Frontal Cerebral Perfusion Dysfunction in Elderly Late-Onset Major Depression Assessed by 99MTC-HMPAO Spect

NeuroImage 14, 202–205 (2001) doi:10.1006/nimg.2001.0787, available online at http://www.idealibrary.com on

Frontal Cerebral Perfusion Dysfunction in Elderly Late-Onset Major Depression Assessed by 99MTC-HMPAO Spect Vı´ctor Navarro,* Cristo´bal Gasto´,* Francisco Lomen˜a,† Jose´ J. Mateos,† and Teodoro Marcos* *Clinical Institute of Psychiatry and Psychology; and †Department of Nuclear Medicine, Hospital Clinic, Barcelona, Spain Received August 7, 2000; published online May 11, 2001

Baseline regional cerebral blood flow of thirty unmedicated late-onset unipolar major depressed patients over the age of 60 years and 20 sex-, age-, and vascular risk factor-matched healthy controls was imaged with single photon emission computed tomography, using technetium-99m hexamethylpropylene amine oxime as a tracer. To avoid errors of diagnosis—in particular, confusion between major depression and organic cognitive impairment— only treatment responders were included in the final sample. Statistically significant differences were observed in both left and right anterior frontal regions, with reduced uptake in depressed patients; these differences were more pronounced in the left hemisphere. Among patients, there was no correlation between regional cerebral blood flow and the severity of baseline symptoms. Our results support the hypothesis that certain neuroanatomic regions of the central nervous system may be functionally involved in elderly unipolar major depression, particularly in the late-onset subgroup. © 2001 Academic Press

INTRODUCTION It is often difficult to distinguish clinically between elderly patients with a depressive disorder and reversible cognitive impairment and those with progressive neurodegenerative dementia and comorbid depression (Alexopoulos et al., 1993; Emery and Oxman, 1992). As a result, studies describing accurate diagnostic methods are of considerable interest. It has been suggested that functional neuroimaging studies, such as single photon emission-computed tomography (SPECT) and positron emission tomography (PET), could complement studies of brain structure which have demonstrated structural neuroimaging abnormalities in depressed patients, particularly in older subjects (Alexopoulos et al., 1992; Coffey et al., 1993; Ketter et al., 1994). To our knowledge, only four previous controlled SPECT studies have exclusively targeted depressed patients over 60 years (Curran et al., 1993; Ebmeier et 1053-8119/01 $35.00 Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.

al., 1997, 1998; Philpot et al., 1993; Upadhyaya et al., 1990). None of these studies focused solely on unmedicated late-onset unipolar depressed patients without progressive cognitive impairment over a follow-up period. The main aims of our study were to compare brain SPECT images in a group of non-demented unmedicated elderly late-onset unipolar major depressed patients and a group of non-depressed age-matched control subjects, and to examine the relationship between brain uptake ratios and certain clinical and sociodemographic characteristics in depressed patients. MATERIALS AND METHODS Subjects The study was conducted at the Hospital Clı´nic of Barcelona. Right-handed in- and out-patients aged 60 or over with DSM-IV criteria (American Psychiatric Association, 1994) for current unipolar major depression were recruited. Only late-onset depressed subjects were included, i.e. those in whom depression had begun after the age of 50. Patients were clinically assessed to exclude those with associated psychiatric diagnoses or neurological disease, and those taking medication with potential central nervous system side effects. Depressive symptoms were rated on the 17-item Hamilton Rating Depression Scale (HRDS; Hamilton, 1960) and on the Newcastle Scale (Carney et al., 1965). All patients had to have a baseline HRDS score of 21 or greater. A baseline Newcastle Scale score of 7 or higher was used to define endogenous depression. We also screened for reduced global cognitive function, defined as a score of 25 or lower on the Mini-Mental State Examination (MMSE; Folstein et al., 1975). Vascular risk factors were rated as suggested in Baldwin and Tomenson (1995; score 0 ⫽ absent, score 3 ⫽ severe). All subjects were studied off psychotropic drugs. In those receiving antidepressant therapy, a minimum of 10 days washout period was required. None had been receiving fluoxetine or monoamine oxidase inhibitors.

