Plasma dehydroepiandrosterone sulfate in Alzheimer's disease

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BRIEF REPORT

Plasma Dehydroepiandrosterone Sulfate in Alzheimer's Disease Lon S. Schneider, Mark Hinsey, and Scott Lyness

Introduction Administration of dehydroepiandrosterone (DHEA) is associated with improved performance in normal-aged animals, in animals with nuclei basalis lesions, and in animals given scopolamine or a benzodiazepine (Hood et al 1988a, 1988b). In addition, DHEA has trophic effects on cholinergic neurons and neuroglial cell cultures (Bologa et al 1987; Roberts et al 1987). It has been speculated that the administration of DHEA to humans may augment acetylcholine function, retard deterioration, or exert salutary effects by helping to reestablish communication among inadequately functioning neuronal subsystems in AIzheimer's disease (AD) or in ..~aing (Roberts 1988). One small, open trial in male AD subjects suggested modest improvements in cognition and behavior following administration of DHEA (Fitten et al, personal communication). Recently, plasma DHEA-SO4 concentration in presenile AD subjects was reported to be markedly decreased compared with controls (Sunderland et al 1989). Three subsequent reports, however, did not support this finding (Spiith-Schwable et al 1990; Leblhuber et al 1990; Cuckle et al 1990). Therefore, to obtain a more stable estimate of possible differences, we assayed plasma

From the Departme,lt of Psychiatry and the Behavioral Sciences, University of Southern California School of Medicine, Los ~ ngeles, California. Address reprint requests to l.on S. Schneider, M.D., USC School of Medicine 1934 Hospital Place, Los Angeles, CA 90033. Received April 18, 1991; revised July 25, 1991.

© 1992 Society of Biological Psychiatry

DHEA-SO4 in a much larger group of AD subjects and in age- and gender-matched controls. Methods

Subjects Subjects included outpatients with probable AD who were undergoing evaluation for entry into multicenter clinical trials of cholinesterase inhibitors. Briefly, inclusion criteria were age --50 years, good physical health as verified by history, physical examination, and normal screening clinical laboratory studies, including thyroid function tests, probable AD of at least l year's duration by NINCDS criteria (McKhann et al 1984), normal electrocardiogram, normal chest x-ray, normal CT or MRI scan, and provision of informed consent. Exclusion criteria were insulin-depender, t diabetes, hypertension, other CNS disorders, head injury with loss of consciousness, DSM lll-R criteria for any Axis I disorder, significant cardiovascular, renal, hepatic, gastrointestinal, pulmonary, or hematologic disease, modified Hachinski ischemic score > 4, use of medication with intrinsic CNS activity, and blood pressure > 170 mm Hg systolic or 100 mm Hg diastolic. Controls were evalfiated by means of the Structured Clinical Interview for DSM-III-R (SCID-NP) (Spitzer and Williams 1986), medical history, physical examination, routine clinical laboratory tests, and electrocardiogram to ensure the absence of significant past or present psychiatric or medical illness Four female controis were t~ing low-dose estrogens. 0006-3223/92/$05.00

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Procedure Controls were one-to-one matched to available subjects on the basis of sex and age. All blood samples were taken in the morning. Stored frozen EDTA anticoagulated plasma was assayed in duplicate for DHEA-SO4 using a no-extraction, solid-plr.~ase ~251radioimmunoassay method (DPC, Los Angeles, CA) [sensitivity 21 ng/ml, intraassay coefficient of variation (CV) < 6.0%, interassay CV < 10%].

Statistical Analysis A two-factor analysis of variance (ANOVA) was used (Table |). Correlations were obtained comparing DHEA-SO4 with age, Mini-Mental State Examination score, a,d duration of illness in the AD subjects, and with WAIS-R vocabulary subscale score in controls. Results Ages of subjects and controls and gender distributions are displayed in Table 1. Mini-Mental State Score (MMSE) of the AD group ranged from 0 to 24 (mean 15.9 +_. 6.4). Mean duration of illness was 5.2 _+ 3.2 yr. There was no significant difference in DHEA-SO4 concentration

between the AD group and controls (Table 1). As expected, DHEA-SO4 concentrations were significantly higher in men than women. There was no significant interaction between group and gender. DHEA-SO4 was inversely correlated with age in both AD patients (r = - 0 . 5 0 , p = 0.002) and controls (r = - 0 . 2 8 , p = 0.10). Neither MMSE score (r = 0.16, p = 0.35) nor duration of illness ( r = - 0 . 0 8 , p = 0.66) was significantly correlated with DHEA-SO4 concentrations in the AD patients. Nor was WAISR vocabulary zcale scores and DHEA-SO4 levels correlated in controls (r = - 0 . 1 1 , p = 0.55). Discussion The failure to observe differences in plasma DHEA-SO4 concentration between controls and AD subjects does not mean that DHEA is not associated with learning and memory in AD or in normal aging, not' does it imply that treatment with pharmacological or physiological doses of DHEA is unwarranted. DHEA and DHEA-SO,,, secreted in equal amounts by the adrenals, ~u'e the most abundant steroids in the body. DHEA-SO4 compared with

