Q J Med 2001; 94: 631-635
© 2001 Association of Physicians
Plasma somatostatin and gastrointestinal peptides in Alzheimer's disease and vascular dementia
From the Department of Geriatric Medicine, Queens University of Belfast, 1 Department of Medicine, Royal Victoria Hospital Belfast, and 2 Department of Radiology, Belfast City Hospital, Belfast, UK
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Summary |
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Few markers distinguish between different dementia types. As dementia affects many body systems outside the central nervous system, we investigated gastrointestinal regulatory peptides as possible disease markers in Alzheimer's Disease (AD) and vascular dementia (VaD). Subjects with mild-to-moderate dementia were diagnosed as probable AD and VaD according to defined criteria. Gastrointestinal peptides were stimulated using a standardized meal test, administered after an overnight fast to 58 dementia patients (40 AD, 18 VaD) and 47 controls matched for age and sex. Blood samples were taken at designated time intervals, and basal and stimulated plasma concentrations of eleven peptides were determined by radio-immunoassay. Results were analysed using the Kruskal-Wallis one-way analysis of variance; the Mann-Whitney U test was used in post hoc analysis where appropriate. There were significant differences in somatostatin levels but in none of the other peptides. Basal somatostatin was significantly increased in VaD compared to controls (p<0.05), and AD (p<0.005). Maximum stimulated levels were significantly elevated in VaD compared to AD (p<0.01). Median basal and stimulated levels of somatostatin were increased in VaD compared to AD, but the overlap in individual values between the groups makes it unlikely to be useful in distinguishing the two types of dementia.
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Introduction |
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Dementia is a common disorder which is easily recognized. However, the clinical diagnosis of specific dementias can be difficult. Two of the most common dementia syndromes are Alzheimer's disease (AD) and vascular dementia (VaD). Antemortem diagnoses are made in these diseases as probable AD and probable VaD, respectively. There are few disease markers to aid differentiation.
A number of abnormalities in centrally-controlled, peripheral hormones have been described in AD. Adrenal and thyroid axes have been studied.1–3 No similar studies have been undertaken in VaD subjects, and the gastrointestinal regulatory peptides have not been investigated in either dementia illness. This area is important for a number of reasons. Some gut peptides may be centrally controlled, and a hypothesis of a brain-gut axis has been formulated.4 If central control is disrupted, abnormalities may be evident in peripheral regulatory peptides. Several gut peptides are also recognized as neurotransmitters. These may be influenced by neurodegenerative disease, either by leakage from the damaged neurones or by a decrease in synthesis, thus contributing to a change in circulating levels. Evidence is accumulating that AD is a multisystem disease affecting many systems outside the CNS,5–7 and regulatory peptide abnormalities may be an independent effect of AD. There is also evidence for a hypermetabolic state in AD, which is manifested by weight loss occurring in the mid-to-late stages of the disease, despite adequate calorific intake.8–12 Regulatory peptide abnormalities may either be a cause or an effect of hypermetabolism.
Finally, there is a complex regulatory network between these regulatory peptides, individually and with other anatomically unrelated peptide systems.13,14 A change in one peptide may effect changes in others by increasing or decreasing levels to a greater or lesser degree. Therefore it is possible that a subtle change in a centrally controlled peptide may have an easily detectable amplified effect on other non-centrally controlled peptides, and although not a direct effect, may still provide a peripheral marker of disease.
We investigated whether measurable differences existed in basal and stimulated gastrointestinal regulatory peptides between AD, VaD and healthy controls. We also wished to establish whether any of these proposed abnormalities were specific for AD and could be used as a peripheral marker of disease.
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Methods |
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This study was approved by the local ethical committee. Patients with dementia were recruited from the Belfast City Hospital Memory Clinic. Written informed consent was obtained from patients and carers prior to inclusion. Written informed consent was also obtained from healthy age- and sex-matched controls, who were recruited from retirement groups and were screened for dementia and concomitant disease.