202

203

SPECT IN ELDERLY DEPRESSION

Patients who had been receiving benzodiazepine therapy were drug-free for a minimum of 2 days prior to the study. Right-handed, drug-free control subjects aged 60 or over were recruited. They had no personal history of psychiatric illness or substance abuse. To reduce the chance of errors of diagnosis both patients and controls included in the final sample had to meet three longitudinal criteria: absence of dementia according to the DSM-IV criteria, MMSE score was above 25, and HRDS score was below 8 after a 12-month follow-up period. Treatment (drug or electroconvulsive therapy) was adjusted to standard therapeutic norms. The study was approved by our hospital’s ethical committee. All patients and control subjects gave informed written consent. SPECT Procedure A drug-free baseline technetium-99m hexamethylpropylene amine oxime ( 99mTc-HMPAO) brain SPECT study was performed in each subject. A plastic cannula was inserted into an arm vein 10 –20 min before the injection of the tracer. The subjects were seated in a quiet room with their eyes open 5 min before and after the tracer injection. SPECT was performed using a rotating dual-head gammacamera (Helix, G.E.M.S.), fitted with a high resolution fanbeam collimators. Data acquisition started 20 min after intravenous injection of 740 MBq of 99mTc-HMPAO (Ceretec, Nycomed-Amersham). Sixty 30-s frames were collected in a 360° circular orbit, step, and shoot mode, using a 128 ⫻ 128 matrix. Image data were processed on a Elscint SP1 computer (Apex SP-X software, Version 3.12). Reconstruction was performed by filtered backprojection and using a Metz Filter (FWHM ⫽ 10; power factor ⫽ 3). No attenuation correction was performed. The final pixel size was 3.9 mm and the full-width at half-maximum (FWHM) in the transaxial plane was 10 mm. Semiquantitative regional cerebral blood flow (rCBF) analysis was performed using irregular regions of interest (ROIs) stored in the computer as a template. The template was obtained from a standard T1weighted magnetic resonance imaging. The ROIs were placed by the same nuclear medicine physician in ten 7.8-mm-thick oblique slices, which were parallel to the frontocerebellum plane. For each hemisphere, anterior frontal-to-cerebellum ratios were obtained as 100 ⫻ mean counts per pixel of anterior frontal ROIs divided by the mean counts per pixel of cerebellum ROIs. Using the same formula, posterior frontal, anterior and posterior temporal, parietal, occipital, striatum, thalamus, and superior and inferior cingulate ratios were also obtained. The nuclear medicine physician was blind to the diagnosis.

We used the mean count per pixel in cerebellum ROIs as a reference. We are aware of a report describing rCBF abnormalities in the cerebellum vermis of depressed patients (Bench et al., 1992). Our reference ROIs did not include this region. The intra- and interobserver variation of our SPECT semiquantitative analysis was calculated following Catafau et al. (1999). In our control subjects, all ratios were obtained by two different nuclear medicine physicians on separate days. The mean within assay coefficient of variation for all ratios was 0.34 (range 0.30 to 0.43) and the mean between assay coefficient of variation for all ratios was 0.54 (range 0.33 to 0.82). Statistical Method T tests were carried out to assess differences between depressed patients and normal subjects for each ROI, left hemisphere, right hemisphere, and global brain, and to compare the left/right uptake for each ROI. The statistical significance level was defined as P ⬍ 0.05. Furthermore, P values were adjusted by the Bonferroni correction when a large number of comparisons were made. The associations between activity ratios and baseline clinical and demographic characteristics were also explored in the depressed group using Spearman’s P, Pearson’s product–moment correlations or t test. RESULTS A total of 30 patients and 20 control subjects were included in the final sample. Clinical and demographic data for both subgroups are presented in Table 1. There were no significant differences in age, sex, or vascular risk factor score between depressed patients and controls. The averaged uptake ratios for individual brain regions of interest/cerebellum for the two groups are shown in Table 2. No differences were observed in either global brain or hemisphere perfusion between the late-onset depressives and the controls. Statistically significant differences were observed in both the left and the right anterior frontal regions, with reduced uptake in depressed patients. Table 3 shows the uptake ratios for left/right individual brain region and for the left/right global brain. Significant lateral asymmetry in the anterior frontal area was observed in depressed patients, with a more pronounced reduction in perfusion in the left hemisphere. No other significant differences in uptake brain region ratios or in lateral asymmetry (regional or hemispherical) were found nor there were any significant correlations between the rCBF of depressed patients and their baseline clinical and demographic characteristics.

