Leukoencephalopathy and major depression: A preliminary report

Psychiatry Research: Neuroimaging, 45:169-175

169

Elsevier

Leukoencephalopathy and Major Depression: A Preliminary Report Barry H. Guze and Martin P. Szuba Received January 21, 1992; revised version received July 17, 1992; accepted September 5, 1992.

Abstract. The comparative prevalence of leukoencephalopathic changes in 119 young and old inpatients and outpatients with major depression was examined. Patients underwent magnetic resonance imaging (MRI) examinations with T land T2-weighted pulse sequences. Leukoencephalopathic changes were uncommon in depressed patients and medical control subjects younger than 45 years of age. Such changes were, however, seen in approximately 44% of older depressed patients and 30% of elderly medical control subjects. Key Words. Magnetic resonance imaging, affective disorder, aging. Reports have described leukoencephalopathy (also called periventricular white matter hyperintensities, deep white matter hyperintensities, or unknown bright objects ["UBOs"]) in elderly depressed patients (Coffey et al., 1987, 1988, 1989; Krishnan et al., 1988; Swayze et al., 1990; Zubenko et al., 1990; Lesser et al., 1991; Rabins et al., 1991) and young bipolar subjects (Dupont et al., 1990; Swayze et al., 1990; Figiel et al., 1991). These lesions are thought to reflect changes ranging from arteriosclerotic disease of the medullary arteries supplying subcortical brain regions (Coffey et al., 1988) to arteriolar hyalinization and rarefaction (George et al., 1986a). They are not usually seen in healthy individuals younger than age 45 (George et al., 1986b). A study of the prevalence of deep white matter hyperintensities in a tertiary care adult psychiatric population revealed that 42% of all patients, regardless of age or diagnosis, had such lesions compared with 12% of control subjects (Deicken et al., 1991). We examined the comparative prevalence of leukoencephalopathic changes in young and old inpatients and outpatients with major depression who were receiving psychiatric care at the UCLA Neuropsychiatric Hospital, a tertiary care center. Because the prevalence of leukoencephalopathy changes as a function of age in normal adults (George et al., 1986b; Deicken et al., 1991), our hypothesis was that these changes would be uncommon in younger depressed patients, but not uncommon in older subjects.

Barry H. Guze, M.D., is Assistant Professor of Psychiatry and RadiologicalSciencesand Director of the Adult Psychiatry Inpatient Service at the University of California at Los Angeles (UCLA). Martin P. Szuba, M.D., is Assistant Professor of Psychiatry and Associate Director, Adult Psychiatry Inpatient Service, UCLA. (Reprint requests to Dr. B.H. Guze, NeuropsychiatricInstitute, UCLA, 760 Westwood Plaza, Rm. 27-384 NPI, Los Angeles, CA 90024-1759, USA.) 0165-1781/92/$05.00 © 1992 ElsevierScientificPublishers Ireland Ltd.

Methods During a 33-month period, 119 patients who met D S M - I I I - R criteria (American Psychiatric Association, 1987) for major depressive disorder (unipolar type) underwent magnetic resonance imaging (MRI) while receiving psychiatric care at the UCLA Neuropsychiatric Institute and Hospital. All scans were independently reviewed by board-certified UCLA radiologists. Patients fulfilled established criteria for neuroimaging (Weinberger, 1984) and were, therefore, a selected sample rather than consecutive admissions. Control patients underwent MRI examinations for the evaluation of headache or migraine~ They were inpatients and outpatients seen in the Departments of Medicine or Neurology at the UCLA Hospital and Clinics. Control subjects were free of hypertension, prior neurosurgery, brain tumors, or a history of significant head injury. Control subjects were also free of a history of psychiatric illness and substance abuse. Subjects received physicaL, neurological, and mental status examinations from their treating physician. Four groups were established: There were two young groups, one consisting of all depressed patients younger than 45 years of age, and the other consisting of all control patients younger than age 45. The two older groups consisted of all depressed patients older than 45 and a group of control patients older than 45. The 60 control patients were selected so as to consist of 30 individuals below age 45 and 30 individuals older than 46. The cutoff age of 45 was chosen because of the reported low prevalence of leukoencephalopathic changes in patients younger than 45 years of age (George et al., 1986b). Patients were examined using a Fonar 0.3 Tesla MR scanner. T~- and T2-weighted transaxial images were obtained (typically, TE - 28 and TR = 500; TE = 84 and TR = 2000). FOV was 25.6; NEX was 4 for T~, and 2 for T 2. Slice thickness was 7 mm with a 3-mm interslice gap. The brain was imaged from the base of the skull to the vertex. Lesions were identified on review of T~ and T 2 images by experienced neuroradiologists. Images were read from standardized format film copies. Statistical analyses for categorical data were done with Fisher's exact test (two-tailed) when the combined number of subjects in two groups was fewer than 100, and with X 2 tests when the combined number of subjects was more than 100.

