Serum and cerebrospinal fluid cystatin C levels in vascular and Alzheimer's dementia

INTRODUCTION: Cystatin C, a cysteine protease inhibitor, has been implicated in the neurodegenerative and repair processes of the nervous system, and the deposition of the same protein together with beta amyloid peptide was found as cerebral amyloid angiopathy (CAA) in different types of dementias. OBJECTIVE AND METHODS: Because of the differential diagnostic importance, serum and cerebrospinal fluid (CSF) cystatin C levels of 24 late onset Alzheimer's demented (AD) and 16 ischemic type of vascular demented (VD) probands were compared with 17 aged control (AC) persons. RESULTS: The serum and CSF cystatin levels were found in the normal range in all groups. The ischemic VD probands had the tendency to have higher cystatin C levels than the AD. No correlation has been found with the severity and duration of dementia and with the other measured parameters. CONCLUSION: These results indicate that lower than normal CSF cystatin C level is not a diagnostic marker in ischemic VD and CAA related to AD.     

Intra vitam lumbar and post mortem ventricular cerebrospinal fluid immunoreactive interleukin-6 in Alzheimer's disease patients

OBJECTIVES: In view of contradictory findings in previous studies, to examine the diagnostic value of interleukin-6 measurements in cerebrospinal fluid (CSF) of Alzheimer's disease patients. MATERIAL AND METHODS: Interleukin-6-immunoreactivity (IL-6-IR) was measured in 169 intra vitam lumbar and 21 post mortem ventricular CSF samples of patients with probable and neuropathologically confirmed Alzheimer's disease (AD), non-AD dementias (NAD), neurological disorders without cognitive impairment (OND) and controls (CON) using a specific sandwich enzyme immunoassay. RESULTS: Intra vitam lumbar samples had significantly elevated (P < 0.03) IL-6-IR not only in the AD, but also in the NAD and OND group compared with controls. AD patients with late onset (> 65 years) had slightly (P > 0.05) higher values than patients with early onset (< 65 years). In post mortem ventricular fluid, differences among groups did not reach significance (P > 0.05). CONCLUSION: We conclude that elevations of CSF IL-6-IR can not serve as a diagnostic marker of the disease, but, hypothetically, could reflect presence or activity of IL-6 mediated immunological phenomena in single AD patients.     

Sulfatide as a biochemical marker in cerebrospinal fluid of patients with vascular dementia

The myelin-associated glycosphingolipid sulfatide in cerebrospinal fluid (CSF) was investigated in 20 patients with vascular dementia (VAD), 43 with Alzheimer's disease (AD) and 20 age-matched controls. The sulfatide concentration in the VAD group (307 +/- 118 nmol/l) was significantly (p less than 0.0001) higher than that in controls (145 +/- 86 nmol/l) and the AD group (178 +/- 79 nmol/l). Among the VAD patients, 8/20 had a significantly increased concentration of sulfatide (greater than mean + 2 S.D.), as compared with controls, while only 2/43 of the AD patients had a sulfatide concentration above this level. It is suggested that the elevated concentration of sulfatide in CSF from VAD patients reflects demyelination. Furthermore, sulfatide determinations, when combined with clinical findings, may be of diagnostic value, for discriminating between VAD and AD.     

CSF biomarker profile and diagnostic value in vascular dementia

Background and purpose:  The differential diagnosis between vascular dementia (VD) and Alzheimer's disease (AD) or mixed dementia (MD) is not always easy in clinical practice. The purpose of the present study was to evaluate the cerebrospinal fluid (CSF) biomarkers tau protein in its total (τ_T) or hyperphosphorylated at threonin-181(τ_P-181) form and beta amyloid peptide 1–42 (Aβ42) alone and their combinations to investigate their diagnostic value in the discrimination between VD and AD or MD.
Methods:  The above CSF biomarkers were determined in duplicate and blind to the clinical diagnosis by double sandwich, enzyme-linked immunosorbent assay (ELISA) commercial kits (Innogenetics, Gent, Belgium) in 92 AD patients, 23 VD patients, 17 patients with MD and 68 controls.
Results:  Alzheimer's disease and MD showed increased levels of τ_T, τ_P and reduced levels of Aβ42 as compared with the controls. The best discrimination between VD and AD or MD was achieved by the combination of all three biomarkers, correctly classifying ≥85% of patients, either in the form of a discriminant function or in the form of the τ_T × τ_P-181/Aβ42 formula.
Conclusions:  Cerebrospinal fluid biomarkers may be a useful adjunct for the discrimination between AD/ MD and VD in every day clinical practice.     