204

NAVARRO ET AL.

TABLE 1

TABLE 2

Demographic and Clinical Characteristics of Study Sample a

Variable

Controls (N ⫽ 20)

a

Patients (N ⫽ 30)

99m

Tc-HMPAO Uptake Ratio for Each Region of Interest, Hemispheres, and Global Brain

Statistic (t, U, or ␹ 2) P value Brain regions

Sex (% men) Age (y) Vascular risk factor Baseline HRDS score Baseline MMSE score Final HRDS score Final MMSE score Age at onset (y) Previous depression (%) Current episode duration (m) Psychotic (%) Endogenous (%) Inpatient (%)

30 33.3 70.55(4.91) 72.37(7.65) 1.4(0.68) 1.2(0.71)

0.06 0.94 0.99

0.80 0.35 0.32

1.90(1.48) 30.43(6.31)

5.95

⬍0.0001

29.00(0.79) 26.60(0.56) 2.50(1.10) 3.03(1.27) 29.1(0.64) 29.20(0.76) NA 70.93(7.27)

12.51 1.53 0.48 NA

⬍0.001 0.13 0.63 NA

NA

23.3

NA

NA

NA NA NA NA

7.6(8.94) 13.3 30.0 20.0

NA NA NA NA

NA NA NA NA

a All values are mean(standard deviation) unless indicated otherwise; NA, not applicable.

DISCUSSION The major finding of this study was that the perfusion values in the anterior frontal ROIs, particularly in the left hemisphere, were significantly lower in lateonset depressive patients than in controls. Previous elderly major depression HMPAO SPECT reports have shown globally decreased uptake of the radiotracer (Upadhyaya et al., 1990), decreased uptake in the thalamus, right posterior cingulate, right parietal cortex, and right caudate (Curran et al., 1993), and significant reductions in perfusion in the right and left parietal, left temporal and left occipital regions (Philpot et al., 1993) in depressed patients when compared with normal controls. Ebmeier et al. (1997, 1998) found no significant differences between early and late onset depressed patients in brain HMPAO SPECT. We found no significant correlations between baseline clinical or demographic characteristics of depressed patients and their brain uptake values. Other researchers, in contrast, have found regional uptake to be correlated with Newcastle score (Upadhyaya et al., 1990), sex (Curran et al., 1993), psychotic features (Philpot et al., 1993) and HRDS score (Ebmeier et al., 1997, 1998). Few controlled studies using functional neuroimaging techniques other than HMPAO SPECT in elderly major depression have been published. In a 133Xe SPECT work, Lesser et al. (1994) reported a significantly lower bilateral perfusion in orbital frontal and anterior temporal regions in elderly (aged 50 or over) major depressed patients than in healthy subjects. Two [ 18F]fluorodeoxyglucose (FDG) PET studies have assessed cerebral glucose metabolism in elderly

Left anterior frontal Right anterior frontal Left posterior frontal Right posterior frontal Left anterior temporal Right anterior temporal Left posterior temporal Right posterior temporal Left parietal Right parietal Left occipital Right occipital Left superior cingulate Right superior cingulate Left inferior cingulate Right inferior cingulate Left thalamus Right thalamus Left striatum Right striatum Left hemisphere Right hemisphere Brain a

Controls a (N ⫽ 20)

Patients a (N ⫽ 30)

100.25(2.88)

94.84(3.52)

5.71

⬍0.001

101.35(3.27)

98.03(3.12)

3.61

0.001

91.94(4.70)

91.16(4.00)

0.63

0.53

92.44(4.87)

92.22(3.82)

0.18

0.86

100.13(5.94) 101.86(6.43)

0.96

0.34

101.77(5.74) 102.59(5.42)

0.51

0.61

103.58(2.95) 103.85(3.62)

0.28

0.78

104.03(4.25) 99.53(4.14) 100.67(3.88) 106.62(5.28) 106.61(4.64)

106.03(3.64) 101.20(4.00) 102.82(5.10) 105.21(6.08) 105.98(6.90)

1.77 1.42 1.60 0.84 0.36

0.08 0.16 0.12 0.40 0.72

91.10(8.70)

