January 14, 2008

A New Label
By Dan Harvey
Radiology Today
Vol. 9 No. 1 P. 10

A study presented in November at RSNA 2007 offered new information about the relationship existing between high blood pressure and Alzheimer’s disease. The results strongly indicated how hypertension worsens the debilitating effects of Alzheimer’s disease and underscores the value of arterial spin labeling (ASL) MRI in this research area.

ASL MRI, a relatively new and noninvasive imaging technique, can effectively measure cerebral blood flow (CBF), which has proven to be an integral parameter in the study of neurodegenerative diseases, including Alzheimer’s disease.

The study, conducted by researchers from the University of Pittsburgh, demonstrated that hypertension leads to reduced blood flow to the brain of older adults afflicted with Alzheimer’s disease. In turn, the reduced flow aggravates the condition. This revelation begged the question: Do the findings mean that individuals affected by hypertension could be more prone to developing Alzheimer’s disease compared with people with normal blood pressure?

Not necessarily, said Cyrus Raji, MD, a doctoral candidate at the University of Pittsburgh who gave the RSNA presentation. At this point, Raji said it appears that hypertension doesn’t trigger Alzheimer’s, only increases the brain’s susceptibility to the disease’s devastating effects.

“What the study really demonstrated is that hypertension only confers a vulnerability,” says study coauthor Oscar L. Lopez, MD, professor of neurology at the University of Pittsburgh.

If the disease is going to show up, he says, it will probably occur sooner in individuals with hypertension. “Then, after they develop the dementia, the blood flow compromise becomes even worse.

“The bottom line is that it is extremely important to treat hypertension,” Lopez adds, “not only when a person is cognitively intact but also when a person is going into a dementia or Alzheimer’s disease.”

According to the National Heart, Lung, and Blood Institute, approximately 50 million Americans have hypertension. It’s well-known that the condition elevates the risk of heart attack, stroke, and aneurysm. Now it appears that vascular health can significantly impact brain health. “It is important to healthy cognitive function,” says Lopez.

The ASL Factor
ASL MRI, the imaging modality that the researchers used in the study, is an effective way to measure blood flow to the brain, and it provides users with a noteworthy advantage of not requiring a contrast agent.

During the procedure, the arterial blood is magnetically labeled and then imaged. Specifically, it labels the protons in water molecules and tracks their flow. In this way, it can be effectively deployed to measure CBF, using the water molecules as natural tracers.

“ASL MRI is a part of functional MR imaging that allows you to generate an image that represents CBF without having to use radioisotopes or injected contrast agents,” explains Jeffrey Mendel, MD, chair of the department of radiology at Caritas St. Elizabeth’s Medical Center in Boston.

CBF is an important parameter in measuring patients with cognitive dysfunctions, according to William T. C. Yuh, MD, MSEE, professor and vice chair of the department of radiology at Ohio State University. “Traditionally, to acquire this kind of parameter, MR contrast agents and radioisotopes were employed,” he says. “Now, ASL MRI provides us with an endogenous contrast agent as opposed to an exogenous, or outside-the-body, contrast agent. That is, we are able to use blood inside the body as the agent. Similar to how we label the radioisotope for the nuclear medicine studies, we magnetically label the blood and, thus, use it as a contrast agent.”

ASL MRI eliminates the need for contrast injections or radioisotopes, offering a safer, more cost-efficient, and more convenient option to other imaging methods that provide the same kind of information. “You remove the radiation exposure, as well as the expense of the radioisotopes. Also, you don’t have to place an IV [intravenous] into the patient,” Mendel says.

He adds that ASL MRI is one of the most promising techniques for examining patients who either have Alzheimer’s disease or mild cognitive impairment (MCI). People with MCI have some changes in their brain processes, but they haven’t been diagnosed as having a dementia. ASL MRI is also effective in examining patients with other forms of dementia, such as frontotemporal dementia (FTD). “Without having to do a PET scan, you can see if patients have patterns of decreased blood flow into their brain that might suggest that they have Alzheimer’s or might confirm that there is something else taking place, such as FTD. So it helps to distinguish among Alzheimer’s, FTD, and MCI,” he says.

ASL Mechanics
Mendel explains that in ASL MRI, blood converts into a tracer for perfusion via a specific MRI pulse. When it comes to measuring CBF, the pulse is applied to the arteries flowing into the brain (usually in the neck) and to the arteries by the MRI unit. The radiofrequency pulse labels the blood flowing into the brain—or, more specifically, the water in the blood. “You can then use different MRI sequences to actually see the areas into which this labeled blood is flowing, and you can judge how much blood is flowing into any one area,” says Mendel.

Further clarifying the procedure, as far as CBF, Yuh explains that arterial blood is magnetically labeled before it enters the brain. “That is, we magnetically label the blood supply to the brain before it flows into the area of interest. There is a little delay after the magnetification and when the area of interest receives the blood flow or the endogenous tracer,” he says. “Subsequently, we can use that information to study the changes in the MRI signals and, thus, quantify the CBF.”

Tracking Disease Evolution
For the Pittsburgh study, which was part of the larger Cardiovascular Health Study (Cognition Study), an ongoing observational study of various risk factors, the researchers used ASL MRI to image 88 older adults with an average age of 70.

“Dr. Lopez approached me about using ASL MRI as a perfusion measurement technique to see how the blood flow changes during the disease evolution,” explains H. Michael Gach, PhD, director of imaging research at the Nevada Cancer Institute in Las Vegas, whose role in the study involved providing imaging technology expertise. “That is how we got together on this project.”

