8 things we now know about the toxicity of gadolinium to the brain

When it comes to imaging the nervous system, nothing but an MRI will do for the fastidious neurologist. CT has its uses, such as in detecting acute intracranial bleeding, but it lacks the sophistication to detect or differentiate between less glaring abnormalities. It also comes with a hefty radiation dose. MRI on the other hand, relying on powerful magnetic fields, is a ‘cleaner’ technology.

SLEIC 6. Penn State on Flickr. https://www.flickr.com/photos/pennstatelive/4946556307

MRI scans on their own are however often insufficient to sate the craving of the neurologist for precision. A plain MRI scan, for example, will not tell if a multiple sclerosis lesion is old or new, and it may fail to detect subtle but significant lesions such as low grade brain tumours or lymphoma. Many lesions on routine MRI scan are also ill-defined and non-specific, and could pass for abscesses, vasculitis, inflammation or just small vessel disease (wear and tear) changes.

The Brain. I has it. Deradrian on Flickr. https://www.flickr.com/photos/mgdtgd/3507973704

To silence the niggling doubts, the neurologist often requests an MRI scan with contrast. The idea is to use a dye to separate the wheat from the chaff, the active lesions from the silent ones. This works because sinister lesions have a bad and dangerous habit of disrupting the blood brain barrier. All such insurgencies across the hallowed BBB is sacrilege, a sign that something serious is afoot, (or is it underfoot?). Contrast dyes, on the other hand, are adept at detecting these breaches, traversing them, and staining the sinister lesion in the process. This stain appears on the MRI scan as contrast enhancement. MRI with contrast is therefore invaluable, and a positive study is a call to arms.

By © Nevit Dilmen, CC BY-SA 3.0, Link

Without any doubt, gadolinium is the favoured dye for contrast MRI scans. Gadolinium (Gd) is a lanthanide rare earth metal and it is one of the heavier elements of the periodic table with atomic number 64. It is named after the thrice-knighted Finnish chemist Johan Gadolin, who also discovered the first rare earth metal, yttrium.

Periodic table model. Canada Science and technology Museum on Flickr. https://www.flickr.com/photos/cstmweb/4888243867

We know a lot about some of the risks of injecting gadolinium into the body, such as its tendency to accumulate in people with kidney impairment (who cannot excrete it efficiently). We also know that it may cross the placenta to damage the developing baby. These are however hazards with simple and straight-forward solutions: avoid gadolinium in pregnancy, and don’t use it in people with poor renal function.

By Hi-Res Images ofChemical Elements – http://images-of-elements.com/gadolinium.php, CC BY 3.0, Link

Much more challenging is the problem of gadolinium deposition in the brain of people with normal renal function. This is concerning because it is unpredictable, and because it has the potential to compromise brain structure and function. This blog has previously asked the question, “Is gadolinium toxic?“. The question remains unanswered, and regulatory agencies are still studying the data to provide guidance to doctors. Patient groups on the other hand have been up in arms, as one would expect, impatiently waiting for answers. What then is the state of play with gadolinium? Should neurologists and their patients really be worried? Below are 8 things we now know about gadolinium and its potential brain toxicity.

By Peo at the Danish language Wikipedia, CC BY-SA 3.0, Link

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1. Gadolinium deposition is related to its insolubility at physiological pH

The toxic potential of gadolinium is thought to be the result of its insolubility at physiological pH. Furthermore, gadolinium competes against calcium, an element fundamental to cellular existence. This competition is obviously detrimental to the body.

064 Gadolinium-Periodic Table of Elements. Science Activism on Flickr. https://www.flickr.com/photos/137789813@N06/22951789105

2. The less stable gadolinium agents are the most toxic

There are two forms of gadolinium based contrast agents (GBCAs): the less stable linear GBCAs, and the more stable macrocyclic GBCAs. The linear GBCAs are more toxic, of which Gadodiamide (Omniscan) stands out. Other linear agents are gadobenate dimeglumine (MultiHance), gadopentetate dimeglumine (Magnevist), gadoversetamide (OptiMARK), gadoxetate (Eovist), and gadofosveset (Ablavar). The macrocyclic GBCAs, even though safer, are not entirely blameless. They include gadobuterol (Gadavist), gadoterate meglumine (Dotarem), and gadoteridol (ProHance). Therefore, choose your ‘gad’ wisely.

By زرشکOwn work, CC BY-SA 3.0, Link

 

3. Gadolinium deposits in favoured sites in the brain

It is now established that gadolinium deposits in three main brain areas. The most favoured site is the dentate nucleus of the cerebellum. Other popular regions are the globus pallidus and the pulvinar. This deposition is, paradoxically, visible on plain T1-weighted MRI scans where it shows as high signal intensity.

By Polygon data were generated by Database Center for Life Science(DBCLS)[2]. – Polygon data are from BodyParts3D[1], CC BY-SA 2.1 jp, Link

4. The risk of deposition depends on the number of injections

The risk of gadolinium deposition in the brain is higher with multiple administrations. Stated another way, and to stretch this paragraph out a bit longer, the more frequently contrast injections are given, the higher the chances gadolinium will stick to the brain. The possible risk threshold is 4 injections of gadolinium. The fewer the better…obviously!