Results T a b l e 1 presents d e m o g r a p h i c a n d clinical characteristics of the subjects. T h e r e was no significant difference in the presence of psychosis in the t w o d e p r e s s e d p a t i e n t g r o u p s ; 16% o f the y o u n g patients were psychotic, a n d 18% of the elderly patients were also psychotic. Psychosis was defined as the presence of h a l l u c i n a t i o n s , delusions, or both. O f the 75 o l d e r d e p r e s s e d p a t i e n t s w h o u n d e r w e n t an M R I e x a m i n a t i o n , 42 (56%) h a d negative scans and were, therefore, free of visualized s t r u c t u r a l b r a i n p a t h o l o g y . Three patients (4%) had significant positive results u n r e l a t e d to l e u k o e n c e p h a l o p a t h y ( T a b l e 2). O f the 44 y o u n g e r d e p r e s s e d p a t i e n t s , only two (5%) had leukoenc e p h a l o p a t h i c changes (Table 3). Ten (22%) of the y o u n g depressed patients h a d s t r u c t u r a l b r a i n a b n o r m a l i t i e s u n r e l a t e d to l e u k o e n c e p h a l o p a t h y . N o n e of the y o u n g c o n t r o l p a t i e n t s h a d l e u k o e n c e p h a l o p a t h y , but three (10%) o f the o l d e r c o n t r o l subjects d i d have such findings. Overall, 35 (29%) o f the patients, regardless of age, h a d l e u k o e n c e p h a l o p a t h i c changes. In the o l d e r d e p r e s s e d g r o u p , l e u k o e n c e p h a l o p a t h y , when noted by the n e u r o r a d i o l o g i s t s , was m o s t frequently o b s e r v e d in f r o n t a l lobe white matter.

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Table 1. Patient characteristics

n

Mean age (yr)

Mean age at % % onset Female Psychotic (yr)

Mean duration Mean of number illness of (yr) hospitalizations

Younger depressed patients

4 4

33.4

70%

16%

21

11.6

2

Younger controls

3 0

34.1

70%

0%

N.A.

N.A.

N.A.

Older depressed patients

7 5

66.2

60%

18%

43

24.2

5

Older controls

3 0

68.7

60%

0%

N.A.

N.A.

N.A.

Note. N.A.= not applicable.

Statistical analysis for categorical data, using the X 2 method, revealed a significant difference in the prevalence of leukoencephalopathic changes between older and younger patients 0(2 _-- 21, df = 1, p = 0.00005). There was also a significant difference between younger and older patients in the prevalence of all lesions, leukoencephalopathic and otherwise 0( 2 = 7.5, df-- 1, p -- 0.006). Fisher's exact test revealed no differences between younger patients and younger controls in the prevalence of leukoencephalopathic lesions (p = 0.35), but there were differences in the prevalence of all lesions seen on M R I between young depressed patients and young control patients 0(2 = 7.8, df = 1, p -- 0.003). There were no differences

Table 2. Abnormal MRI findin~ls Patient #

Age (yr)

1 2 3 4 5 6 7 8

19 21 23 27 31 38 40 40

9 10 11 12 13

40 41 49 56 58

Findings Hyperintense cerebellar lesion 5-6 mm hyperintense circular orbit Temporal lobe gliosis Enlargement of the lateral ventricles; periventricular bright lesions Demyelinization, frontal lobe disease Caudate atrophy Encephalomacia with sclerosis in the anterior temporal lobe Central atrophy of the deep structures; several deep white matter ischemic lesions; diffuse cortical atrophy Sclerosis in the temporal lobe Frontal lobe tumor Multiple, small infarcts in the basal ganglia, mid-pons Pineal cyst Infarction of the corona radiata

Note. These are the nonleukoencephalopathicchangesfound in 119 depressedpatients.

r72 between older depressed patients and older control patients in the prevalence ol leukoencephalopathic changes (p ::- 0.2), while there were differences in tilt prevalence of all lesions between older depressed patients and older control patient~ (X2 = 21.9, d f =- 1, p = 0.000003). Further, young control patients had fewe~ leukoencephalopathic changes than did the older control patients (X: .... i0.6, d / - : p = 0.001).

