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REDUCED PLASMA DEHYDROEPIANDROSTERONE CONCENTRATIONS IN ALZHEIMER'S DISEASE
570 linear scale. It might have been better if we had mentioned this P/N ratio explicitly in the legend of fig 1 in our paper. on a
Our discussion was indeed based on the premise that there is a safe and effective therapy for C pylori and that patients with Cpylori infection should be treated. While we agree with Graham’s criticism on the second part of this premise, we maintain that C pylori infection can be safely and effectively treated with colloidal bismuth subcitrate. Despite his criticisms, Graham’s line of thinking-as indicated by his quotations from the 1989 Gastroenterology paper with which his letter ends-almost entirely coincides with the views expressed in our paper. We tried to estimate, on the basis of morbidity figures in our hospital, the decrease in endoscopies that might result from adoption of the proposed strategy and we expressed doubts about the need to treat C pylori infection in the last sentence of our paper. So what conceptual errors did we make-or have Dr Graham’s views been subject to dramatic change recently? University Hospital Maastricht, 6210 BX Maastricht, Netherlands
R. J. L. F. LOFFELD E. STOBBERINGH
J. W. ABENDS
REDUCED PLASMA DEHYDROEPIANDROSTERONE CONCENTRATIONS IN ALZHEIMER’S DISEASE
SIR,-Steroid hormones are intimately involved in the maturing and ageing processes of man. Dehydroepiandrosterone (DHEA), with its sulphonated metabolite DHEA-S, is the most abundant steroid in the circulation and serum levels of DHEA and DHEA-S fall rapidly with age and in certain medical conditions. Brain concentrations ofDHEA are 65 times higher than concentrations in plasma.’ Persistent circadian rhythms of DHEA in the brain have been found in rodents even after adrenalectomy or orchiectomy,2 suggesting the possible importance of this steroid in the central nervous system. DHEA and DHEA-S enhance memory retention in mice3 and block the memory-impairing effects of scopolamine.1 We have used the scopolamine model to simulate the memory impairment of Alzheimer’s disease,s and since the cholinergic neurotransmitter system is much impaired in Alzheimer’s disease we postulated that DHEA concentrations would be lower in Alzheimer patients than in age-matched controls. 10 patients with Alzheimer’s disease, 10 age and sex matched healthy controls (table), and 9 young healthy controls (37 4 [ SD 61]] years) were studied. Patients and controls were in good medical health and had been off all psychotropic medications for at least 3 weeks. Any patient (or control) with a Hachinski score of 3 or greater (reflecting non-Alzheimer multi-infarct dementia) was excluded. Other exclusion criteria are given elsewhere.6 Blood was obtained after an overnight fast and plasma was stored at - 70°C. Coded samples were assayed in duplicate for DHEA-S (Radioassay System Laboratories). All samples were tested in the same assay, and intra-assay variability for duplicate samples was 7-5%. Data were analysed by t test and presented as mean (SD). Correlations were done by Pearson and Spearman rank methods. DHEA-S concentrations were on average 48% lower in Alzheimer patients than in age-matched controls (625 [442] vs 1209 [937]) ng/ml; p < 0-05 [one-way]). As expected the older controls had significantly lower concentrations than the younger controls (1209 [937] vs 2853 [965] ng/ml; p < 0,01) (figure). There were no significant correlations with serum cortisol, dementia severity, or baseline cognitive testing; however, there was a strong correlation in the controls between age and DHEA-S concentration. CLINICAL CHARACTERISTICS OF ALZHEIMER PATIENTS AND AGE-MATCHED CONTROLS
Correlation of DHEA-S plasma concentration with age in 19 controls.
