1H-MRS Differentiates White Matter Hyperintensities in Subcortical Arteriosclerotic Encephalopathy From Those in Normal Elderly
Background and Purpose White matter hyperintensities in MRI of the brain are often seen in normal elderly subjects. Radiologically, these hyperintense regions are similar to those in symptomatic patients with subcortical arteriosclerotic encephalopathy (SAE). Our aim was to discriminate white matter hyperintensities (WMH) on MRI in patients with SAE from similar appearing changes in normal elderly.
Methods Three groups of elderly patients were studied: symptomatic patients with WMH of SAE (n=5); asymptomatic subjects with diffuse, confluent WMH (n=4); and elderly control subjects (n=5). Proton density images revealed WMH in the occipital lobes. Proton magnetic resonance spectroscopy (1H-MRS) was used to acquire spectra in these hyperintensities. Metabolite concentrations were calculated from peak areas of N-acetylaspartate (NAA), creatine (Cre), and choline (Cho).
Results The NAA/Cre and NAA/Cho ratios were reduced in the SAE group compared with the two asymptomatic groups (P<.05). NAA was decreased and Cho elevated in SAE compared with control subjects (P<.05). The average volumes of WMH in the SAE group (65.5 cm3) and in asymptomatic control subjects (59.4 cm3) were similar, and greater than those of the normal control group (4.0 cm3).
Conclusions Proton MRS discriminates WMH in SAE patients from those in asymptomatic elderly, suggesting differing causes of the hyperintensities.
- Binswanger’s disease
- spectroscopy, nuclear magnetic resonance
- subcortical arteriosclerotic encephalopathy
White matter hyperintensities in MRI of the brain are seen in many otherwise normal elderly.1 2 3 4 5 Radiologically, these regions appear similar to those seen in patients with SAE and are hyperintense on both proton density and T2-weighted imaging, suggesting ischemia or demyelination as the underlying cause. However, the etiology of these changes in asymptomatic elderly and their relationship with neuropsychological test results are unclear. A method for identifying patients with pathological white matter changes associated with dementia would be valuable for clinical management and long-term studies.
1H-MRS reveals information about brain metabolism. 1H-MRS signals in normal adult brain arise primarily from N-acetyl moieties of NAA, Cre, and Cho. NAA, which is located almost entirely in neurons and axons, is reduced in many diseases, suggesting neuronal injury or death.6 7 Cho is elevated following demyelinating processes or gliosis.7 8
We have now used 1H-MRS to measure metabolites in regions of abnormal-appearing white matter to detect biochemical differences between asymptomatic elderly and symptomatic patients with suspected vascular dementia. We compared these groups with age-matched asymptomatic subjects with normal MRI.
Subjects and Methods
Three subject groups were studied: five subjects with subcortical dementia and diffuse white matter changes; four asymptomatic elderly subjects with diffuse WMH; and five asymptomatic elderly subjects with minimal white matter changes. The protocol was approved by the University of New Mexico (UNM) Human Research Review Committee. All subjects gave informed consent before study.
Asymptomatic Subject Group
Normal independent living elderly subjects were part of the UNM Aging Process Study that began in 1981. Neurological examination of both groups of normal elderly subjects was unremarkable except for several subjects with reduced ankle reflexes and difficulty with tandem gait.
Symptomatic Patients With Diffuse White Matter Hyperintensities
This subgroup comprised patients with large, confluent WMH similar in size to those in the asymptomatic elderly subjects with WMH. Each had subcortical dementia, extensive white matter changes, and other neurological findings, such as gait problems, hyperreflexia, and visual disturbances, consistent with the diagnosis of probable vascular dementia.9 10 Clinical data are summarized in Table 1⇓.
