Cerebrospinal fluid vasopressin, oxytocin, somatostatin, and beta-endorphin in Alzheimer's disease

As a first step toward assessing the status of brain neuropeptide systems that may be involved in Alzheimer's disease (AD), the cerebrospinal fluid (CSF) concentrations of the neuropeptides arginine vasopressin, somatostatin, oxytocin, and beta-endorphin were measured in patients with AD, normal elderly subjects, and normal young subjects. The plasma arginine vasopressin level was also measured in the three groups. The CSF arginine vasopressin level was significantly lower in patients with AD than in either elderly or young normal subjects, but oxytocin and beta-endorphin levels did not differ between groups. The CSF osmolarity also did not differ between groups. The plasma arginine vasopressin level did not significantly differ between groups, but high plasma arginine vasopressin values were absent in the patients with AD. The CSF somatostatin level was significantly lower in patients with AD than in normal elderly persons, but it did not differ in young normal subjects. These results suggest that central vasopressinergic activity may be decreased in AD and confirm reports of low CSF somatostatin levels in AD.     

CSF monoamine metabolites and somatostatin in Alzheimer's disease and major depression.

Decreased cerebrospinal fluid (CSF), somatostatinlike immunoreactivity (SLI) and alterations in the CSF monamine metabolites 3-methoxy-4-hydroxyphenylethylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) have been reported in patients with probable Alzheimer's disease (AD) and in patients with major depression. In this study, we found CSF SLI to be significantly lower in a large group of AD patients (n = 60) and in a group of age-matched patients with major depression (n = 18) as compared with normal controls (n = 12). Mean CSF, MHPG, 5-HIAA, and HVA levels were not significantly different among diagnostic groups. Within a group of "depressed" AD patients, CSF levels of 5-HIAA showed a significant positive correlation (p = 0.03) with CSF SLI; a similar relationship was found within the group of patients with major depression. Further exploration of the relationship between the somatostatin and serotonin systems may provide clues as to how neuropeptides interact with monoamine neurotransmitters and what role they have in depression.     

Cerebrospinal fluid levels of angiotensin-converting enzyme, acetylcholinesterase, and dopamine metabolites in dementia associated with Alzheimer's disease and Parkinson's disease: a correlative study

Mean levels of the two hydrolases angiotensin-converting enzyme (ACE) and acetylcholinesterase (AChE), the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and total protein concentration were examined in cerebrospinal fluid (CSF) samples from a group of patients with dementia of the Alzheimer's type, a group of comparably demented patients with Parkinson's disease, and a neurologically healthy elderly control group. Both pathological groups exhibited a significant decrease in the mean levels of ACE activity and DOPAC per milliliter and were distinguishable from one another based on mean CSH HVA levels. Unlike the Parkinson's disease group, whose mean concentration of HVA was lower than, but not significantly different from that of the control group, the mean HVA concentration of the Alzheimer's disease group was significantly elevated. In contrast, comparisons of the mean CSF AChE activity (expressed per milliliter or per milligram of protein) and CSF total protein concentration did not reveal significant differences for any of the groups. Independent of CSF protein concentration, ACE activity per milliliter exhibited a positive correlation with AChE activity per milliliter within the control and Parkinson's disease groups, whereas a statistically significant correlation for these CSF hydrolases was not observed within the Alzheimer's disease group. Thus, the CSF profiles for patients with mild dementias associated with Alzheimer's or Parkinson's disease differed by at least two neurochemical criteria. Based on the levels of ACE activity, DOPAC, and HVA per milliliter of CSF, two discriminant functions were derived and resulted in the correct classification of 71% of all subjects (n = 38) into Alzheimer's disease, Parkinson's disease, and neurologically healthy control groups.     

A correlation study of CSF neuropeptides in Alzheimer's and Parkinson's disease.

