BIOL PSYCHIATRY 1992;32:452-456
Cerebrospinal Fluid Neuropeptides in Dementia Csaba M. Banki, Lajos Karmacsi, Garth Bissette, and Charles B. Nemeroff
Cerebrospinal fluid concentrations of corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH) and somatostatin (SRIF) were measured in 77 female inpatients with moderate to extreme dementia and in 17 elderly female controls. Both multi-infarct (MID) and Alzheimer-type (SDAT) demented patients had equally elevated CSF CRH and TRH but not SRIF levels as compared with the controls. This elevation was, however, not seen in patients with simple dementia while it was most prominent in those exhibiting marked depressive symptoms. It is concluded that depression rather than dementia itself may be associated with CSF CRH and TRH elevation in elderly patients with cognitive impairment.
Introduction Dementia disorders are among the most frequent psychiatric diseases, affecting at least 5%-8% of the population aged 65 years or older (Ban 1980; Kramer 1980). However, the pathophysiology of these disorders is only partially understood. In senile dementia of Alzheimer type (SDAT) a central cholinergic deficit has been demonstrated (Coyle et al 1983; Mohs et ai 1985) and other neurotransmitter systems may also be affected (Crook 1988). In addition, hypothalamic-pituitary-adrenocortical (HPA) dysfunctions have been reported both in SDAT and in multi-infarct dementia (MID) patients (Balldin et al 1983; Carries et al 1983; Reding et al 1985). CSF immunoreactive neuropeptide concentrations have been found to be altered in various psychiatric disorders. Elevated levels of corticotropin-releasing hormone (CRH) and thyrotropin-releasing hormone (TRH) were reported in patients with major depression (Kirkegaard et al 1979; Nemeroff et al 1984; Banki et al 1987; Banki et al 1988) whereas somatostatin (SRIF) levels in major depression showed significant reduction (Rubinow et al 1984). Brain and CSF SRIF concentration in SDAT ("senile dementia") was also reported to be reduced (Soininen et ai 1984; Sagar et al 1984; Bissette et al 1986), but there are very scarce data on CSF CRH and TRH in dementia, which do not allow definite conclusions (Oram et al 1981; Nemeroff et ai 1984). CSF CRH may be related to cognitive factors in major depression (Roy et al 1987; De Jong and Roy 1990). The CSF SRIF data also appear to be nonspecific and/or contradictory (Bissette et al 1986; Wallin et al 1991).
From the Regional NeuropsychiatricInstitute (CMB, LK), Nagykallo, Hungary; Department of Psychiatry (GB), Duke University Medical Center, Durham, North Carolina; and Department of Psychiatry (CBN), Emory University School of Medicine, Atlanta, Georgia, USA. Address reprint requests to Csaba M. Banki, MD, PhD, H-4321 Nagykallo, P.O.Box 37, Hungary. Received November 9, 1991; revised April 6, 1992. © 1992 Society of Biological Psychiatry
Ce~brospina! Huid Neuropeptides in Dementia
BIOL PSYCHIATRY 1992;32:452-456
Table 1. Clinical and Background Variables in Demented and Elderly Control Patients Dementia Age (years) Weight (kg) Height (cm) Duration (years)" G.A.F. score MMS score
(54-9O) (38-102) (138-167~, (1/2-9) (3-60) (0-24)
74.6 56.1 151.6 3.7 22.9 9.8
Control +± -
7.6 12.8 6.2 1.7 11.7 6.4
(54-81) 66.7 _ 8.1 (43-90) 68.2 _ 13.2 (146-165) 155.4 ± 5.9
" = Reportedduration of prominent symptomsof dementia. G.A.F. - Current Global Assessmentof Functioning (DSM-HI-R's Axis V.). All control subjects had current G.A.F. > 60 and MMS > 25. Values are (range) and mean ± standard deviation.
The coincidence of dementia and depression has long been recognized (Lauter and Dame 1991; Davidson et al 1991). In addition, dementia patients often have associated symptoms such as delirium or delusion. In order to investigate the relationship between neuropeptide changes and the clinical manifestations of dementia disorders we measured CRH, SRIF, and TRH concentrations in the CSF of both SDAT and MID patients with and without associated psychiatric features.
