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NEUROIMAGING PROVIDES NEW DATA ON MULTIPLE SCLEROSIS AND ALZHEIMER DISEASE

Since the advent of positron emission tomography (PET) scanning in the late 1970s and of magnetic resonance imaging (MRI) in the early to mid-1980s, neuroimaging has become an integral part of neurology. As the diverse imaging modalities – including various MRI and PET techniques, single-photon emission computed tomography (SPECT), ultrasound, and computed tomography (CT) – have steadily improved, the diagnosis of neurological disorders and monitoring of therapy and research have advanced correspondingly, allowing neurologists and other medical scientists to begin to decipher the pathophysiology of these complex disorders.

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Dr. Rohit Bakshi said imaging studies have shown that generalized atrophy in the brain and spinal cord begins early in the MS disease process and in the majority of patients, often leading to physical disability, cognitive dysfunction, lowered quality of life, and depression.

Not all institutions have all the imaging modalities. For example, PET scanners and MRI scanners capable of doing perfusion-weighted imaging are not abundant, but because there is some redundancy among the modalities, experts say, advances in the field of neuroimaging have not been impeded.

In phone interviews with Neurology Today, leaders in the field highlighted noteworthy advances in neuroimaging as it applies to multiple sclerosis, Alzheimer disease, and cerebrovascular disease and stroke.

MULTIPLE SCLEROSIS

When MRI first began to be used in multiple sclerosis (MS), its value was primarily in the diagnosis of early cases. In the past five years, however, both MRI and PET studies have gradually shown that MS is a neurodegenerative disease with cortical and subcortical gray matter involvement, not just a demyelinating disorder.

Neurologist Rohit Bakshi, MD – Associate Professor of Neurology at the State University of New York at Buffalo School of Medicine and Director of the Buffalo Imaging Analysis Center of the Jacobs Neurological Institute – and colleagues use an MRI-based software program that enables them to automatically trace and analyze areas of damage in the brains of MS patients, yielding quantitative three-dimensional information on areas of brain damage.

COGNITIVE DYSFUNCTION

Their studies, as well as autopsy studies showing axonal transection in MS lesions, have shown that generalized atrophy in the brain and spinal cord begins early in the disease process in the majority of patients, often leading to physical disability, cognitive dysfunction, lowered quality of life, and depression, although its precise cause is not yet understood.

Such atrophy is an important predictor of the subsequent course of the disease. Depression in MS, Dr. Bakshi noted, is particularly linked to atrophy in the frontal and parietal parts of the brain.

Cognitive dysfunction eventually affects approximately half of MS patients. Researchers at Buffalo used several common MRI techniques – fluid-attenuated inversion recovery (FLAIR), T1-weighted, and gradient-echo scans – to study 60 patients with MS and 50 age- and sex-matched control subjects. They found that cognitive dysfunction is particularly related to subcortical atrophy (Archives of Neurology 2002; 59:275–280).

These imaging studies have provided evidence that interferon-beta-1a can slow down the development of atrophy and that this can be monitored with imaging, Dr. Bakshi said. In addition, he said, R. Zivadinov, MD, and his Italian colleagues presented the unexpected preliminary findings in a 2001 report that pulsed treatment with intravenous methylprednisolone can show the rate of brain atrophy.

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Dr. Joseph Masdeu said MRI T1-weighted imaging with gadolinium contrast can quantify subclinical abnormalities in MS.

“We believe that early and aggressive therapy of MS is warranted, and that every MS patient should receive early treatment,” said Dr. Bakshi. “Unfortunately, only about 50 percent of MS patients in this country are on these treatments.”

SUBCLINICAL ABNORMALITIES

Joseph Masdeu, MD, PhD, Professor and Chairman of the Department of the Neurological Sciences at the University of Navarre Medical School in Pamplona, Spain, said quantitative T1-weighted MRI with gadolinium contrast can disclose subclinical or “subimaging” abnormalities in MS.

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In this PET study, arrows indicate the characteristic metabolic deficit in the parietal cortex in Alzheimer disease in comparison with the frontal metabolic deficit in Pick disease, the subcortical metabolic deficits of the caudate and putamen in Huntington disease, and the distribution of metabolic deficits in multiple infarct dementia. All patients had a normal MRI or CT, with the exception of the multiple infarct dementia.

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This PET sudy of glucose metabolism in Alzheimer disease was performed at the stage of questionable Alzheimer disease (AD) and illustrates the characteristic metabolic deficits of AD in the parietal and temporal cortices.

A basic mechanism of damage in the disease, he explained, is the increased permeability of the blood-brain barrier owing to the fact that metalloproteinases – a family of proteins that contain zinc ions – cause loosening of the junctions in the endothelial cells lining brain capillaries, allowing the gadolinium to leak out of the vessels into the surrounding tissue.

“This leaking of gadolinium is a sensitive indicator of activity,” said Dr. Masdeu, “more so than overt white matter lesions seen on T2-weighted images or T1 enhancement. It tells you how active the disease really is and indicates that it is in a stage that may require treatment with interferon or immunosuppressants.”