Oligoclonal immunoglobulin bands in cerebrospinal fluid of patients with Alzheimer''s disease and vascular dementia

We examined serum and cerebrospinal fluid (CSF) of 16 patients with Alzheimer's disease (AD), 28 patients with vascular dementia (VD), their age-matched controls and multiple sclerosis (MS) patients in order to evaluate the humoral immune response within the central nervous system both quantitatively and qualitatively. Intra-blood-brain barrier (BBB) protein synthesis was calculated by CSF IgG index. The presence of oligoclonal banding (OCB) was investigated with agarose isoelectric focusing (IEF) followed by immunoblotting with antihuman IgG. No patient with AD and only 4 patients with VD had slightly elevated IgG indexes, and no statistically significant differences in the indexes were found between the two groups. No bands were found in the CSF of AD patients but 3 VD patients had OCB in both serum and CSF. One VD patient had bands in serum but no bands in CSF. No kappa or lambda free light chains were found in those demented patients with demonstrable bands in the CSF and serum. No OCB were found in control sera and CSF. For comparison, the majority of patients with MS had OCB in CSF. Thus, no consistent increase of intrathecal protein synthesis was found in patients with AD and VD. Methodological differences explain at least part of the conflicting results published earlier.     

Use of cerebrospinal fluid biomarkers in diagnosis of dementia across Europe

Background and purpose:  Cerebrospinal fluid (CSF) biomarkers have been reported to be useful in dementia diagnosis. Not much is known about their use in clinical practice in Europe.
Methods:  We analyzed data from a survey on the use of CSF biomarkers in the diagnosis of dementia across Europe using a questionnaire which was filled out by representatives of the 25 member countries of the European Federation of Neurological Societies (EFNS).
Results:  Cerebrospinal fluid beta-amyloid, total tau, and phosphorylated tau proteins are frequently evaluated in the majority of the countries (in 18 out of 23 countries). No major technical or ethical issues were found that would hamper the procedure's ability to become routine in early and differential diagnostics of Alzheimer's disease. Cut-off values for beta-amyloid (median 500, range 300–849 pg/ml), total tau (367; 195–450 pg/ml) and phosphorylated tau (60; 40–85 pg/ml) varied considerably amongst countries and even within every country.
Conclusions:  Cerebrospinal fluid analysis of beta-amyloid, tau, and phosphorylated tau is frequently used in Europe. However, the use of various cut off values seriously hampers comparability and yields a potential threat to an interpretation and balanced use in clinical practice. We recommend that each laboratory establishes normative data and that multi-centered studies should be organized to explore the reasons for any differences.     

Serum interleukin-6 levels correlate with the severity of dementia in Down syndrome and in Alzheimer's disease

Introduction - Inflammatory processes are suspected in the pathomechanism of Alzheimer's dementia (AD) but the serum and cerebrospinal fluid (CSF) levels of inflammatory cytokines are not yet determined in the different forms of the disorder. Subjects and methods - Interleukin-6 (IL-6) levels were examined in the sera and CSF of patients with mild-moderate and severe stage of late onset sporadic type of AD and in the sera of demented Down syndrome (DS) probands with similar stages of AD and compared with data of age-matched healthy controls. Results - Normal serum IL-6 levels were found in the mild-moderate stage, but significantly increased levels were found in the severe stage of both dementia groups. The CSF concentrations remained within the normal range in all groups. Positive correlations between the serum IL-6 levels and age and the severity of the disease were present. Conclusion - These findings suggest a disease stage dependent general activation of the immune system both in sporadic AD and in DS with AD.     

Decreased soluble interleukin-6 receptor in cerebrospinal fluid of patients with Alzheimer''s disease

The function of the cytokine interleukin-6 (IL-6) is augmented by soluble IL-6 receptors (sIL-6R). We investigated cerebrospinal fluid sIL-6R concentrations in patients with Alzheimer's disease (AD) compared to age-matched healthy subjects and individuals with at least one first degree relative with AD. We found a statistically significant decrease in sIL-6R levels in the AD group compared to controls. Complete analysis of the IL-6R complex seems crucial to better understand the impact of IL-6 in AD pathophysiology.     