The concentrations of somatostatin (SRIF), vasoactive intestinal polypeptide (VIP), beta-endorphin (beta-EP), adrenocorticotropin (ACTH) and corticotropin-releasing factor (CRF) immunoreactivity were measured in cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD), patients with Parkinson's disease (PD) and controls. In order to study the mechanisms that regulate peptide levels in CSF and peptide interactions, correlations between CSF peptides were determined. Within all patient groups a number of significant correlations were shown to exist between CSF peptides. The correlations were apparently not coincidental, since there was no such relation between the concentrations of CSF peptides and CSF protein content. Neither age, sex, severity of dementia nor the presence of extrapyramidal signs could explain the number of significant correlations. These results indicate, that the correlations found between CSF peptides may be due to common regulatory mechanisms or general physiological behaviour of peptides in the CSF.     

Intra vitam lumbar cerebrospinal fluid and serum and postmortem ventricular immunoreactive apolipoprotein E in patients with Alzheimer''s disease.

Using a specific enzyme linked immunosorbent assay (ELISA) method, total apolipoprotein E immunoreactivity (tApoE-IR) was measured in premortem lumbar CSF and serum of patients with "probable" Alzheimer's disease and in postmortem ventricular CSF of patients with Alzheimer's disease confirmed by necropsy. Concentrations were compared with those from patients with other neurological diseases and controls. The mean serum:lumbar CSF ratio of ApoE-IR was 15.9 suggesting that the main portion of lumbar ApoE-IR is synthesised intrathecally. No significant differences in ApoE-IR between patients with Alzheimer's disease and the other groups were detected in either CSF compartment. In lumbar CSF, there was no correlation between ApoE-IR of patients with Alzheimer's disease and their mini mental state scores. These results suggest that the diagnostic value of ApoE-IR measurements in CSF of patients with Alzheimer's disease as a single determination is less than that of other markers, in particular tau protein. On the other hand, ApoE determinations could be useful as part of a neurochemical profile of Alzheimer's disease.     

The specificity of depressive symptoms in patients with Alzheimer's disease

OBJECTIVE: This study assessed the specificity of depressive symptoms in patients with Alzheimer's disease and examined the discrepancies between patient and caregiver symptom reports. METHOD: The study group was composed of a series of 233 patients with Alzheimer's disease, 47 patients with depression but without dementia, and 20 healthy comparison subjects; the latter two groups were comparable in age with the patients with Alzheimer's disease. The patients and comparison subjects received a comprehensive psychiatric evaluation, which included administration of the Hamilton Depression Rating Scale and the Structured Clinical Interview for DSM-IV. RESULTS: Patients with Alzheimer's disease with a score of 2 or higher on the "depressed mood" item of the Hamilton depression scale, as scored by their respective caregivers, comprised a group with depressed mood (N=92), whereas patients who scored 0 on this item comprised a group without depressed mood (N=62). A statistical comparison of the scores on the remaining Hamilton depression scale items (2-16) between the Alzheimer's disease patients with and without depressed mood revealed significant differences on all items, except "loss of appetite." However, there were no significant differences on any single Hamilton depression scale item between the Alzheimer's disease patients without depressed mood and the age-comparable healthy comparison subjects. CONCLUSIONS: Depressive symptoms are not widespread among patients with Alzheimer's disease but are significantly related to an underlying depressed mood. Patients with Alzheimer's disease may not be fully aware of the extent of their depressive symptoms.     

Somatostatin cerebrospinal fluid levels in dementia

Summary Somatostatin levels were measured in cerebrospinal fluid of patients with Alzheimer's disease, multi-infarct dementia and normal pressure hydrocephalus and compared with levels from a normal control group. All pathological groups showed a statistically significant decrease of somatostatin with respect to the control group, but no significant differences were found amongst them. A negative correlation was found between the Mini Mental State Test and the somatostatin levels in Alzheimer's disease patients but not in the other groups. Our results confirm that the lower levels of somatostatin in cerebrospinal fluid are not specific to Alzheimer's disease and indicate that the decrease found in all the groups is probably the result of neuronal destruction or damage in the diseases examined.     