89.00(6.34)

0.97

0.34

90.10(7.50)

89.42(5.60)

0.37

0.71

100.63(5.43)

99.86(4.79)

0.53

0.60

101.98(4.42) 101.00(4.71) 100.94(8.70) 98.22(8.59) 97.51(7.57) 98.77(8.70) 97.50(5.48) 98.39(7.22) 96.66(7.02) 99.91(7.58) 99.24(1.84) 98.35(1.17) 99.31(1.41) 99.68(1.75) 99.28(1.43) 99.02(1.00)

0.74 1.09 0.53 0.34 1.53 1.91 0.77 0.71

0.46 0.28 0.60 0.74 0.13 0.06 0.44 0.73

Statistic (t) P value

All values are mean(standard deviation).

TABLE 3 99m

Tc-HMPAO Uptake Left/Right Ratio for Each Region of Interest and Hemispheres

Brain regions

Controls a (N ⫽ 20)

Patients a (N ⫽ 30)

Statistic (t)

P value

Anterior frontal Posterior frontal Anterior temporal Posterior temporal Parietal Occipital Superior cingulate Inferior cingulate Thalamus Striatum Hemisphere

98.93(1.65) 99.51(3.08) 98.47(4.62) 99.69(4.03) 98.90(3.37) 100.00(2.15) 101.13(5.20) 98.70(4.27) 100.92(9.83) 101.37(5.54) 100.06(1.68)

96.77(2.28) 98.89(4.09) 99.42(5.75) 98.00(3.28) 98.55(5.88) 99.44(3.09) 99.68(6.34) 98.91(3.27) 99.73(7.75) 98.73(6.81) 98.81(2.11)

3.65 0.57 0.61 1.63 0.24 0.70 0.85 0.20 1.68 1.45 2.32

0.001 0.57 0.54 0.11 0.81 0.48 0.40 0.84 0.10 0.15 0.02

a

All values are mean(standard deviation).

SPECT IN ELDERLY DEPRESSION

major depression. Kumar et al. (1993) observed a widespread decline in glucose metabolism in depressed patients compared with controls, including reductions in neocortical, subcortical, and paralimbic regions. In the second FDG PET study (Smith et al., 1999) there were no differences in glucose metabolism between the elderly depressed patients and the comparison subjects. The major finding of a recent [ 18F]altanserin PET study (Meltzer et al., 1999) was the absence of significant differences in central 5-HT 2A receptor binding of [ 18F]altanserin between late-life major depressive patients and control subjects. Despite the lack of homogeneity in the results obtained in functional neuroimaging studies of elderly major depression, due probably to the wide range of methodological approaches, statistical analyses, and demographic characteristics of the samples in each study, our results provide strong evidence in favor of the existence of specific neurofunctional alterations, particularly in anterior frontal areas, in late-onset elderly major depression. This conclusion should be considered in the context of the main methodological limitation of this study. Because of the lack of conclusive studies of the minimum washout period needed to avoid interferences between drug treatment and brain uptake ratios, we cannot be entirely sure that this factor did not influence our results. ACKNOWLEDGMENTS The study was supported in part by a research grant from the Institute of Biomedical Research August Pi i Sunyer (IDIBAPS) and by the FIS Grant 99/0171. The authors thank Lundbeck Espan˜a S.A. for their assistance.

REFERENCES Alexopoulos, G. S., Meyers, B. S., Young, R. C., Mattis, S., and Kakuma, T. 1993. The course of geriatric depression with “reversible dementia”: A controlled study. Am. J. Psychiatry 150: 1693– 1699. Alexopoulos, G. S., Young, R. C., and Shindledecker, R. D. 1992. Brain computed tomography findings in geriatric depression and primary degenerative dementia. Biol. Psychiatry 31: 591–599. American Psychiatric Association. 1994. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. American Psychiatric Association, Washington, DC. Baldwin, R. C., and Tomenson, B. 1995. Depression in later life. A comparison of symptoms and risk factors in early and late onset cases. Br. J. Psychiatry 167: 649 – 652. Carney, M. P. W., Roth, M., and Garside, R. F. 1965. The diagnosis of depressive syndromes and the prediction of ECT response. Br. J. Psychiatry 111: 659 – 674.