Number-04. StefanSzczelkun on Flickr. https://www.flickr.com/photos/stefan-szczelkun/3931901057

5. Gadolinium also deposits outside the brain

The favoured site of gadolinium deposition outside the brain is the kidney, where it causes nephrogenic systemic fibrosis, a scleroderma-like disorder. This however occurs mostly in people with renal impairment. Gadolinium also deposits in other organs outside the brain including bone, skin, and liver. (Strictly speaking, this item has nothing to do with the brain, but it helped to tot up the number to 8 in the title of this blog post, avoiding the use of the more sinister se7en).

By JudgefloroOwn work, CC BY-SA 4.0, Link

 6. Harm from gadolinium brain deposition has not been established

Whilst we know for sure that gadolinium deposits in the nervous system, harm from deposition has not been definitively established. There are, however, reports that gadolinium deposition may produce muscle and eye symptoms, and chronic pain. There are also reports of cognitive impairment manifesting as reduced verbal fluency.

Words words words. Chris Blakeley on Flickr. https://www.flickr.com/photos/csb13/4276731632

7. Precautions may reduce the risk of gadolinium brain deposition

The current recommendation is not to withhold the appropriate use of gadolinium, but to observe simple precautions. Sensibly, use GBCAs only when absolutely necessary. Also consider preferentially using macrocyclic GBCAs and evaluate the necessity for giving repeated GBCA administrations.

 

By IntropinOwn work, CC BY-SA 3.0, Link

 

8. There are emerging ways to avoid gadolinium toxicity

The safest use of gadolinium is not to use it at all. There are some developments in the pipeline to achieve this, although probably not in the very near future. Such developments include manganese based contrast agents such as Mn-PyC3A. A less definitive option is to mitigate the effects of gadolinium by using chelating agents; two such potential agents are nanoparticles and 3,4,3-LI(1,2-HOPO).

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Why not get the snapshot view of gadolinium toxicity in the neurochecklist:

Gadolinium-based contrast agent (GBCA) toxicity

…and leave a comment!

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MRI scan. NIH Image Gallery on Flikr. https://www.flickr.com/photos/nihgov/30805879596

The emerging research boosting Parkinson’s disease treatment

Parkinson’s disease (PD) is probably the most iconic neurological disorder. It has diverse manifestations, typical of many neurological diseases. PD is a result of brain dopamine deficiency, and its clinical picture is dominated by motor symptoms- tremor, rigidity and bradykinesia (slowing of movements). It however also manifests with a variety of non-motor symptoms which rival the motor symptoms in their impact. PD is responsive to treatment with several oral medications such as levodopa, infusions such as apomorphine, and interventions such as deep brain stimulation (DBS).

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Regardless of the intervention used, PD is a neurodegenerative disorder that grinds, slowly and steadily, along a chronic progressive course. This often manifests with disabling features such as freezing, hallucinations, and dyskinesias (drug-induced writhing movements). These symptoms creep or barge in unannounced, challenging the wits of the neurologist, and pushing the resolve of patients and their families to the limit. What hope does research offer to smooth the journey for people with PD? Here are my top 7.

1. Increasing evidence for the benefit of exercise

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OK, not every advance has to be groundbreaking. It is self-evident that exercise is beneficial for many chronic disorders, but proving this has been difficult…until now that is. Researchers, publishing in the journal Movement Disorders, looked at the benefits of exercise on cognitive function in PD, and their verdict is-yes, it works! The study, titled Exercise improves cognition in Parkinson’s disease: The PRET-PD randomized, clinical trial, comes with strings attached- you have to keep at the exercise for 2 years! A review  in the same journal indicates that exercise also improves mood and sleep in PD.

2. Lithium for treatment of dyskinesias

By Dnn87 - Self-photographed, CC BY 3.0, Link
By Dnn87Self-photographed, CC BY 3.0, Link

Dyskinesias are abnormal, fidgety movements that develop as side effects of the drugs used to treat PD. Most people with dyskinesias are not overly concerned about the movements because the alternative, disabling freezing and immobility, is worse. Dyskinesias are however energy-sapping, and are distressing for family members. Amantadine is one drug neurologists add-on to improve dyskinesias, but many people do not tolerate or benefit from this. The suggestion that lithium may help dyskinesias is therefore welcome news. The report comes from a study in mice reported in the journal Brain Research titled The combination of lithium and l-Dopa/Carbidopa reduces MPTP-induced abnormal involuntary movements (AIMs). A long way to go yet, but hope.