CSF somatostatin increase in patients with early parkinsonian syndrome

Summary Somatostatin-like immunoreactivity levels (SLI) in cerebrospinal fluid (CSF) were determined in twenty-three patients with untreated parkinsonian syndrome (15 with Idiopathic Parkinson's disease (IPD) and 8 with other forms of parkinsonism) at the moment of clinical diagnosis (mean duration of disease 1.1±0.2 years), and in 26 subjects without neurological symptoms. None of the IPD patients had a diagnosis of dementia at the moment of inclusion in the study. CSF-SLI content was found to be significantly higher in patients with parkinsonian syndrome (107.9±9.8 pg/ml) than in control subjects (73.5±8.4 pg/ml). The increase was also significant when controls were compared with IPD patients. In addition, a positive correlation between SLI and homovanillic acid was found in CSF of all patients. A test of learning memory was used to evaluate the mental state of patients and a significant increase in CSF-somatostatin levels was observed in patients with Idiopathic Parkinson's disease and severe affectation of memory. These results indicate that in the early steps of untreated parkinsonian syndrome, somatostatin concentration in cerebrospinal fluid may increase, probably due to the neurodegenerative depletion of somatostatin from striatal or cortical neurons.     

Neurochemical markers in the cerebrospinal fluid of patients with Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis and normal controls

Summary Several neurotransmitter markers were investigated in the cerebrospinal fluid (CSF) from patients with Alzheimer's disease (AD) (n=27), Parkinson's disease (PD) (n=35) and ALS (n=26) and from control subjects (n=34) to compare the possible alterations in the biochemical profiles of these different neurodegenerative diseases. The main proportion of the patients represented an early phase of the illness at the time of the diagnosis. Correlations of the degree of dementia and the stage of the disease with CSF measures were evaluated. The CSF levels of somatostatin like-immunoreactivity (SLI) were significantly reduced in AD patients when compared with those of normals and ALS patients. The CSF concentrations of homovanillic acid (HVA) were significantly decreased for PD patients and the decrease focused on the nondemented patients. A trend of decreasing HVA values towards the most advanced stage of Parkinson's disease assessed by Webster's scale was also displayed. The content of 3-methoxy-4-hydroxyphenylglycol (MHPG) in the CSF was higher for ALS patients than for other groups. The lowest 5-hydroxy-indoleacetic acid (5HIAA) levels were observed in the PD group and the lowest acetylcholinesterase (AChE) activities were found in the PD patients with the most severe disease. Changes in CSF measures were too subtle to be beneficial for diagnostic purposes, but adequate for reflecting the different neurochemical profiles of these three degenerative neurological disorders.     

Somatostatin content and receptors in the cerebral cortex of depressed and control subjects.

Somatostatin-like immunoreactivity is reduced in the cerebrospinal fluid in depression and this is presumed to reflect alterations in cerebral somatostatinergic systems. We have examined this hypothesis by measuring this immunoreactivity and somatostatin receptors in post-mortem cortical tissue from depressed patients and control subjects. There was no significant difference in the temporal and occipital cortex in somatostatin-like immunoreactivity or in somatostatin receptor affinity and binding capacity between depressed and control groups. It is concluded that there may not be an alteration of cortical somatostatin function in depression.     

Galanin immunoreactivity in human CSF: studies in eating disorders and Alzheimer's disease

Galanin is a peptide which stimulates feeding behavior in animals and is found within those basal forebrain cholinergic neurons which degenerate in Alzheimer's disease. Galanin was measured in cerebrospinal fluid (CSF) by radioimmunoassay. The nature of the immunoreactivity was characterized chromatographically as authentic galanin. CSF galanin levels were determined in subjects with Alzheimer's disease, involutional depression, anorexia nervosa and bulimia. No differences between any diagnostic group and age and sex-matched controls were found.     

Cerebrospinal fluid (CSF) neuropeptide Y- and somatostatin-like immunoreactivities in man

We have measured cerebrospinal fluid (CSF) neuropeptide Y-like immunoreactivity (NPY-LI) and somatostatin-like immunoreactivity (SLI) in control subjects and in patients with various neurologic disorders. We observed a significant reduction in CSF SLI in control subjects over 60 years of age, compared with the younger controls. CSF SLI was significantly decreased in multiple sclerosis (MS), or Guillain-Barre syndrome, compared with that of age-matched control subjects. A reduced concentration of NPY-LI was found in CSF of patients with MS. We have also examined the molecular heterogeneity of peptide-LI in CSF. Gel chromatography, not high performance liquid chromatography (HPLC), suggested two NPY immunoreactive materials in CSF. Gel chromatography and HPLC revealed three SLI components in CSF: somatostatin 14, somatostatin 28 and a higher molecular weight precursor. Our results suggest that 1) there may be more than one form of NPY in human CSF, and 2) somatostatin neurons might be more susceptible to alteration than NPY neurons in various pathological conditions and aging.     