In most earlier neuroscientific studies, researchers first looked at the brain structure to determine what changes occurred as the disease developed, says Gach, whose recent research focus has involved application of imaging technologies (particularly MRI) in the in vivo measurement of venous and arterial blood flow, along with tissue perfusion and diffusion. “Changes in brain structure have been a primary marker,” he says. “In previous studies, investigators saw that the hippocampus shrinks in patients with Alzheimer’s disease. They also observed that the brain ventricles enlarged; that is, they grew as the patients’ disease progressed. But Dr. Lopez was interested in other imaging markers that may be associated with dementia progression. One of those markers is blood flow, or perfusion.”

Gach says ASL MRI can be applied to other neurological diseases, as well as diseases such as cancer. Similarly, Yuh points out that at Ohio State, clinicians have applied it to cancer studies and stroke evaluation. “We also use ASL brain perfusion to assist us in biopsies of brain tumors,” he adds. “We’re also looking at using it with other organ systems such as the renal and lung, as well as myocardial perfusion.”

In the Pittsburgh study, the cohort included 48 normal subjects (38 with hypertension and 10 without) and 20 subjects with Alzheimer’s disease (10 with hypertension and 10 without). The remaining 20 subjects (10 with hypertension and 10 without) had MCI, considered a precursor to Alzheimer’s and affecting brain functions such as language, attention, and reasoning.

ASL MRI results showed that in all patient groups, CBF was substantially decreased in individuals with hypertension. In addition, CBF was lowest among Alzheimer’s patients with hypertension. Further, the normal group with hypertension had significantly lower CBF than the normal group without hypertension. Specifically, ASL MRI showed that in patients with hypertension and MCI, CBF to the prefrontal cortex was reduced, while CBF to the posterior cingulate and thalamus was increased. And in hypertensive Alzheimer’s patients, the regions with the most restricted blood flow were the posterior cingulate, prefrontal cortex, and left thalamus.

As the researchers reported, the results suggest that hypertension, which changes CBF, may enhance Alzheimer’s pathology. “The implication is that, by using ASL MRI, we can determine that people with hypertension, with or without cognitive deficits, have abnormal CBF,” says Lopez. “This abnormal blood flow seems to be worse in people with cognitive deficits, especially those with dementia.”

Lopez says that in people with Alzheimer’s disease, it is important to detect and aggressively treat hypertension and also focus on disease prevention.

Gach also notes that the study’s hypertensive subjects had a history of hypertension and reduced CBF, but they all received treatment and were no longer hypertensive. “Thus, one cannot state definitively if it is the history of hypertension or the treatment that caused the reduced blood flow in our cohort,” he says. “Reducing the blood pressure to ‘normal’ may in turn cause hypoperfusion. In future research, we will try to determine if the hypoperfusion is caused by a long history of hypertension and its long-term impact of cerebral hemodynamics or the effects of antihypertensives.”

Clinical Frontier
While ASL MRI isn’t widely available yet, Yuh sees it as transitioning from a research to a clinical tool. “We’re now looking at a large clinical frontier,” he says. “With advances in the technique and MRI technology, I think this could eventually find routine usage. I also think that it is very exciting that we now have this alternative method to assess organ blood flow, particularly for those patients with contraindications for contrast studies, such as contrast, renal or risk nephrogenic systemic fibrosis.”

When ASL MRI does gain more widespread application, Yuh believes it’s likely that people will come to know it in the pulsed form. Currently, there are two major versions: continuous and pulsed. With continuous ASL (CASL), labeling of arterial blood continuously takes place throughout application of a long, continuous radiofrequency pulse lasting one to two seconds, Yuh explains. With pulsed ASL (PASL), labeling arterial blood uses a radiofrequency pulse with a higher peak amplitude and a shorter duration (about 100 times shorter than CASL). “The main difference is that the shorter radiofrequency pulse is applied to a thicker slab of blood in PASL. CASL involves much thinner slices of blood with a stronger radiofrequency of longer duration,” says Yuh. “As such, PASL requires less hardware.”

The pulse technique is easier to implement on the scanner, adds Gach. “It is less stressful on the MRI. It has been turned into a product, and a lot of people use it for fMRI [functional MRI]. It is not necessarily as quantitative as the continuous ASL MRI technique that we used for our study. Also, it is harder to cover the brain as quickly. But it has its uses.”

CASL typically has to be specially designed, thus requiring more specific hardware. “But it has the advantage of better signal-to-noise ratio, or contrast. Both images and the quantification are better,” says Yuh.

Getting Ready for Prime Time
Mendel agrees that ASL MRI is an exciting area. “It is certainly something that people who image patients with dementia are looking at with great interest,” he says. “Right now, the big question is, ‘When will this start filtering down to other medical centers and hospitals?’”

In the meantime, he says there’s a need for more studies that confirm the idea that it is as sensitive as something such as PET scanning. “Research experience needs to be duplicated before people start investing in the infrastructure,” Yuh says.

Another limiting factor may be MRI unit field strength. “ASL MRI appears to be more effective at higher field strengths,” Yuh says. “So, we may see greater application as more and more facilities move up to 3T units. Right now, the vast majority of MRI units in the country are 1.5T.”

That’s an important consideration, as ASL utilized in a higher magnetic field offers greater signal-to-noise ratio, and it would enhance the labeling effect. “While this is a new area, we’ve already witnessed rapid progression and recognize the enormous potential,” Yuh says.

— Dan Harvey is a freelance writer based in Wilmington, Del., and a frequent contributor to Radiology Today.