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Editorial |
1 From the Department of Radiology, Division of Neuroradiology, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. Received December 29, 2000; accepted January 5, 2001. Address correspondence to the author (e-mail: rbschwartz@partners.org).
Index terms: Alzheimer disease, 10.83, 1341.83 • Brain, MR, 13.121412, 13.121413, 13.121416, 13.12146 • Editorials • Hippocampus, 1341.83 • Magnetic resonance (MR), diffusion study, 13.121412, 13.121413, 13.121416, 13.12146, 13.92 • Magnetic resonance (MR), tissue characterization, 13.121412, 13.121413, 13.121416, 13.12146, 13.92
In their article in this issue of Radiology, Kantarci et al (1) examine the apparent diffusion coefficient (ADC) and anisotropy index from various brain regions obtained at magnetic resonance (MR) imaging in 21 patients with probable Alzheimer disease, 19 patients with mild cognitive impairment (MCI), and 55 normally aging elderly control subjects. They found that the ADC of multiple brain areas, including the hippocampus, temporal stem, posterior cingulate, and occipital and parietal white matter, are significantly elevated in patients with Alzheimer disease compared with ADCs in control subjects. Moreover, hippocampal ADCs were significantly higher in patients with MCI than in control subjects (1).
This is the latest in a series of excellent articles from the Mayo Clinic group that aim to investigate the clinical-radiologic correlates in Alzheimer disease and associated conditions. Alzheimer disease is a degenerative brain disease that accounts for more than 85% of all dementing illnesses. Its cause is uncertain, but its ramifications are all too clear. The disease starts with subtle memory and cognitive impairments and proceeds inexorably to rob its victims of their ability to function independently and finally of their very identity. Alzheimer disease imposes a severe emotional and financial burden on the patients and their caregivers. On the national scale, Alzheimer disease affects approximately 4 million Americans, and the cost of caring for them is more than $80 billion per year. Moreover, on the basis of current rates of disease, it is estimated that in 50 years there will be as many as 14 million cases of Alzheimer disease in the United States alone. Alzheimer disease has been characterized as "the coming plague of the twenty-first century" (2).
Identification of patients at risk for Alzheimer disease is an important goal, because this might allow early therapeutic intervention with cholinesterase inhibitors, vaccines, or other drugs that might forestall cognitive decline. Such early treatment might prolong the period of patient autonomy and even prevent the onset of severe dementia. MCI is a recently characterized clinical entity that appears to represent a boundary or transitional state between normal aging and Alzheimer disease (3,4). Patients with MCI have memory complaints but have normal general cognitive function, and they progress to frank Alzheimer disease at a rate of 10%–15% per year (4). To establish the prognostic importance of MCI, studies such as that performed by Kantarci et al (1) are important and necessary.
Many studies have described volumetric analysis of the brain with MR imaging in Alzheimer disease. The most constant finding in these reports is decreased volumes of the hippocampal and perihippocampal regions. This is in keeping with autopsy data showing that neurofibrillary tangles, amyloid plaques, and atrophy occur first in the hippocampal formation and entorhinal cortex before progressing elsewhere (5). Jack et al (6) and Csernansky et al (7) showed that hippocampal measurements provide a sensitive marker of anatomic degeneration in patients in the earliest stages of Alzheimer disease. Fox et al (5) found significantly decreased hippocampal volumes in patients at risk for the disease prior to developing overt clinical symptoms. Visser et al (8) found that among patients with MCI, those who developed Alzheimer disease within 3 years had significantly decreased volume of the perihippocampal regions compared with those who did not develop Alzheimer disease in that time period. Johnson et al (9) performed single photon emission tomography, or SPECT, studies that depicted abnormal cerebral perfusion or metabolism in the perihippocampal regions and in the cingulate and thalamus in patients with mild cognitive impairment who developed Alzheimer disease within 2 years.
There have been very few studies, however, that have examined ADCs in Alzheimer disease and none prior to the report of Kantarci et al (1) that have investigated ADCs in MCI, to my knowledge. The authors have performed a thoughtful and careful analysis that improves on earlier work (10,11); by specifically segmenting out the hippocampus and other structures and excluding cerebrospinal fluid from their data, they were able to accurately establish consistent regional differences in ADCs between subject groups. It should be stressed that these differences are quite subtle and are not visible to the naked eye on MR images; ADCs have to be calculated and the values compared with statistical tests. The authors admit that owing to variability in ADCs and overlap between subject groups, ADC cannot be reliably used in an individual patient to help diagnose MCI or Alzheimer disease or predict the likelihood of progression from MCI to Alzheimer disease. Similarly, substantial variability in anisotropy indexes between groups negated any possible effects of decreased fiber density that may have been present in patients with MCI or Alzheimer disease. Higher field strengths and improvements in gradient coils and postprocessing techniques will almost certainly continue to increase the accuracy of diffusion-weighted MR imaging techniques in the evaluation of patients with MCI and Alzheimer disease. In the future, ADC and anisotropy indexes might also be used to help differentiate patients with these diseases from those with other dementing illnesses such as multi-infarct dementia, Pick disease, or progressive supranuclear palsy.
Kantarci et al (1) believe that the diffusivity of water is focally increased in patients with Alzheimer disease because of loss of myelin and axonal processes and damage to cell membranes that result in expansion of the extracellular spaces. It is possible, even likely, that ADCs increase before differences in hippocampal volume manifest radiologically and possibly even before abnormalities become evident on functional MR imaging studies. It would be very interesting to directly assess this possibility by comparing focal volumetric and functional data with ADCs.
As described in a recent State of the Art article in this journal by Shaefer et al (12), diffusion-weighted MR imaging is now used clinically in the evaluation of an increasing variety of other neurologic conditions including ischemia or infarction, neoplasms, infection, trauma, and demyelination. However, Kantarci et al (1) suggest that this technique might also be applied in investigation of the functional neuroanatomy of normal brain. One of the more intriguing results of their study is that ADC in the left thalamus in normally aging elderly people is significantly lower than that in the right thalamus. The authors hypothesize that this finding might reflect tighter packing of neurons in the left thalamus. If so, one wonders whether ADCs might also be asymmetrically reduced in the Broca and Wernicke areas, reflecting the known histologic differences in these regions that may underlie language dominance (13). Indeed, in the near future, with improvements in diffusion-weighted MR imaging techniques, regional variations in the cytoarchitecture of the brain may be reflected in focal differences in the diffusivity of water on ADC maps; furthermore, refinements in anisotropy mapping could help define the intracortical fiber connections between these regions. Such data might ultimately enable us, at the dawn of the 21st century, to generate a map of the living human brain to rival or even surpass that developed by Brodmann (14) at the outset of the 20th.
FOOTNOTES
Abbreviations: ADC = apparent diffusion coefficient, MCI = mild cognitive impairment
See also the article by Kantarci et al (pp 101–107 ) in this issue.
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