IMAGING IRON DEPOSITS

Dr. Masdeu has also used MRI to distinguish the “pseudotumor variety of MS,” or Schilder disease, from tumors of the brain. Misdiagnosis of this uncommon demyelinating disorder, which occurs primarily in young adults, has frequently occurred, resulting in these patients undergoing surgery or radiation therapy for a tumor rather than being given appropriate anti-inflammatory agents.

Another MRI study of MS and control subjects showed that gray matter T2 hypointensity, which may be associated with iron deposition, is a stronger predictor of disability and clinical course than conventional MRI findings, Dr. Bakshi said (Archives of Neurology 2002; 59:62–68). The number of iron deposits, which probably come from the blood, appears to correlate with a worsening clinical condition in patients. “We also know that high levels of iron are toxic to nerve cells and that iron deposits accumulate in other neurodegenerative diseases like Alzheimer disease and Parkinson disease,” he added.

Diffusion-weighted MR imaging – which relates to slowed water molecule motion in injured cells – can show tissue injury in MS in the vicinity of later plaque formation. However, this technique, as well as MR spectroscopy (MRS), functional magnetic resonance imaging (fMRI), and magnetization transfer imaging (occasionally used to monitor therapy because it is based on the interaction between free protons and those bound in macromolecules) is largely used for MS research, rather than clinically, at this time.

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Dr. Gary Small has used imaging technologies to study people at genetic risk for AD by virtue of having the ∊-4 allele of the apolipoprotein E gene (APOE ∊-4) on chromosome 19.

ALZHEIMER DISEASE

MRI techniques have assumed an important role in imaging and diagnosis of Alzheimer disease (AD). MRI can also distinguish AD from other neurodegenerative diseases like Pick disease, from prion diseases, and from vascular dementia.

Among the more advanced MRI techniques, perfusion-weighted MRI shows low blood flow in the bilateral parietal and bilateral temporal lobes of AD patients, which can indicate the diagnosis. In addition, MRS can show increases in certain chemicals, the most important one being myo-inositol, in the temporal lobes of AD patients.

PET and SPECT can also distinguish AD from other types of dementia. Similar to perfusion-weighted MRI, SPECT offers information on blood flow and functioning of the tissues, among other characteristics.

PRESYMPTOMATIC DIAGNOSIS

In the past few years, the use of PET scanning and fMRI has stimulated considerable excitement and interest in presymptomatic diagnosis and treatment of AD.

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This FDG-PET scan of a patient with dementia with Lewy bodies shows parietal and occipital hypometabolism.

Psychiatrist Gary Small, MD, Director of the University of California-Los Angeles (UCLA) Center on Aging, and others at UCLA have been at the forefront of this research, studying people at genetic risk for AD by virtue of having the ∊-4 allele of the apolipoprotein E gene (APOE ∊-4) on chromosome 19.

In the mid-1990s they reported that PET studies identified parietal deficits in glucose metabolism in people aged 47 to 82 years who were cognitively normal but had the APOE ∊-4 allele. The allele appears to have a dose-related effect on increasing risk and lowering onset age for late-onset familial and sporadic AD (Journal of the American Medical Association 1995; 273:942–947).

In 2000, along with neurologist John Mazziotta, MD, PhD, Director of the Brain Mapping Center at UCLA, the group reported on patterns of brain activation determined by fMRI in people with this allele versus people homozygous for a different apolipoprotein ∊ allele.

Subjects were given a learning task, or cognitive stress test, that was particularly sensitive to damage to the medial temporal lobe and then scanned for differences in relative cerebral blood flow during performance of the task. The amount of neural activity in the medial temporal lobe was lower in the 14 control subjects than in the 16 carriers of the APOE ∊-4 allele, reflecting how much harder that area of their brains had to work.

MILD MEMORY COMPLAINTS

Also in 2000, a report on PET scanning with [18F]fluorodeoxyglucose (FDG) in middle-aged and older nondemented persons with mild memory complaints showed that a single copy of the APOE ∊-4 allele was associated with lowered inferior parietal, lateral temporal, and posterior cingulate metabolism, which predicted cognitive decline after two years of follow-up (Proceedings of the National Academy of Sciences 2000; 97:6037–6042). Twenty patients who were not demented were followed longitudinally. Although their memory performance did not decline significantly, their cortical metabolic rates did, particularly in APOE ∊-4 carriers.

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Dr. Carolyn C. Meltzer: “The fact that fMRI and PET scans can pick up preclinical AD and other dementias in people who may have the APOE ∊-4 allele but have only mild memory complaints is very exciting.”

Another study of nearly 300 people undergoing evaluation for dementia – who were followed up either for three years or to autopsy – revealed that a single FDG PET baseline scan showing a deficit in regional brain metabolism could identify those with AD and neurodegenerative disease in general. If the PET scan was negative, progression of cognitive impairment during three years of follow-up was unlikely.