Nitric oxide metabolites and interleukin-6 in cerebrospinal fluid from multiple sclerosis patients

Interleukin-6 (IL-6) and nitric oxide (NO) are implicated in the pathology of multiple sclerosis (MS). We have investigated the levels of these mediators in the cerebrospinal fluid (CSF) from 50 patients with MS and 23 control subjects. Mean CSF IL-6 level was higher in the total MS group in comparison with controls, but not significantly, whilst the difference between patients with stable MS and controls reached the level of statistical significance. Mean CSF nitrite/nitrate level was significantly higher in the total MS group compared with the control group, as well as in active MS patients versus controls. There was significant difference neither in the mean CSF IL-6 nor in nitrite/nitrate levels between active and stable MS patients. Interestingly, we observed a significant negative correlation between IL-6 and nitrite/nitrate levels in the CSF in the total MS group. Such a trend existed in both subgroups with active and stable MS, but without reaching the level of statistical significance. Our data further support the involvement of IL-6 and NO in ongoing pathological processes in MS, suggesting their potential interplay within the central nervous system in this disease.     

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.     

Increased tau protein level in postmortem cerebrospinal fluid

Abstract Microtubule-associated protein tau has been reported to be significantly increased in cerebrospinal fluid (CSF) of the patients with Alzheimer's disease (AD), which suggests that it is possibly a biological marker for the diagnosis of AD. The underlying mechanism of the increased tau level in CSF, however, is not known. In this study, the tau levels were compared between antemortem and postmortem CSF. The postmortem tau levels in CSF were significantly increased in all groups including AD, neurological control, and nondemented control. A striking elevation of CSF tau was observed during the postmortem change with the nondemented subjects. These findings may offer some insight into the understanding of the mechanism of the increased tau level in CSF with AD and other related disorders.     

Chitotriosidase and inflammatory mediator levels in Alzheimer's disease and cerebrovascular dementia

Inflammation has been reported to be involved in the pathogenesis of cerebrovascular dementias (CvDs). This study investigated the involvement of Chitotriosidase (ChT), a chinolitic enzyme mainly produced by activated macrophages, in the pathophysiology of Alzheimer's disease (AD) and ischemic CvD. In addition, the levels of interleukin (IL)-16, IL-18, transforming growth factor (TGF)-beta1 and superoxide anion (O2(-)) were determined to evaluate the relationship between ChT levels, these cytokines and oxidative stress in both AD and ischemic CvD patients. The levels of ChT and IL-16, IL-18, and TGF-beta1 mRNA were investigated using quantitative real-time polymerase chain reaction on macrophages of peripheral blood of 40 patients with AD, 40 patients with ischemic CvD and 40 non-demented age-matched subjects. The results show that ChT, IL-16 and O2(-) levels significantly increased in ischemic CvD patients compared with AD patients and were significantly and positively correlated with IL-18 and O2(-). The production of IL-18 was increased in both AD and ischemic CvD patients. TGF-beta1 expression was higher in AD patients and was inversely correlated with the expression of ChT, IL-16 and IL-18, respectively. In non-demented age-matched subjects no significant changes in ChT and IL-16, IL-18, and TGF-beta1 expression were found. Our results indicate that ChT, IL-16, IL-18 and TGF-beta1 are increased in ischemic CvD and AD, confirming that the immune system may play an important role in the development and progression of neurodegenerative disorders. In addition, the present findings suggest that ChT could also play a crucial role in pathological conditions such as CvD in which the inflammatory process is activated.     

The urate and xanthine concentrations in the cerebrospinal fluid in patients with vascular dementia of the Binswanger type, Alzheimer type dementia, and Parkinson's disease

Summary We determined the urate and xanthine concentrations in the cerebrospinal fluid (CSF) in patients with vascular dementia of the Binswanger type (VDBT), Alzheimer type dementia (ATD), and Parkinson's disease (PD). We found that the urate concentration was significantly increased in VDBT patients, but significantly decreased in ATD patients compared with controls. The ratio of the concentrations of uric acid (U_CSF) to xanthine (X_CSF) in the CSF (U_CSF/X_CSF) had a significant correlation with the ratio of the U_CSF to the urate concentration in serum (U_serum) (U_CSF/U_serum) in ATD and PD, whereas U_CSF/U_serum increased independently of U_CSF/X_CSF in VDBT. We concluded that the significant increase in the urate concentration in VDBT is mainly due to an impairment of the blood-brain barrier (BBB), and its significant reduction in ATD may reflect impaired brain metabolism.     