205

Catafau, A. M., Etcheberrigaray, A., Perez de los Cobos, J., Estorch, M., Guardia, J., Flotats, A., Berna, L., Mari, C., Casas, M., and Carrio, I. 1999. Regional cerebral blood flow changes in chronic alcoholic patients induced by naltrexone challenge during detoxification. J. Nucl. Med. 40: 19 –24. Coffey, C. E., Wilkinson, W. E., Weiner, R. D., Parashos, I. A., Djang, W. T., Webb, C. M., Figiel, G. S., and Spritzer, C. E. 1993. Quantitative cerebral anatomy in depression. A controlled magnetic resonance imaging study. Arch. Gen. Psychiatry 50: 7–16. Curran, S. M., Murray, C. M., Van Beck, M., Dougall, N., O’Carroll, R. E., Austin, M. P., Ebmeier, K. P., and Goodwin, G. M. 1993. A single photon emission computed tomography study of regional brain function in elderly patients with major depression and with Alzheimer-type dementia. Br. J. Psychiatry 163: 155–165. Ebmeier, K. P., Glabus, M. F., Prentice, N., Ryman, A., and Goodwin, G. M. 1998. A voxel-based analysis of cerebral perfusion in dementia and depression of old age. NeuroImage 7: 199 –208. Ebmeier, K. P., Prentice, N., Ryman, A., Halloran, E., Rimmington, J. E., Best, J. K. K., and Goodwin, G. M. 1997. Temporal abnormalities in dementia and depression: A study using high resolution single photon emission tomography and magnetic resonance imaging. J. Neurol. Neurosurg. Psychiatry 63: 597– 604. Emery, V. O., and Oxman, T. E. 1992. Update on the dementia spectrum of depression. Am. J. Psychatry 149: 305–317. Folstein, M. F., Folstein, S. E., and McHugh, P. R. 1975. Mini-Mental State: A practical method for grading the cognitive state of patients for the clinician. J. Psychiatr. Res. 12: 189 –198. Hamilton, M. 1960. A rating scale for depression. J. Neurol. Neurosurg. Psychiatry 23: 56 – 62. Ketter, T. A., George, M. S., Ring, H. A., Pazzaglia, P., Marangell, L., Krimbell, T. A., and Post, R. M. 1994. Primary mood disorder: Structural and resting functional studies. Psychiatric. Annal 24: 637– 642. Kumar, A., Newberg, A., Alavi, A., Berlin, J., Smith, R., and Reivich, M. 1993. Regional cerebral glucose metabolism in late-life depression and Alzheimer disease: A preliminary positron emission tomography study. Proc. Natl. Acad. Sci. USA 90: 7019 –7023. Lesser, I. M., Mena, I., Boone, K. B., Miller, B. L., Mehringer, C. M., and Wohl, M. 1994. Reduction of cerebral blood flow in older depressed patients. Arch. Gen. Psychiatry 51: 677– 686. Meltzer, C. C., Price, J. C., Mathis, C. A., Greer, P. J., Cantwell, M. N., Houck, P. R., Mulsant, B. H., Ben-Eliezer, D., Lopresti, B., DeKosky, S. T., and Reynolds III, C. F. 1999. PET imaging of serotonin type 2A receptor in late-life neuropsychiatric disorders. Am. J. Psychiatry 156: 1871–1878. Philpot, M. P., Banerjee, S., Needham-Bennett, H., Campos-Costa, D., and Ell, P. J. 1993. 99mTc-HMPAO single photon emission tomography in late life depression: A pilot study of regional cerebral blood flow at rest and during a verbal fluency task. J. Affect. Disord. 28: 233–240. Smith, G. S., Reynolds III, C.F., Pollock, B., Derbyshire, S., Nofzinger, E., Dew, M. A., Houck, P. R., Milko, D., Meltzer, C. C., and Kupfer, D. J. 1999. Cerebral glucose metabolic response to combined total sleep deprivation and antidepressant treatment in geriatric depression. Am. J. Psychiatry 156: 683– 689. Upadhyaya, A. K., Abou-Saleh, M. T., Wilson, K., Grime, S. J., and Critchley, M. 1990. A study of depression in old age using singlephoton emission computerised tomography. Br. J. Psychiatry 157 (Suppl 9): 76 – 81.