PET PROBES

PET studies cannot be done unless markers – or probes that attach to the compound of interest and can be radiolabeled – are available. In January, Jorge R. Barrio, PhD, Professor of Molecular Medicine and Pharmacology at UCLA, reported that he and colleagues developed an [18F]-labeled probe that would cross the blood brain barrier of humans and bind directly to extracellular amyloid plaques and intracellular neurofibrillary tangles that characterize the neuropathology of AD (American Journal of Geriatric Psychiatry 2002; 10: 24–35).

“There is a very good correlation between the accumulation of these probes and the number of plaques and tangles that define the pathology of AD and the memory tests, which are used to establish the initial diagnosis of the disease,” said Dr. Barrio, who has developed many probes for AD and Parkinson disease through the years.

“Even some ‘controls’ turned out to have problems based on these studies,” he said. Dr. Barrio added that radiochemist Chester Mathis, PhD, and William Klunk, PhD, of the University of Pittsburgh Medical Center, also have developed some promising similar probes, but they have not published human studies with their compounds.

“The fact that fMRI and PET scans can pick up preclinical AD and other dementias in people who may have the APOE ∊-4 allele but have only mild memory complaints is very exciting,” said Carolyn C. Meltzer, MD, Associate Professor of Radiology and Psychiatry and Chief of Neuroradiology at the University of Pittsburgh Medical Center.

Dr. Meltzer said it means that these people can be treated with cholinesterase inhibitors, anti-inflammatory drugs or other to-be-developed pharmacological agents, and then monitored with PET scans during therapy to learn if the metabolic decline in the brain will slow down. “We will want to see if new drugs dissolve the amyloid as opposed to just slowing disease progression.”

Another indication of the power of these neuroimaging techniques is that they make it possible to reduce the number of subjects in a clinical trial of a new antidementia drug to a very small number – say, 40 subjects at genetic risk and known to be in the preclinical stage of AD studied over a two-year treatment period – and still obtain valid results. These imaging techniques reveal changes in cerebral metabolism in these patients before changes in memory have occurred.

NEUROIMAGING TERMS AND DEFINITIONS:

  • Magnetic Resonance Imaging (MRI)
  • MRI is a noninvasive technology that applies radiowaves at a frequency that resonates with the hydrogen nucleus in tissue water, resulting in a shift of a small percentage of protons into higher energy states. Following the radiofrequency pulse, the protons relax back to their original energy state and emit radiowave signals that are characteristic of particular tissue.
  • T1- and T2-Weighted Images
  • Differences in tissue relaxation times enable MRI to distinguish between fat, muscle, bone marrow, and gray or white matter of the brain. T1-weighted images – the longer time constant for tissue relaxation – measure the interaction of protons during the relaxation process, and outline anatomy well. T2-weighted images – the shorter time constant for tissue relaxation – measure the interaction of protons during the relaxation process, and highlight pathology.
  • Positron Emission Tomography (PET)
  • PET studies use a machine called a cyclotron to produce the radioactive tracers: Oxygen-15, Nitrogen-13, Carbon-11, and Fluorine-18 are common radioisotopes. Using different compounds, PET can show blood flow, oxygen and glucose metabolism, and drug concentrations in the tissues of the working brain.
  • Single Photon Emission Computer Tomography (SPECT)
  • Similar to PET, this imaging modality also uses radioactive tracers, but it involves the detection of individual photons (gamma rays) rather than positrons emitted at random from the radionuclide to be imaged. The SPECT scanner uses two or three cameras, which rotate around the patient to record data at different angles. Images of active brain regions are then reconstructed by combining a finite number of projections.
  • Computed Tomography (CT)
  • A CT combines the use of x-rays with computer technology. A narrow beam of x-rays is delivered to the brain, passes through it, and exits on the other side. The exiting beam is then collected by a set of detectors, converted into digital data, and fed into a computer for image reconstruction. As the beam passes through, the brain undergoes attenuation due to interaction with the various tissues along the pathway. The degree of attenuation depends on the tissue density: very dense tissue, like bone, attenuates lots of x-rays; gray matter attenuates some, and fluid even less.

TO USE MAGNETIC RESONANCE IMAGING – OR NOT

Advantages:

  • Greater soft tissue contrast provides better definition of anatomic structures and greater sensitivity to pathologic lesions;
  • Multiplanar capability of MRI displays dimensional information and relationships. MRI can better demonstrate physiologic properties of tissue such as water diffusion or biochemical makeup (using magnetic resonance spectroscopy).

Disadvantages:

  • Many patients feel claustrophobic inside the MR unit, because a complete study can last 20 to 60 minutes. Some low-magnetic-field “open” systems are available, but these systems sacrifice image quality because of the lower signal-to-noise ratio.
  • MRI is contraindicated in patients with some metallic implants — cardiac pacemakers and cochlear implants, for example.
  • Although no harmful effect of MRI has been demonstrated in pregnant women or fetuses, some authorities consider pregnancy a relative contraindication to MRI because safety data are incomplete. The need and benefits of the MRI study should be considered in relation to potential unknown risk to the fetus in early pregnancy.

Source: Merritt's Neurology. Tenth Edition. Lippincott, Williams & Wilkins. 2000.