DHEA-S, a precursor of androgen and oestrogen steroids, influences cellular processes, and concentrations of DHEA and DHEA-S in 70-year-olds have been found to be only 20% of those in younger people.7 Whether the reduced DHEA-S in Alzheimer patients is clinically relevant is uncertain, but intriguing lines of evidence suggest the need for further study in Alzheimer’s disease: besides anti-amnestic effects3,4 DHEA-S may protect partly degenerated or at-risk brain cells.11,9 Clinical trials of DHEA-S in Alzheimer patients are under way. TREY SUNDERLAND CARL R. MERRIL MICHAEL G. HARRINGTON Unit on Geriatric Psychopharmacology, BRIAN A. LAWLOR Laboratory of Clinical Science, SUSAN E. MOLCHAN and Laboratory of Biochemical Genetics, RICK MARTINEZ National Institute of Mental Health, DENNIS L. MURPHY Bethesda, Maryland 20892, USA 1. Lacroix
C, Fiet J, Benais J-P, et al. Simultaneous radioimmunoassay of progesterone, androst-4-enedione, pregnenolone, dehydroepiandrosterone and 17-hydroxyprogesterone in specific regions of human brain. J Steroid Biochem 1987,
28: 317-25. 2. Robel P, Synguelakis M, Halberg F, Baulieu E-E. Persistance d’un rythme circadien de la dehydroepiandrosterone dans le cerveau, mais non dans le plasma, de rats castres et surrenalectomises. C R Acad Sci III 1986; 303: 235-38. 3. Flood JF, Roberts E. Dehydroepiandrosterone sulfate improves memory m aging mice. Brain Res 1988; 448: 178-81. 4. Flood JF, Smith GE, Roberts E. Dehydroepiandrosterone and its sulfate enhance memory retention in mice. Brain Res 1988; 447: 267-78. 5. Sunderland T, Tariot PN, Weingartner H, et al. Pharmacologic modelling of Alzheimer’s disease Progr Neuropsychopharmacol Biol Psychiatry 1986; 10: 599-610. 6. Sunderland T, Tanot PN, Cohen RM, Weingartner H, Mueller EA, Murphy DL. Anticholinergic sensitivity m patients with dementia of the Alzheimer type and age-matched controls a dose-response study Arch Gen Psychiatry 1987; 44: 418-26. 7. Orentreich N, Brind JL, Rizer RL, Vogelman JH. Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. J Clin Endocrinol Metab 1984; 59: 551-55. 8. Roberts E, Bologa L, Flood JF, Smith GE. Effects of dehydroepiandrosterone and its sulfate on brain tissue in culture and on memory in mice. Brain Res 1987; 406: 357-62. 9. Bologa L, Sharma J, Roberts E. Dehydrooepiandrosterone and its sulfated derivative reduce neuronal death and enhance astrocytic differentiation in brain cell cultures. J Neurosci Res 1987, 17: 225-34.
CONTINUED FUNCTION OF PANCREATIC ISLETS AFTER TRANSPLANTATION IN TYPE I DIABETES
SIR,-Significant advances 1-3 have made it feasible to renew clinical trials of pancreatic islet transplantation in insulin-dependent diabetes mellitus (IDDM). Our studies in dogs suggest that to induce normoglycaemia without insulin in a 70 kg man would require more than 200 000 human islets of mean diameter 150 J.I111" Largiader et als have reported successful withdrawal of insulin in a diabetic adult given 200 000 islets. This progress, with advances in immunosuppression (cyclosporin and polyclonal antibody preparations) prompted us to start a clinical trial of islet transplantation. We report here the first two cases. Patient 1 (35, M; IDDM for 17 years, retinopathy, neuropathy, and end-stage nephropathy) was on insulin 05-06 U/kg daily and
Our discussion was indeed based on the premise that there is a safe and effective therapy for C pylori and that patients with Cpylori infection should be treated. While we agree with Graham’s criticism on the second part of this premise, we maintain that C pylori infection can be safely and effectively treated with colloidal bismuth subcitrate. Despite his criticisms, Graham’s line of thinking-as indicated by his quotations from the 1989 Gastroenterology paper with which his letter ends-almost entirely coincides with the views expressed in our paper. We tried to estimate, on the basis of morbidity figures in our hospital, the decrease in endoscopies that might result from adoption of the proposed strategy and we expressed doubts about the need to treat C pylori infection in the last sentence of our paper. So what conceptual errors did we make-or have Dr Graham’s views been subject to dramatic change recently? University Hospital Maastricht, 6210 BX Maastricht, Netherlands
R. J. L. F. LOFFELD E. STOBBERINGH
J. W. ABENDS
REDUCED PLASMA DEHYDROEPIANDROSTERONE CONCENTRATIONS IN ALZHEIMER’S DISEASE
SIR,-Steroid hormones are intimately involved in the maturing and ageing processes of man. Dehydroepiandrosterone (DHEA), with its sulphonated metabolite DHEA-S, is the most abundant steroid in the circulation and serum levels of DHEA and DHEA-S fall rapidly with age and in certain medical conditions. Brain concentrations ofDHEA are 65 times higher than concentrations in plasma.’ Persistent circadian rhythms of DHEA in the brain have been found in rodents even after adrenalectomy or orchiectomy,2 suggesting the possible importance of this steroid in the central nervous system. DHEA and DHEA-S enhance memory retention in mice3 and block the memory-impairing effects of scopolamine.1 We have used the scopolamine model to simulate the memory impairment of Alzheimer’s disease,s and since the cholinergic neurotransmitter system is much impaired in Alzheimer’s disease we postulated that DHEA concentrations would be lower in Alzheimer patients than in age-matched controls. 10 patients with Alzheimer’s disease, 10 age and sex matched healthy controls (table), and 9 young healthy controls (37 4 [ SD 61]] years) were studied. Patients and controls were in good medical health and had been off all psychotropic medications for at least 3 weeks. Any patient (or control) with a Hachinski score of 3 or greater (reflecting non-Alzheimer multi-infarct dementia) was excluded. Other exclusion criteria are given elsewhere.6 Blood was obtained after an overnight fast and plasma was stored at - 70°C. Coded samples were assayed in duplicate for DHEA-S (Radioassay System Laboratories). All samples were tested in the same assay, and intra-assay variability for duplicate samples was 7-5%. Data were analysed by t test and presented as mean (SD). Correlations were done by Pearson and Spearman rank methods. DHEA-S concentrations were on average 48% lower in Alzheimer patients than in age-matched controls (625 [442] vs 1209 [937]) ng/ml; p < 0-05 [one-way]). As expected the older controls had significantly lower concentrations than the younger controls (1209 [937] vs 2853 [965] ng/ml; p < 0,01) (figure). There were no significant correlations with serum cortisol, dementia severity, or baseline cognitive testing; however, there was a strong correlation in the controls between age and DHEA-S concentration. CLINICAL CHARACTERISTICS OF ALZHEIMER PATIENTS AND AGE-MATCHED CONTROLS
Correlation of DHEA-S plasma concentration with age in 19 controls.