"Fable I. Characteristics and DHEA-SO4 Plasma Concentration in Patients with Probable Alzheimer's Disease and Controls"

Total sample n Age (yr ± SD) DHEA-SO4 (ng/ml - SD)" Female subjects n Age (yr) DHEA-SO4 (ng/ml) Male subjects n Age (yr) DHEA-SO4 (ng/ml)

AD

Controls

p Value

35 69,3 - 6.9 971 ± 844

35 69.3 ± 6.4 860 ± 561

0.99 0.85

20 70.2 ± 7,2 700 ± 414

20 69.9 ± 5.6 685 - 480

0.88 0.93

15 68,3 ± 6.6 1333 ± 1118

15 68.5 _ 7.4 1094 ± 589

0.92 0.86

OData are reported as mean ± SD, Statistical results from a two-factor ANOVA, with group (Aizheimer's disease versus controls) and gender (male versus female) as factors, performed on log-transformed DHEA-SO4 values, Untransformed data ate displayed. There was no statistically significant groupby-gender interaction for DHEA-SO4 (F~l,~ = 0.00, NS). There was a significant gen,Jer effect (F~l,~ = !!.42, p = 0.001) and no significant group effect (F~l,~ = 0,03, p = 0.85).

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Table 2. Summary of Serum DHEA-SO4 Levels in Aizheimer's Disease Patients in Four Studies Using Age- and Gender-Matched Controls° DHEA-SO4 [ng/ml (SD)]

Sunderland et al (1989) Sp~ith-Schwable et al (1990) Leblhuber et al (1990) Present s,ady

% Female

nb

Age [yr (SD)]"

Alzheimer's disease

Controls

60

10

61 (9.6)

625 (442)

1209 (937)

0.76

[ - 0 . 1 4 , + 1.67l

86

7

75 (5.5)

716 (241)

721 (282)

0.02

[ - 1.03, + 1.07]

100

10

74 (4.5)

475 (496)

566 (367)

0.20

[ - 0 . 6 8 , + 1.08]

57

35

69 (6.5)

971 (844)

860 (561)

-0.15

dd

95% CI e for d

[ - 0 . 6 2 , + 0.32]

°Metannalysis results: The 95% confidence interval for the overall mean weighted (studies weighted by sample size) effect size (d = 0.06) is - 0.29 to + 0.42, suggestir.g no significant difference between the Alzheimer and control groups in DHEA. The r corresponding to d was 0.03, pr~o.,.Jted = 0.73. The d statistic indicates that across the four studies, the effect size was quite small. When the Sunderland et al (1989) study was removed from the analysis, d = -0.06, r = -0.03. The homogeneity statistic indicated that the effect sizes from these four studies were consistent [Qw(3) = 3.20, p = 0.36 (Johnson 1989)]. bNumber in each group. cStandard deviation is pooled. ad statistic representing the difterence between the means divided by the pooled standard deviation corrected for sample size bias. 'Confidence interval.

DHEA has a much slower turnover (half-life about one day), a plasma concentration about 1000 times higher, and no significant diurnal rhythm. Although only we',&ly androgenic, DHEA can be metabolized to androstenedione and testosterone. Pronounced changes in DHEASO4 plasma concentrations occur throughout the life cycle, peaking around ages 20-24 years and then progressively declining to less than 20% of maximum about the seventh decade (Orentreich et al 1984). In animal paradigms in which DHEA enhances memory (Flood et al 1988a, 1988b), it was administered intraventricularly, thus ensuring its availability to the brain. Plasma levels of DHEA and DHEA-SO4 may not reflect brain concentrations. A possible cognitive enhancing effect of exogenous DHEA in normal humans has not been assessed (and probably should be), but a pilot study in AD patients suggested mild to moderate improvement (Fitten, personal communication). Sunderland et al (1989) reported that ten AD inpatients (61.4 -- 7.9 yr) had significantly lower levels than ten healthy age- and gender-matched controls (61.4 4- 11.2 yr) (625 4- 442 versus