Magnetic Resonance Examination
Subjects were studied using a 1.5-T scanner (GE Medical Systems). Axial proton density/T2 weighted images (TE=30/100 ms, TR=2800 ms, 5 mm slices) were acquired to locate hyperintensities. 1H-MRS was carried out in WMH in the occipital lobe posterior to the lateral ventricle. Double spin-echo localization and selective excitation/homospoil water suppression were used (TE=136 ms, TR=2000 ms, 128 scans, 8 cm3 voxels). Voxels were located to ensure most of their volume comprised WMH. An automated sequence, which set radiofrequency pulse power, optimized the magnetic field homogeneity, and adjusted the water suppression was used.11 The total imaging and spectroscopy scan time was about 40 minutes.
Total volumes of WMH were determined by manual tracing of each lesion by a reviewer blinded to subject category using custom-designed software and a Digital MicroVax GPX II (Digital Equipment Corp). A Sun Sparcstation 10/30 workstation (Sun Microsystems) was used for spectral data analysis using SAGE/IDL software (GE Medical Systems). Following exponential filtering (LB=1 Hz), zero filling, and Fourier transformation, the peaks for water, NAA, Cre, and Cho were fitted using a Marquardt fitting algorithm, and the ratios for NAA/Cre, NAA/Cho, and Cho/Cre were then calculated. Absolute concentrations of metabolites were determined for all but 2 SAE subjects using water as an internal standard and assuming a constant water content.12 13
Data were expressed as mean±SD. Comparisons were done using two-tailed Student’s t tests at the 95% significance level.
The mean metabolite ratios for NAA/Cre, NAA/Cho, and Cho/Cre; total WMH volumes; and age of each subject group are summarized in Table 2⇓. The symptomatic group was younger than either of the asymptomatic (control) groups. Volumes of the WMH were similar in symptomatic and asymptomatic groups, and the lesion load for each of these groups was considerably greater than the normal control group (P<.01).
1H-MRS revealed three major peaks: NAA at 2.0 ppm, Cre at 3.0 ppm, and Cho at 3.2 ppm. Lactate was not found in any spectra. The Figure⇓ shows proton-density–weighted images and spectra from representative patients: (panel a) a normal control subject, (panel b) an asymptomatic subject with severe WMH, and (panel c) a subject with SAE with large confluent periventricular white matter hyperintense regions.
There were no differences in age or spectroscopic results between the asymptomatic groups and they were combined into a single asymptomatic control group. This combined group showed marked spectroscopic differences from the SAE patients. NAA/Cre and NAA/Cho were significantly decreased (P<.05 and P<.01, respectively) and Cho/Cre increased (P<.05) (Table 2⇑).
The concentration of NAA was reduced in symptomatic subjects compared with asymptomatic subjects (P<.05) and Cho was elevated (P<.05). There was no significant difference in Cre between the groups.
Proton MRS shows biochemical abnormalities in many brain diseases. A fall in NAA is nonspecific and has been associated with neuronal injury in stroke and multiple sclerosis.14 15 Our results using metabolite ratios suggest that large, confluent WMH in asymptomatic elderly subjects were metabolically indistinguishable from normal-appearing white matter in age-matched control subjects. However, WMH in symptomatic patients with SAE showed marked changes consistent with neuronal injury; decreased NAA/Cre and NAA/Cho, and elevated Cho/Cre compared with asymptomatic subjects. Thus, spectroscopy showed biochemical differences in WMH regions that appeared similar on MRI, suggesting that WMH of aging may have different underlying metabolic causes.
We examined left occipital white matter beside the posterior horn of the lateral ventricle in all subjects. Other investigators have reported differences in NAA/Cre in asymptomatic subjects with occipitoparietal WMH16 and in frontal hyperintense white matter regions contralateral to ischemic stroke.17 In contrast to each of these studies, our age-matched asymptomatic subjects with WMH, who are participating in a long-term study of aging, were well-characterized elderly without known vascular disease. None had other recorded clinical events likely to cause hyperintensity in the brain.