Patients and Methods Seventy-seven female psychiatric inpatients were studied with moderate to extreme dementia. DSM-HI-R criteria were used throughout (the intraclass correlation coefficient for diagnosing dementia, using a semi-structured interview, exceeded kappa = 0.96). The initial examination included an extensive~'physical, neurological, and laboratory test battery to exclude majc~ physical, endocrinological, or neurological diseases (except cerebro-vascular disease in the MID patients). Minor physical diseases, such as latent diabetes, mild hypertension, mild ECG alterations, etc., did not constitute exclusion criteria as far as they did no~ r~i~i~ specific treatment. Computerized tomography and serum hormone measurement1~ could not be performed regularly but patients with known or suspected endocrine disordet's (from the medical history or with clinical symptoms) were not included. The control group consisted of elderly female inpatients (n = 17) suffering from personality and/or adjustment disorders, who were free from dementia (MMS > 25) or mood or psychotic disorders. Background characteristics of patients and controls are given in Table 1. None of the subjects had received major psychotropic medication fox at least 2 weeks, but single doses of benzodiazepines were allowed (n = 23) and stabilized maintenance drug treatments (with vasodilators, vitamins, etc.) were left unchanged. Fourteen demented patients had prominent depressive features (24-item Hamilton Depression Scale score I> 22) superposed on a preexisting dementia; other causes of the depressive symptoms and the possible depressive pseudodementia cases were carefully excluded from the study. Forty-one other demented patients had prominent episodes of delirium (with reduced level of consciousness and attention, disorganized thinking, agitation, hallucinations, etc.), and 22 subjects had no associated symptoms. The study was approved by the regional research committee and all subjects gave written informed consent. All patients were initially rated on the Mini-Mental Status
C.M. Banki et al
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Table 2. Corticotropin-ReleasingHormone (CRH), Somatostatin (SRIF), and ThyrotropinReleasing Hormone (TRH) in the CSF of Demented Patients and Controls Dementia (n = 77) CRH SRIF TRH
59.2 ± 33.9 ± 5.2 ±
25.5 17.8 2.5
Control (n = 17) 42.7 ± I1.1 28.7 ± 11.2 3.2 ± 2.1
Two-tailed Student's t-tests after log-transformation: CRH t = 2.59, p < 0.015; SRIF t = 1.14, p > 0.25; TRH t -3.01, p < 0.004; all df = 92. The log-variances for each test were statistically homogeneous. Values are pg/ml, mean _ standard deviation.
(MMS) scale (Cockrell and Folstein 1988). After 2-5 days of stabilization, lumbar punctures were performed at 9:00-10:00 AM and the first 10 ml of CSF was collected for peptide measurement. Details of storage, transport, and laboratory assays of immunoreactive CRH, SRIF, and TRH were described earlier (Nemeroff et al 1984; Bissette et al 1986; Banki et al 1988). The date were log-transformed and analyzed by standard uniand multivariate analysis of variance methods (Dillon and Goldstein 1984).
Results Both CSF and TRH, but not SRIF, mean concentrations were significantly higher in demented patients than in controls (Table 2). Age and weight were significantly different bc*:~'.~::~~. patients and controls as shown in Table 1. However, after controlling for their effects on all three CSF neuropeptides by a multivariate analysis of covariance (MANCOVA) the group differences remained practically unchanged (Wilks' iambda ffi 0.87, p = 0.0002). A two-way MANOVA (following a Box's test for covariance homogeneity: X2(30) 41.3, p > 0.085) indicated no significant neuropeptide difference between SDAT and MID patients but it revealed significant heterogeneity among the symptomatic subtypes (Table 3). Age, weight, height, duration, and GAF scores, but not MMS scores, were homogeneous in these six subgroups; performing again a MANCOVA to control for all these variables did not noticeably alter the results (Table 3). Based on the MANOVA results, a univariate analysis of the subtypes and control indicated no significant differences among the SRIF means (ANOVA F(3,90) ffi 0.77, p > 0.50) but both CRH (F(3,90) = 7.03, p < 0.0005) and TRH (F(3,90) = 3.93, p < 0.012) means were heterogeneous. Post-hoe tests showed significant elevation of both CRH and TRH in the depressed subgroups (F(3,90) ffi 6.03, p < 0.001 and F(3,90) ffi 3.2, p < 0.03, recpectively) but neither simple demented patients nor those with delirium differed significantly from the control group. Twentyothree demented patients received single doses of 1 mg alprazolam or 10 mg diazepam before the LP; this group showed no significant neuropeptide difference from the 54 subjects who had remained free from such medication (MANOVA lambda = 0.96, p > 0.50).