Dementia subjects were assessed using a structured interview with patient and carer. Patients had full physical examinations and cognitive impairment was established by neuropyschological testing including the Folstein Mini Mental State Examination (MMSE).15 Blood screens for systemic disease were analysed and CT scanning of brain was performed. Dementia subjects were diagnosed as probable AD and probable VaD according to NINCDS ADRDA and AIREN criteria, respectively.16,17 Patients with mixed dementia, other forms of dementia and severe dementia (MMSE<10) were excluded from the study. Patients with concomitant gastrointestinal disease, previous abdominal surgery, endocrine disease, other neurological or other serious disease were excluded. Subjects taking medication that may influence gut peptide secretion, e.g. proton pump inhibitors or histamine receptor antagonists, were excluded.
After an overnight fast, subjects attended for assessment. A 16-gauge cannula was inserted into a large vein. After 15 min rest in the semi-supine position, two baseline samples were taken 5 min apart. Once the basal samples were taken, the patient consumed a standardized amount of food containing 50 g carbohydrate, 20 g fat and 18 g protein in the form of a milk shake, the modified standardized mixed meal test (SMM). The conventional SMM, which is an established stimulatory test of islet and gut hormones, and can also be used in assessment of carbohydrate intolerance, uses ham sandwiches and orange juice to administer the same quantity of carbohydrate, fat and protein. A milkshake form of the SMM was used because it was easier for dementia patients to consume. The milkshake was consumed within 10 min, and stimulated samples were taken at 5, 10, 15, 30, 45 and 60 min from beginning of consumption. Blood samples were collected into heparinized tubes and placed on ice. Plasma was separated within 2 h of sampling, and was frozen at -70 °C for subsequent analysis.
Regulatory peptides were measured using standard radioimmunoassay techniques. Individual assays for each peptide studied have been developed in the Welcome Laboratories of the Royal Victoria Hospital, Belfast.18 Many of these assays are available in only one or two centres in the UK, and as a result national or international standards and quality control are not available. Insulin, gastrin and calcitonin-gene-related peptide were measured directly on plasma specimens. The other peptides were measured in alcohol extracts of plasma. The following peptides were measured: cholecystokinin (CCK); calcitonin-gene-related peptide (CGRP); gastrin; glucagon C-terminal, pancreatic glucagon (C-GLI); glucagon N-terminal, total pancreatic and gut glucagon (N-GLI); gastrin-releasing peptide (GRP); insulin; neurokinin A (NKA); pancreatic polypeptide (PP); somatostatin (SRIF); and vasoactive intestinal polypeptide (VIP).
The resulting data were skewed, and non parametric tests were used in the analysis. The Kruskal–Wallis one-way analysis of variance was used to find significant differences between the subject groups for each of the peptides, and the Mann–Whitney U Test was used in post hoc analysis. Significance was taken at the 5% level. Several variables were tested. Baseline peptide levels and maximum stimulated levels were compared for the following peptides: PP, SRIF, N-GLI, PP, insulin, gastrin, C-GLI. Multiple timed samples were taken. Fast responses to the SMM, with little further increases in stimulated levels after 10 min, were predicted for VIP, NKA, GRP, CGRP, CCK. Therefore only basal and 10-min levels were measured. Baseline level and the change in peptide concentrations between baseline and 10 min were analysed for these peptides. It was felt that the change in peptide concentration was a better representation of stimulation than the absolute 10 min level.
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Results |
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The demographic details of the subjects are displayed in Table 1. There were no differences between groups in terms of age or gender. Significant differences in basal and maximum stimulated SRIF levels were observed between the groups. No significant differences in the other peptides were seen (Table 2). Post hoc analysis showed that basal SRIF was increased in VaD compared to controls and AD (Table 3, p<0.05, p<0.005, respectively), and maximum stimulated SRIF was significantly increased in VaD compared to AD only (Table 3, p<0.01).