Widespread reduction of somatostatin-like immunoreactivity in the cerebral cortex in Alzheimer's disease

Although several studies have documented reduced concentrations of somatostatin-like immunoreactivity (SLI) in the cerebral cortex in Alzheimer's disease, there is controversy concerning the extent and importance of these changes. We measured SLI in brains obtained post mortem from 12 patients with pathologically confirmed Alzheimer's disease and from 13 neurologically normal controls. All major cortical and subcortical regions were examined. Widespread reductions of SLI in Alzheimer's disease cerebral cortex were found, with the most profound changes seen in temporal lobe; but there also were major reductions in both the frontal and occipital cortex. There were no significant reductions in subcortical regions. Characterization of SLI by high-pressure liquid chromatography showed no significant difference in profiles between Alzheimer's disease and control frontal cortex. These results suggest that the reduction in somatostatin immunoreactivity in Alzheimer's disease may be caused by degeneration of intrinsic somatostatin cortical neurons.     

Screening for Early Alzheimer's Disease: Is There Still a Role for the Mini-Mental State Examination?

Background: The objective of this study was to compare the performance of the Mini-Mental State Examination (MMSE) total score as well as item scores in separating 4 groups of elderly (55-85 years of age) subjects-normal controls, subjects with mild cognitive impairment (MCI), subjects with mild Alzheimer's disease, and subjects with depression.Method: The MMSE scores of 86 subjects (25 normal elderly controls, 26 subjects with MCI, 10 subjects with mild Alzheimer's disease, and 25 subjects with depression) were analyzed. Statistically significant differences between groups in both overall MMSE score and individual item scores were documented. Receiver operating characteristic curves were constructed to yield further data.Results: The overall MMSE scores of the mild Alzheimer's disease group were significantly below those of subjects in the control, MCI, and depression groups (p < .001). The overall MMSE scores of MCI subjects were significantly lower than those of control subjects (p = .005) but not different from those of subjects with depression. Furthermore, individual item responses were not significantly different between MCI subjects and controls. The delayed recall item scores were statistically lower in the mild Alzheimer's disease group versus the other 3 groups but did not separate the control, MCI, and depression groups from each other.Conclusion: The MMSE effectively separates those with mild Alzheimer's disease from the other 3 groups and MCI from normal aging, but it is relatively ineffective in separating normal elderly individuals from those with depression and individuals with MCI from those with depression. Measures other than the MMSE may need to be implemented to evaluate mental status to more effectively separate MCI from depression and depression from normal aging.     

CSF cortisol in patients with depression, mania, or anorexia nervosa and in normal subjects

The authors studied CSF cortisol in 30 depressed patients, 10 manic patients, 21 women with anorexia nervosa, and 22 normal control subjects. All patients were also rated on a global severity scale for mania or depression. Results indicated higher CSF cortisol levels in all three patient groups than in the control group. Only the depressed group had a significant positive correlation between CSF cortisol and severity ratings. The authors recommend further research into the hypothalamic mechanisms associated with cortisol secretion and regulation.     