Moderate to severe WMH are observed on MRI in 30% of normal elderly.2 The clinical significance of these changes is intensely debated. Patients with hypodensity of the frontal white matter on CT have a higher incidence of gait problems.18 Correlation of WMH with intellectual function has been observed by one group19 but not by others.2 3 20 Differences in study populations and in the battery of tests administered may explain these discrepancies. Lesions of the white matter are more prevalent in patients with hypertension.21 Pathological studies of brains with WMH have shown a variety of findings including demyelination, ischemia, and enlarged perivascular spaces of Virchow-Robin.1 22 23
Classification of elderly demented patients with nonhereditary, chronic, progressive forms of leukoencephalopathy is controversial. Most agree that within the vascular dementias there is one group with a stepwise, fluctuating course involving large vessel disease with multiple infarctions, and a second group with a progressive form of dementia associated with disease of the smaller blood vessels. Various names have been given to the latter syndrome, including leukoaraiosis, SAE, Binswanger’s disease, probable vascular dementia, and chronic microvascular leukoencephalopathy. WMH in patients with neurological symptoms and signs can have a variety of causes, including multiple sclerosis, familial and nonfamilial forms of adult-onset leukodystrophy, systemic lupus erythematosus, antiphospholipid syndrome, encephalitis, progressive multifocal leukoencephalopathy, CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), and cerebrovascular disease. Although exact classification will remain difficult without autopsies, our patients could be best classified as probable vascular dementia or SAE because of a progressive course with subcortical dementia, gait disturbances, hyperreflexia, visual disturbances, and extensive changes in the white matter on MRI.9 10
Several theories have been proposed to explain the observed changes in white matter. These include brain edema, hypoperfusion of the tissue secondary to episodes of hypotension, and a primary abnormality of myelin. Multiple pathological substrates underlying the radiological changes are likely. Clinical findings in SAE invariably include a gradual progression with subcortical dementia and white matter changes on MRI. Other features that are variably present include hypertension, syncope, seizures, and gait difficulty with imbalance and spasticity.24 25 Demyelination with arteriosclerotic vascular change is seen at autopsy in SAE.26 27
Results from 1H-MRS have commonly been reported as ratios normalized to Cre. However, to confirm that our findings were due to changes in NAA rather than Cre we used quantitative methods to measure NAA, Cre, and Cho concentrations.12 13 Comparing the two asymptomatic groups, we found that the concentration of each metabolite was reduced by a similar amount in WMH, ie, NAA (12%), Cre (11%), and Cho (9%), suggesting a common cause for the decrease, such as increased water reducing metabolite concentration across the voxels. In contrast, the SAE group had a 27% mean decrease of NAA, little change in Cre, and a 33% elevation of Cho. These data are consistent with neuronal damage as shown by decreased NAA and probable demyelination indicated by Cho changes, consistent with the clinical findings in SAE.28
The main conclusions of this study are that WMH in elderly, asymptomatic individuals are metabolically similar to normal-appearing white matter in age-matched subjects with minimal brain changes. 1H-MRS in patients with SAE shows metabolic changes consistent with chronic demyelination or ischemia, separating them from asymptomatic elderly with WMH. Further long-term follow-up studies of a larger group of symptomatic and asymptomatic subjects will be required to confirm the current findings and to learn whether clinical and biochemical progression takes place. Presently the classification of vascular dementias is based mainly on clinical criteria with supporting radiological findings. Biochemical data obtained by 1H-MRS may be additional criteria.
Selected Abbreviations and Acronyms
|1H-MRS||=||proton magnetic resonance spectroscopy|
|SAE||=||subcortical arteriosclerotic encephalopathy|
|WMH||=||white matter hyperintensities|
Patients were studied in the General Clinical Research Center at the University of New Mexico under grant 5MO1-RR00997. Other funding came from the State of New Mexico, NIH RO1 [AG12845 and AG02049], and a VA Merit Review to Dr Rosenberg. We thank Dr Peter Barker and Helen Petropoulos for analysis software.
Presented in part at the American Academy of Neurology meeting, May 1992 (Neurology. 1992;42:397); the XVth World Congress Neurology, Vancouver, Canada, 1993; and the 3rd Scientific Meeting of the Society of Magnetic Resonance, Nice, France, 1995.
- Received February 10, 1997.
- Revision received June 24, 1997.
- Accepted June 24, 1997.
- Copyright © 1997 by American Heart Association
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