Discussion We found a marked elevation of CSF CRH and TRH, but not SRIF, concentration in demented patients with clinical depression, but no such changes were demonstrable in simple demented individuals. The elderly psychiatric control group had mean CSF neu-
Cerebrospinal Fluid Neuropeptides in Dementia
BIOL PSYCHIATRY 1992;32:452-456
Table 3~ Two-Way MANOVA of CSF Neuropeptides in Dementia Subtypes S D A T (n = 50) Dementia with delirium C R H (n = 27) SRIF TRH Dementia with depression C R H (u = 7) SRIF TRH Simple d e m e n t i a C R H (n = 16) SRIF TRH
M I D (n = 27)
58.8 - 26.9 33.3 .4. 13.1 5 . 6 -- 2.8
(n = 14)
58.9 .4. 23.2 28.8 .4. 17.6 4.5 .4. 2.1
70.7 .4. 13.0 27.8 _ 12.9 6 . 0 .4. 3 . 0
(n = 7~
83.3 .4. 38.4 56..9 .4. 29.5 5.8 .4. 1.7
4 9 . 7 .4. 19.0 32.3 .4. 17.5 4 . 8 .4. 2.3
(n = 6)
46.4 ± 17.7 32.5 - 9 . 6 4.3 .4. 3.0
Two-way MANOVA: SDAT versus MID ffi Wilks' lambda Subtypes ffi Wilks' lambda Interaction ffi Wilks' lamlxla MANCOVA (using all variables from Table I as covariates): SDAT versus MID ffi Wilks' lambda Subtypes ffi Wilks' lambda Interaction ffi Wilks' lambda
-- 0.97, p > 0,60 (ns) - 0,81,p < 0,05 ffi 0,92, p > 0.50 (ns) = 0.99, p > 0.86 (ns) = 0.77, p < 0.01 = 0.93, p > 0.25 (ns)
ropeptide levels almost identical to those observed in younger control subjects (Banki et al 198"/; Banki et al 1988). This suggests that neither age nor SDAT or MID themselves cause marked CSF neuropeptide alterations. On the other hand, the CSF CRH and TRH elevation in depressed patients, as reported earlier, may be present in elderly and demented subjects as well. However, the specificity of this finding is somewhat weakened by the intermediate mea~ values of the CSF peptides in the delirium subgroup (Table 3). It is also difficult to explain why CSF SRIF appeared to be uniformly normal in this population, in contrast to other findings (Bissette et al 1986). One possibility is the longer duration of illness in this study, although the relationship between dementia and central SRIF metabolism is far from clear (Sagar et al 1984; WaUin et al 1991). Despite the obvious weaknesses of this study (such as the lack of a healthy control group, the lack of baseline hormone measurements, the purely clinical separation of SDAT from MID, the possible drug effects, etc.), it appears to further support the hypothesis that both CRH and TRH may be overproduced in the human CNS of at least some depressed patients. We could demonstrate this elevation in severely demented elderly patients, whereas the subjects with equally severe pure (i.e., non-depressed) dementia exhibited no significant CSF neuropeptide changes. Most of the numerous background variables proved to be independent of the CSF neuropeptide variations in this sample. Thus we propose that depression in dementia may have closely similar neurophysiological correlates at the neuropeptide level to those found in major depression in younger, nondemented individuals (Lauter and Dame 1991; Carnes et al 1983; Nemeroff et al 1984). References
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