Differentiation of geriatric major depression from Alzheimer's disease with CSF tau protein phosphorylated at threonine 231

OBJECTIVE: Differentiation of geriatric major depression from Alzheimer's disease is hampered by overlapping symptoms. Increased CSF concentrations of tau protein phosphorylated at threonine 231 (p-tau(231)) have been suggested as a biomarker for Alzheimer's disease. The authors asked whether p-tau(231) levels improve the differential diagnosis between geriatric major depression and Alzheimer's disease. METHOD: Included were 34 depression subjects, 64 with probable Alzheimer's disease, 17 with possible Alzheimer's disease, and 21 healthy comparison subjects. P-tau(231) concentrations were measured with an enzyme-linked immunosorbent assay. RESULTS: P-tau(231) levels were significantly higher in Alzheimer's disease than in geriatric major depression patients and healthy comparison subjects. For differentiation of probable Alzheimer's disease from major depression, p-tau(231) correctly allocated 87% of subjects. When possible mild Alzheimer's disease was compared to major depression, p-tau(231) correctly allocated 78% of subjects. CONCLUSIONS: CSF p-tau(231) should be evaluated as a potential biological marker for differentiation of geriatric depression from Alzheimer's disease.     

Cerebrospinal fluid ferritin levels of patients with Parkinson's disease, Alzheimer's disease, and multiple system atrophy

Summary Iron is believed to play a role in the pathogenesis of both Parkinson's disease (PD) and Alzheimer's disease (AD). We measured ferritin, which is considered to be the iron storage protein, in CSF of patients with PD, AD, and multiple system atrophy (MSA) as well as control subjects. We found a significant increase in CSF ferritin in AD compared with both PD and age-matched controls. No significant differences were found between PD patients with dementia (PDD) and non-demented PD patients. For non-demented PD patients a positive correlation between CSF ferritin and age was found. Our results may indicate that iron has a role in the pathophysiology of AD.     

Altered neuropeptide concentrations in cerebrospinal fluid of psychiatric patients

Immunoreactive somatostatin, bombesin, and cholecystokinin were measured in cerebrospinal fluid of normal subjects and patients with anorexia nervosa, depression, mania, and schizophrenia. Somatostatin-like immunoreactivity was decreased in anorexic and depressed patients. Bombesin-like immunoreactivity tended to be decreased in schizophrenics. Cholecystokinin-like immunoreactivity did not differ between groups. These data suggest a possible function for neuropeptides in regulation of human behavior.     

Low CSF somatostatin associated with response to nimodipine in patents with affective illness.

BACKGROUND: In patients with depression, treatment with nimodipine has been shown to increase cerebrospinal fluid (CSF) somatostatin (SRIF) and ameliorate baseline global cerebral hypometabolism. This study was conducted to assess whether a low baseline level of CSF SRIF was associated with response to nimodipine treatment.METHODS: Twenty-one depressed patients underwent lumbar puncture for analysis of CSF somatostatin-like immunoreactivity (SRIF-LI) during a medication-free period and after at least 6 weeks of nimodipine monotherapy. Twenty-five healthy control subjects were utilized as a comparison group. Clinical improvement was assessed using the Clinical Global Impression Scale for Bipolar Illness.RESULTS: As predicted, baseline CSF SRIF-LI was significantly lower in eventual nimodipine responders (33.1 +/- 2.8 pg/mol) compared to eventual nonresponders [41.9 +/- 2.6 pg/mL; t(19) = 1.98, p =.03, one-tailed].CONCLUSIONS: Low baseline CSF somatostatin in depression may be associated with response to nimodipine, which in turn may be related to the ability of nimodipine to increase CSF somatostatin.     

Cholinesterases in the cerebrospinal fluid,plasma, and erythrocytes of patients with Alzheimer's disease

Summary In patients with probable Alzheimer's disease and in controls, acetyl- and butyrylcholinesterase activities were studied in cerebrospinal fluid (CSF) and plasma, and acetylcholinesterase activity of erythrocytes was determined. In addition, the molecular forms of acetylcholinesterase were measured in CSF. Severely demented patients had significantly lower acetylcholinesterase (p<0.01) and butyrylcholinesterase (p<0.05) activities in CSF than the controls had, but the activities of these enzymes in plasma and erythrocytes were within the same range in both groups. Acetylcholinesterase and butyrylcholinesterase activities in the CSF of mildly demented patients did not differ from control values. The ratio of the intermediate molecular form of acetylcholinesterase to the light molecular form of the enzyme did not differ significantly between patients with Alzheimer's disease and controls. According to our results, AChE levels were lower in the CSF of severely demented patients, but both light and intermediate molecular forms were affected.