1209 .4- 937 ng/ml). They found no correlation with age, dementia severity, or cortisol. (As a group, our subjects were older, and had mean DHEA-SO4 levels between these values.) Several small subsequent studies, however, did not support this finding. Two used paired gender- and age-matched samples of seven and ten AD subjects each (Spfith-Schwable et al 1990; Leblhuber et al 1990). A third, using unmatched samples, comprising 17 AD outpatients and 1:5 controls, also found no significant difference, with mean values of DHEA-SO4 actually increasing in the AD group (Cuckle et al 1990). Therefore, only one of five studies suggest that DHEA-SO4 is significantly lower in AD patients. A limitation to studies with small sample sizes is that statistically significant differences between groups are less likely to be attained, often leading to false negative conclusions. Further complicating the issue is that age and gender distributions, each strongly influencing DHEA-SO4 levels, differed among the studies, possibly obscuring truly significant differences in DHEA-SO4 associated with the illness. With these considerations in mind we tried to gain a fuller appreciation of relationships of

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DHEA-SO4, gender, and age to AD, by performing a metaanalysis, combining the three previous studies that used matched samples (Table 2) and the present one, using methods described previously (Schneider et al 1990). [One study (Cuckle et al 1990) was not included because of lack of information on effect size.] There was no statistically significant trend for DHEA-SO4 to be diminished in AD when significance levels of the individual studies were combined (Z = - 0 . 0 4 , NS). The combined overall effect size observed was so small (d = 0.06) that a new study would have to comprise a sample of approximately 4400 AD and control subjects each in order to have sufficient experimental power (1 - 13 = 0.80) to detect a significant difference at the ot = 0.0.5 level. A limitation to this analysis is the lack of enough studies to explore possible relationships of gender and age, two verj important determinants of DHEA-SO4, to differences between AD patients and controls. It is possible that DHEA-SO4 might distinguish particular age- and gender-defined subgroups of AD patients from con~,rols. For example, among younger male AD patients, DHEA-80: may be lower than in agematched ,:ontrols, but in older patients this difference r ~ay be lost. There is little evidence that overall i~wasma DHEA-SO4 levels are truly decreased iJ, AD patients.

References Bologa L, Sharma ~, Roberts E (1987): Dehydroepiandrosterone and its sulfated derivative reduce neuronal death and enhance astrocytic differentiation in brain cel~cultures. J Neurosci Res 17:225234. Cuckle H, Stone R, Smith D, et al (1990): Dehydroepiandrosterone sulfate in Aizheimer's disease. Lancet ii:449-550.

Brief Reports

Flood JF, Smith GE, Roberts E (1988a): Dehydroepiandrosterone and its sulfate enhance memory retention in mice. Brain Res 447:269-278. Flood JF, Roberts E (1988b): Dehydroepiandrosterone sulfate improves memory in aging mice. Brain Res 448:178-181. Johnson BT (! 989): DSTAT: Software Fo:" ?'.iieMetaAnalytic Review of Research Literatures. Hillsdale, NJ: Lawrence Erlbaum. tebU~uber P, Windhager E, Reisecker F, ~teinparz FX, Dienstl E (1990): Dehydroepiandmstemne sulfate in Alzheimer's disease. Lancet ii:449. McKhann G, Drachman D, Folstein M, et al (1984): Clinical diagnosis of Alzheimer's disease: Report of the NINCDS-ADRDA Work Group. Neurology 3,::939-944. Ore~treich N, Brind JL, Rizer RL, Vogelman JH (1984): Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. J Clin Endocrinol Metab 58:551-555. Roberts E (1988): Senile dementia of the AIz',~eimer's type: A possible cerebrovascular origin and some therapeutic suggestions. In Scheibel AB, Wechsler AF (eds), The Biological Substrates of Alzheimer's Disease. New York: Academic. Roberts E, Bologa L, Flood JF, Smith GE (1987): Effects of dehydroelfiandrosterone and its sulfaie on brain tissue in cuRure and on memory in mice. Brain Res 406:357-362. Schneider LS, Pollock VE, Lylless SA (1990): A metaanalysis of controlled trials of neuroleptic treatment of dementia. J Am Geriatr Soc 38:553563. Spiith-Schwable E, Dodt C, Dittmann J, Schiittler R, Fehm HL (1990): Dehydroepi~mdrosterone sulfate in Alzheimer's disease. Lancet i: 1412. Spitzer RL, Williams JB (1986): Structured Clinical interviewfor DSM-lil.R (SCID 5/!/86). New York: New York State Psychiatric Institute, Biometrics Research Department. Sunderland T, Merril CR, Harrington MG, et al (1989): Reduced plasma dehydroepiandrosterone concentrations in Alzheir:~er's disease. Lancet ii:570.