potential treatment for HD, maybe by enhancing the retinoic acid pathway through PPAR-delta. Proof of such a hypothesis remains a topic of developing preliminary research.
For Further Reading
Altaba, A. Ruiz i, and T. Jessell. “Retinoic acid modifies mesodermal patterning in early Xenopus embryos.” Genes & Development 5 (1991): 175-187. This study has a lot of technical language, but most of the key points have been summarized above in the RA Signaling and Function section.
Duester, Gregg. “Retinoic Acid Synthesis and Signaling during Early Organogenesis.” Cell 134.6 (2008): 921-931. Web. 13 Apr 2011. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2632951/pdf/nihms76219.pdf>. This is a very in-depth article about the synthesis and function of RA. Some technical language.
Luthi-Carter, R, A Strand, NL Peters, SM Solano, and others. “Decreased expression of striatal signaling genes in a mouse model of Huntington.” Hum Mol Genet 9.9 (2000): 1259-71. Web. 13 Apr 2011. <http://hmg.oxfordjournals.org/content/9/9/1259.full>. The main point to take away from this study is that “mutant huntingtin directly or indirectly reduces the expression of a distinct set of genes involved in signaling pathways known to be critical to striatal neuron function.”
Mey, Jörg, & McCaffery, Peter. Retinoic acid signaling in the nervous system of adult vertebrates. The Neuroscientist 10.5 (2004). Web. 13 Apr 2011. <http://www.accutaneaction.com/Studies/2004_Mey.pdf>. This contains some technical language, but it has a lot of interesting information about RA research and treatment possibilities.
J. Nguyen 2011