DHEA-S, a precursor of androgen and oestrogen steroids, influences cellular processes, and concentrations of DHEA and DHEA-S in 70-year-olds have been found to be only 20% of those in younger people.7 Whether the reduced DHEA-S in Alzheimer patients is clinically relevant is uncertain, but intriguing lines of evidence suggest the need for further study in Alzheimer’s disease: besides anti-amnestic effects3,4 DHEA-S may protect partly degenerated or at-risk brain cells.11,9 Clinical trials of DHEA-S in Alzheimer patients are under way. TREY SUNDERLAND CARL R. MERRIL MICHAEL G. HARRINGTON Unit on Geriatric Psychopharmacology, BRIAN A. LAWLOR Laboratory of Clinical Science, SUSAN E. MOLCHAN and Laboratory of Biochemical Genetics, RICK MARTINEZ National Institute of Mental Health, DENNIS L. MURPHY Bethesda, Maryland 20892, USA 1. Lacroix
C, Fiet J, Benais J-P, et al. Simultaneous radioimmunoassay of progesterone, androst-4-enedione, pregnenolone, dehydroepiandrosterone and 17-hydroxyprogesterone in specific regions of human brain. J Steroid Biochem 1987,
28: 317-25. 2. Robel P, Synguelakis M, Halberg F, Baulieu E-E. Persistance d’un rythme circadien de la dehydroepiandrosterone dans le cerveau, mais non dans le plasma, de rats castres et surrenalectomises. C R Acad Sci III 1986; 303: 235-38. 3. Flood JF, Roberts E. Dehydroepiandrosterone sulfate improves memory m aging mice. Brain Res 1988; 448: 178-81. 4. Flood JF, Smith GE, Roberts E. Dehydroepiandrosterone and its sulfate enhance memory retention in mice. Brain Res 1988; 447: 267-78. 5. Sunderland T, Tariot PN, Weingartner H, et al. Pharmacologic modelling of Alzheimer’s disease Progr Neuropsychopharmacol Biol Psychiatry 1986; 10: 599-610. 6. Sunderland T, Tanot PN, Cohen RM, Weingartner H, Mueller EA, Murphy DL. Anticholinergic sensitivity m patients with dementia of the Alzheimer type and age-matched controls a dose-response study Arch Gen Psychiatry 1987; 44: 418-26. 7. Orentreich N, Brind JL, Rizer RL, Vogelman JH. Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. J Clin Endocrinol Metab 1984; 59: 551-55. 8. Roberts E, Bologa L, Flood JF, Smith GE. Effects of dehydroepiandrosterone and its sulfate on brain tissue in culture and on memory in mice. Brain Res 1987; 406: 357-62. 9. Bologa L, Sharma J, Roberts E. Dehydrooepiandrosterone and its sulfated derivative reduce neuronal death and enhance astrocytic differentiation in brain cell cultures. J Neurosci Res 1987, 17: 225-34.
CONTINUED FUNCTION OF PANCREATIC ISLETS AFTER TRANSPLANTATION IN TYPE I DIABETES
SIR,-Significant advances 1-3 have made it feasible to renew clinical trials of pancreatic islet transplantation in insulin-dependent diabetes mellitus (IDDM). Our studies in dogs suggest that to induce normoglycaemia without insulin in a 70 kg man would require more than 200 000 human islets of mean diameter 150 J.I111" Largiader et als have reported successful withdrawal of insulin in a diabetic adult given 200 000 islets. This progress, with advances in immunosuppression (cyclosporin and polyclonal antibody preparations) prompted us to start a clinical trial of islet transplantation. We report here the first two cases. Patient 1 (35, M; IDDM for 17 years, retinopathy, neuropathy, and end-stage nephropathy) was on insulin 05-06 U/kg daily and