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Discussion |
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We studied the concentrations of eleven regulatory peptides in peripheral blood and found that basal and maximum stimulated SRIF levels were significantly elevated in VaD subjects compared to controls and to AD subjects. However, some caution is needed in interpreting this result because of the large number of comparisons made during the statistical analysis, and the possibility that this is a chance finding. Elevated plasma SRIF has not been previously reported in VaD. One previous study has indicated that CSF SRIF is depleted in VaD19 and other studies examining cortical and CSF SRIF levels report depressed levels in AD.20,21
No significant differences between dementia and control groups were observed for the other ten peptides. These included insulin, which previously has been reported to be increased in AD.22,23 Plasma CCK levels were also not significantly different between groups, although brain levels have been reported to be reduced in AD.24,25 Brain, CSF and plasma levels of the other peptides have not been studied in dementia.
The original rationale for these investigations was that peripheral neuropeptides and regulatory peptides may be disrupted, possibly reflecting similar changes observed in brain and CSF studies. Increases in peripheral peptide levels may be precipitated by leakage from damaged neurones or reduced levels produced by decreased numbers of normal neurones. In VaD, damaged brain tissue could represent a source of SRIF release. However it has yet to be established whether elevated SRIF levels are present in acute stroke or chronic cerebrovascular disease. If cerebral injury causes neuropeptide leakage, increases in other peptides would also be expected.
These are perhaps over-simplistic concepts of peptide secretion and regulation. There are a number of other possible mechanisms that may cause plasma elevations of this peptide. Impaired central regulatory mechanisms may cause elevation of SRIF, and the disregulation may be related to cerebrovascular pathology rather than dementia, since in AD plasma SRIF tended to be depressed. SRIF is also a hormone, as well as having paracrine and neuropeptide properties. An elevation in plasma SRIF may represent increased release into the circulation from a number of tissues, gastrointestinal or genitourinary. It is more likely that increased plasma SRIF is caused by one or more combinations of the numerous metabolic and humoral events known to regulate this peptide.13,14
The negative associations of dementia with the other peptides studied, do not exclude abnormalities of peripheral regulatory peptide systems in dementia. Similarly, these negative studies do not suggest that central neuropeptide systems are not affected in dementia. The relation of plasma regulatory peptides to brain peptides is unclear. It is also not understood precisely how CSF neuropeptides are related to brain peptides. The relationship between brain and plasma is more remote, central nervous tissue being separated from blood by the blood-brain barrier. There is also the added influence of regulatory peptides from other tissues mixing with brain peptides in the blood stream. Changes in regulatory peptides related to the brain may be modest in comparison to the overall peripheral peptide levels, and therefore no significant net change will be detected.
The hypermetabolic state in AD8–11 remains unexplained by these results. Regulatory peptide levels observed in the present study were relatively unchanged, but disruptions may only manifest later in the course of disease when weight loss becomes most marked. At that stage, however, it may be difficult to separate the effects of advanced dementia on diet and feeding from a direct effect upon gastrointestinal peptide levels.
In conclusion, except for SRIF, we found no evidence that the peptide systems investigated in this study were affected by dementing illness. Although median concentrations of SRIF were lower in patients with Alzheimer's disease than in patients with vascular dementia, there was considerable overlap in individual values between the two groups. It seems unlikely that measurement of SRIF concentrations will be useful in distinguishing the two types of dementia.
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Acknowledgments |
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CJF was in receipt of a Fellowship from the Department of Health and Social Services (Northern Ireland). We are grateful to Dr C.C. Patterson for statistical support. We also thank the Alzheimer's Disease Society for their support.
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Notes |
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Address correspondence to Dr A.P. Passmore, Department of Geriatric Medicine, The Queen's University of Belfast, Whitla Medical Building, 97 Lisburn Road, Belfast BT9 7BL
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References |
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