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In the Clinic – Normal Pressure Hydrocephalus: Researchers Assess Normal Pressure Hydrocephalus with Glymphatic MRI Findings Could Apply to Other Neurologic Conditions

Collins, Thomas R.

doi: 10.1097/01.NT.0000526508.52156.b0
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Investigators used a magnetic resonance image with an intrathecal contrast agent to image cerebrospinal fluid characteristics and glymphatic function in patients with idiopathic normal pressure hydrocephalus (iNPH). The investigators say the imaging technique, which has mostly been used in animal studies, has the potential to assess metabolic function in iNPH and other neurologic disorders.

Using the gadolinium-based contrast agent gadobuturol administered intrathecally, magnetic resonance imaging (MRI) showed delayed enhancement and clearance in the glymphatic network of the brains of patients with idiopathic normal pressure hydrocephalus (iNPH) compared to reference patients, according to research published in the August 18 online edition of Brain.



It's the first time the technique, previously used in animal studies, has been shown to be used effectively in humans, other than an earlier case study from the same researchers, at Oslo University Hospital.

Independent observers said the findings could represent an important step beyond the animal studies that have used the approach, but cautioned that there was a significant age difference between the iNPH patients and the reference patients and unresolved safety concerns about the contrast agent.

“The study shows the potential of glymphatic resonance imaging as a method to assess human brain metabolic function and refers a potenmtial for contrast enhanced brain edxtravascular space imaging,” the study authors wrote.

The lead author of the study — Per Kristian Eide, MD, PhD, professor of clinical neurosurgery at the center — said the use of so-called “gMRI” successfully in people, with injection of the agent into the intrathecal space, offers the field a view of the brain network beyond the vascular system, where contrast agents are already commonly used.

“It's in a way an opening to the black box of the brain,” he said.

“What this gMRI actually shows is that we can assess CSF [cerebrospinal fluid] tracer in the extravascular compartment,” he said. “This kind of assessment could apply to many neurological diseases: first, [for] Alzheimer's disease and dementia, and second, for neuroinflammatory diseases like multiple sclerosis, where the inflammatory cells and processes are occurring along the vessels.”

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In the study, researchers used gMRI to assess 15 patients with iNPH — a dementia type that is characterized by gait difficulties and urinary incontinence — and eight “reference” subjects, who included seven patients with suspected CSF leaks and one with an intracranial cyst. Healthy, matched controls could not be used because of ethical reasons, the authors said, so the agent had to be used for a different, indicated purpose. The age difference was large — an average age of 71 for the iNPH patients and 41 for the reference subjects.

Patients were injected intrathecally in the morning and imaged as soon as possible after that, then every 10 minutes for the first hour. Then they were imaged several times every two hours until late afternoon, and imaged again at 24 hours.

Aside from the novelty of the approach, researchers noted several characteristics of the CSF flow in the patients with iNPH.

There was significant delayed enhancement (p<0.05) and clearance of the contrast agent (p<0.05) in the iNPH patients at the Sylvian fissure, which separates the frontal and parietal lobes from the temporal lobe. Enhancement peaked overnight in both groups.

“We see the highest increase in CSF tracer within the brain is occurring after sleep, so this at least indicates a role of sleep for glymphatic circulation in humans,” Dr. Eide said.

Researchers also saw a flow pattern of ventricular reflux of the agent from the subarachnoid space followed by transependmyal migration — contrary to the flow pattern expected.

“It's indicative that the water was actually going from the ventricles into the brain and this is of course very surprising,” Dr. Eide said. “It challenges very much the traditional view” on the direction of CSF flow within the human brain and also within normal pressure hydrocephalus, he said.

“The tracer is moving rapidly into the ventricles and we considered it, in a way, the path of least resistance,” he said. “This probably has something to do with the pathophysiology of the disease.”

Patients with iNPH can benefit from surgery to shunt the flow of CSF, and assessment of this flow pattern could help determine which patients are more likely to improve with surgery, Dr. Edie said.