Table 3. Prevalence of leukoencephalopathic changes and other abnormalities Abnormal Leukoencephalopathy % (n) % (n) Younger patients Younger controls Older patients Older controls

44 30 75 30

23% 0% 4% 0%

(10) ~ (0) (3) ~ (0)

5% (2) 0% (0) 44%(33) 30% (9)

1. Other abnormalities (see Table 2).

Discussion We found that leukoencephalopathic changes characterized 29% of a selected sample of 119 unipolar depressed patients who received treatment in our tertiary care facility. The bulk of these leukoencephalopathic findings occurred in patients older than 45 years of age, and such changes were rare in young depressed patients. We confirmed our hypothesis that the prevalence of leukoencephalopathic changes would increase rapidly in patients older than 45 years of age. It should also be noted that in the population of young depressed patients, 22% had other abnormalities on MRI. This suggests that our tertiary population may not be representative of all nonhospitalized depressed patients, in that they may be more likely to show alterations of the central nervous system. Our finding that 44% of older mood disorder patients have leukoencephalopathy is in keeping with other reported prevalence figures (Coffey et al., 1987, 1988, 1989; Krishnan et al., 1988; Swayze et al., 1990; Zubenko et al., 1990; Lesser et al., 1991; Rabins et al., 1991). In that sense, we have replicated prior work demonstrating that depression in the elderly is associated with a significantly higher prevalence of subcortical leukoencephalopathic changes in the periventricular white matter. We have extended the scope of the study of leukoencephalopathy to include younger depressed patients and found that leukoencephalopathic changes are rare in young unipolar depressives. It should be noted that there are reports of an increased frequency of such changes in young bipolar patients (Dupont et al., 1990; Swayze et al., 1990; Figiel et al., 1991), in contrast to the unipolar depressed patients studied here. However, our finding that 30% of elderly control subjects have leukoencephalopathy is somewhat lower than the percentage reported for the normal elderly (Brant-Zawadzki et al., 1985; Fazekas et al., 1987; Rezek et al., 1987). Rating scales that attempt to quantify the amount of leukoencephalopathic changes seen in an MRI scan may produce significant differences between depressed

173 patients and control subjects, while comparisons based solely on the interpretations of neuroradiologists may not find such differences (Coffey et al., 1990). The fact that we did not use quantitative ratings in this study would tend to result in some degree of underestimation of the prevalence of leukoencephalopathy. While any such underestimation would most likely occur with an equal prevalence in both older and younger patients, caution is still advisable in interpreting our results. It has been suggested that leukoencephalopathy may shed light on the pathophysiology of geriatric depression (Coffey et al., 1988). It is also possible that leukoencephalopathy is more a function of aging and that leukoencephalopathic changes beyond a critical threshold may increase vulnerability to depression. Our data do not directly address this possibility because the leukoencephalopathic changes were not quantified in this study. However, it is clear that a complete explanation for the increased prevalence of leukoencephalopathic changes is still pending. In all probability, such changes will not prove to be due to a simple, single etiology. Rather, multiple factors such as, for example, changes in brain perfusion pressure at the level of the microvasculature secondary to cardiovascular or cerebrovascular disease (George et al., 1986a; Coffey et al., 1988) will be important, but not exclusive, causes. Others have suggested that the increased prevalence and severity of depression in the elderly may be due to cerebrovascular dysfunction (Post, 1962; Roth, 1986). Some have argued that the hypotensive and cerebrovascular effects of antidepressant treatment could contribute to the development or exacerbation of leukoencephalopathic changes (Dupont et al., 1990). However, our finding that younger unipolar depressives with a preexisting disease history have a low prevalence of leukoencephalopathy suggests that antidepressant medications are not the major contributing factor to the development of this pathology. This does not exclude the possibility that chronic use of antidepressants, unlike short-term administration, may play a role. It is quite possible that other "epiphenomena" associated with recurrent episodes of depression may also contribute. Such factors as drug and alcohol abuse and fluctuations in diet and weight, common in depression, could all be contributing factors. The increased prevalence of leukoencephalopathy in the elderly may be a phenomenon of aging or may reflect a different pathology in geriatric depression. The failure to find such lesions with any significant frequency in healthy adults with major depression who are younger than 45 is consistent with either hypothesis. It is clear that the role of aging in the development of these lesions remains undetermined. Our data suggest that unipolar depression in young patients may not be consistently associated with leukoencephalopathy.

Acknowledgments. The authors thank Phyllis Davis for excellent secretarial support and Bobby Keen, B.S.R.T., Valerie Gausche, B.S.R.T., and Lori Bartfield, R.N., for valuable assistance in collecting and organizing the data for this project. The research reported was supported by the National Institute of Mental Health (Academic Career Development Award 1 KO7 MH-00912 to Dr. Guze and National Institute of Mental Health Training Grant T32 MH-17146 to Dr. Szuba) and the National Association for Research in Schizophrenia and Depression (NARSAD Young Investigator Award to Drs. Guze and Szuba).

174

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