3. Transcranial magnetic stimulation (TMS)

By MistyHora at the English language Wikipedia, CC BY-SA 3.0, Link
By MistyHora at the English language Wikipedia, CC BY-SA 3.0, Link

Transcranial magnetic stimulation (TMS) is playing an increasing role in neurology as I discussed in a previous post titled Are magnets transforming neurology? It is almost inevitable therefore that TMS will crop up in attempts to treat PD. And so it has, going by a meta-analysis and systematic review published in JAMA Neurology. The paper is titled Effects of repetitive transcranial magnetic stimulation on motor symptoms in Parkinson disease. The reviewers passed the judgement that repetitive TMS improves motor symptoms in PD. Perhaps time to invest in TMS!

4. MRI guided focused ultrasound (MRgFUS)

By Frmir - Own work, CC BY-SA 3.0, Link
By FrmirOwn work, CC BY-SA 3.0, Link

MRI guided ultrasound (MRgFUS) is not new to medicine. It is used, for example, in the treatment of solid tumours and uterine fibroids. It is however innovative in the treatment of tremor and dyskinesia in PD. This came to my attention via a press release from University of Maryland titled Metabolic Imaging Center uses new ultrasound technology to target deep structures of the brain. MRgFUS non-invasively transmits ultrasound waves to the globus pallidus, one of the deep brain structures involved in PD. How this works still remains fuzzy to me, but it is exciting enough to generate a lot of research activity with articles such as MRI guided focused ultrasound thalamotomy for moderate-to-severe tremor in Parkinson’s disease in the journal Parkinson’s Disease; and Unilateral magnetic resonance-guided focused ultrasound pallidotomy for Parkinson disease, published in Neurology. Watch out, deep brain stimulation!

5. Nasal mucosal grafting

Big Nose Strikes Again. Bazusa on Flikr. https://www.flickr.com/photos/bazusa/260401471
Big Nose Strikes Again. Bazusa on Flikr. https://www.flickr.com/photos/bazusa/260401471

What a great thing, the blood-brain barrier, protecting the brain from all the bugs and toxins running amok in the bloodstream. This iron-clad fence unfortunately also effectively keeps out, or limits the entrance of, many beneficial drugs which need to get to the brain to act. As with all borders however, there are always people ready to break through, without leaving any tracks behind. And the people in this case are neurosurgeons who have successfully bypassed the blood brain barrier, and safely ‘transported’ PD drugs in to the brain. They did this by removing a portion of the blood brain barrier of mice, and replaced it with a piece of the tissue which lines the inside of the nose, a procedure called nasal mucosal grafting. They then delivered glial derived neurotrophic factor (GDNF), a protein that treats PD in mice, across the graft. The neurosurgeons explained all this in their paper titled Heterotopic mucosal grafting enables the delivery of therapeutic neuropeptides across the blood brain barrier. You may however prefer the simpler version from the Boston Business Journal (can you believe it!) titled A new way to treat Parkinson’s disease may be through your nose. It will however take time before human trials of nasal mucosal grafting…this is science after all, not science fiction!

6. Fetal stem cell transplantation

Marmoset embryonic stem cells forming neurons. NIH Image gallery on Flikr. https://www.flickr.com/photos/nihgov/27406746806
Marmoset embryonic stem cells forming neurons. NIH Image gallery on Flikr. https://www.flickr.com/photos/nihgov/27406746806

It doesn’t seem too long ago when all ethical hell broke loose because some scientists were transplanting fetal tissue into human brains. I thought the clamour had put this procedure into the locker, never to be resurrected. Apparently not; fetal stem cell transplantation (SCT) is back, reminiscent of Arnold Schwarzenegger in the Terminator films. Learn more of this comeback in this piece from New Scientist titled Fetal cells injected into a man’s brain to cure his Parkinson’s. The work is from Roger Barker‘s team at the University of Cambridge, and they are planning a big study into this named TRANSNEURO. Watch this space

7. Pluripotent stem cell transplantation

By Judyta Dulnik - Own work, CC BY-SA 4.0, Link
By Judyta DulnikOwn work, CC BY-SA 4.0, Link

The future of stem cell transplantation probably lies with pluripotent, rather than fetal cells. The idea is to induce skin cells, called fibroblasts, to transform into dopamine-producing cells. Fibroblasts can do this because they are pluripotent cells; that is they are capable of becoming whatever type of cells you want, so long as you know the magic words. In this case, the words are likely to be the transcription factors Mash1, Nurr1 and Lmx1a. Beatsopen sesame‘, and surely less controversial than fetal cells. Researchers are taking this procedure very seriously indeed, setting out ground rules in articles such as Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. This was published in the journal Nature, but you may prefer the easier read in New Scientist titled Brain cells made from skin could treat Parkinson’s. But don’t get too excited…pluripotent stem cell transplantation is barely at the starting line yet.

 

Eu Sou. jeronimo sanz on Flikr. https://www.flickr.com/photos/jeronimooo/12069638595
Eu Sou. jeronimo sanz on Flikr. https://www.flickr.com/photos/jeronimooo/12069638595

There is so much more going on in the field of Parkinson’s disease to cover in one blog post. I will review neuroprotection in Parkinson’s disease in a coming post. In the meantime, here are links to 12 interesting articles and reviews on the future of PD:

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