His research group has found previously that the water channel protein aquaporin 4, found along the blood vessels in the brain, is decreased in iNPH patients, and that might be the mechanism that's causing the delay in clearance in these areas, he said. This might represent a molecular target for treatment, he added.

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Independent experts said the findings are a major step in supporting what has been seen in animal studies in which gadolinium-based contrast has been used to assess glymphatics. But they pointed to several caveats with this approach.

Importantly, one of the major issues with this study is that the iNPH subjects were compared to a population that was much younger and probably fairly healthy. Therefore, certain findings attributed to the disease could be age-related differences that have less to do with the disease, said Eric McDade, DO, assistant professor of neurology at Washington University in St. Louis, whose research focuses on dementia. “I think that that's one definite limitation.”

Dr. McDade added that it would have been helpful to have controls that were older and to have comparisons with other dementia types.

“On the other hand,” he said, “it's nice translational work to see as a first step looking at idiopathic normal pressure hydrocephalus and the glymphatic system as it relates to studies done in animal studies.”

The applicability of the findings are “probably still relatively limited,” he said. All the patients in the study already had a diagnosis of iNPH and had responded to shunting procedures, so this approach probably wouldn't offer a “huge diagnostic advantage” yet, he said.

He said he'd like to see the approach extended to other dementia types, including Alzheimer's disease and vascular cognitive impairment.

He also noted that this is “a relatively arduous protocol right now,” with patients having to undergo regular scans for several hours consecutively.

More application could be derived from this approach if gadolinium retention at 24 hours, for example, was correlated to MRI sequences that are done more easily (that is, T2- FLAIR measures of periventricular white changes or characteristic carpus callosum changes).

Jeffrey Iliff, PhD, associate professor of anesthesiology and perioperative medicine at Oregon Health & Science University, who studies the cerebrovasculature and clearance of waste products from the central nervous system, said the study is a bridge to other studies carried out in animals with tracers and work in human subjects, which would ideally employ non-invasive approaches.

“There's an assumption with non-invasive approaches to measuring glymphatic function that what is being measured is the same as what was imaged in animals,” he said, “whereas this study shows the application of an imaging approach, DCE (dynamic contrast enhanced) MRI — which is the same approach that has been used by a couple of different groups in animals — straight into human subjects. These are the first efforts to link findings in animal studies directly with human subjects.”

The problem for now is that safety concerns surrounding the use of gadolinium need to be answered before widespread use could be possible.

“There have been some clinical reports that gadolinium may be depositing in the brains of patients undergoing DCE-MRI after intravenous contrast agent administration. It isn't necessarily clear how widespread this is. It isn't clear whether that's only certain contrast agents that are the culprits in this. And it isn't clear what the biological or pathological consequences of this deposition may be — whether it's a benign thing or whether it's a bad thing. It's an unknown at this point.”

Still, this is an important step, he said, because “this is a study that shows that this CSF tracer exchange does in fact happen in humans and the kinetics of that exchange do seem to be disrupted in the particular pathological setting of NPH.”

Whereas previous studies that have found CSF flow abnormalities in NPH have taken a narrower view of ventricular CSF circulation, this study took a more global approach.

“There seems to be a global derangement of CSF movement, including the path that the CSF takes through the brain tissue itself,” he said.

He also echoed Dr. McDade's concerns about the applicability of an arduous procedure to impaired patients. It would be a challenge to have an 85-year-old Alzheimer's patient, say, undergo intrathecal contrast administration before sitting through such a long series of MRIs.

But these findings could provide a platform from which to evaluate the possibility of less taxing, less invasive approaches, he said.

“The ability to validate those non-invasive approaches against a gold standard type approach like this one,” he said, “is a necessary step in that process.”

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•. Ringstad G, Vatnehol SAS, Eide PS. Glympathic MRI in idiopathic normal pressure hydrocephalus Brain 2017; Epub 2017 Aug 18.
    © 2017 American Academy of Neurology