Monoamine metabolite concentrations and cholinesterase activities in cerebrospinal fluid of progressive dementia patients: relation to clinical parameters

Forty-five well clinically characterized patients with progressive dementia were investigated for lumbar cerebrospinal fluid (CSF) monoamine metabolites and cholinesterase activities. Monoamine concentrations were determined by reverse phase liquid chromatography with electrochemical detection and the cholinergic enzymes were measured photometrically. Firstly, all clinical and CSF parameters were studied in statistical cluster analyses to detect groups of variables which demonstrated a high correlation with respect to each other. The CSF transmitter markers were then used in multiple regression models to explain the variance of clinical variables as chosen from the cluster analyses. The degree of dementia, as assessed by global deterioration score (GDS) and activity in daily life (ADL) status, as well as the Alzheimer-related symptoms dyspraxia and dysphasia, were associated with low AChE activities in CSF. A presumed subgroup of dementia patients clinically characterized by asymmetry of neurological signs, increased unilateral tonus, stepwise progression, and high Hachinski score, showed low HVA concentrations in CSF. These data suggest a coupling of clinical/neurological parameters to different CSF transmitter profils and, thus, that CSF biochemical parameters are of use as antemortem markers in dementia conditions.     

Elevated levels of harman and norharman in cerebrospinal fluid of Parkinsonian patients

Summary Death of dopaminergic neurons in Parkinson's disease (PD) may partially be caused by synthesis and accumulation of endogenous and exogenous toxins. Because of structural similarity to MPTP, -carbolines, like norharman and harman, have been proposed as putative neurotoxins. In vivo they may easily be formed by cyclization of indoleamines with e.g. aldehydes. For further elucidation of the role of -carbolines in neurodegenerative disorders harman and norharman levels in cerebrospinal fluid (CSF) were measured in 14 patients with PD and compared to an age- and sex-matched control group (n=14). CSF levels of norharman and harman in PD were significantly higher compared to controls. These results may suggest a possible role of harman and norharman or its N-methylated carbolinium ions in the pathophysiological processes initiating PD. However the origin of increased levels of these -carbolines remains unclear. On the one hand one may speculate, that unknown metabolic processes induce the increased synthesis of harman and norharman in PD. On the other hand a possible impact of exogenous sources may also be possible.     

High interleukin-6 plasma levels are associated with functional impairment in older patients with vascular dementia

In older individuals, inflammatory mechanisms have been linked to the pathogenesis of both dementia and functional impairment. In this cross-sectional study we have investigated the possible association between some markers of systemic inflammation and functional status, in a sample of one hundred and forty older demented patients including 60 patients with late onset Alzheimer's disease (LOAD) and 80 with vascular dementia (VD). Functional status was evaluated by Barthel Index (BI); the total score ranged from 0 (total dependency) to 20 (total autonomy). Interleukin-1beta, Tumor Necrosis Factor-alpha, Interleukin- 6, Interleukin- 8, and Transforming Grow Factor beta were quantified by ELISA. Among the cytokines evaluated, only IL-6 was correlated with the BI (r: -0.32, p < 0.001). The mean levels of IL-6 progressively decreased from I (9.50 pg/mL), to II (6.40 pg/mL), to III BI tertile (4.80 pg/mL) (p < 0.02). At multiple regression analysis, IL-6 was associated with BI in the whole sample and in VD, but not in LOAD, independent of age, gender, smoking, alcohol consumption, hypertension, diabetes, coronary heart disease, previous stroke, and mini mental state examination score. Our study suggests the existence of an independent and negative relationship between IL-6 plasma levels and functional status in older individuals with vascular dementia. This finding might contribute to explain the 'excess of disability' phenomenon described in older demented patients.     

The role of neuroimaging in the diagnosis of vascular dementia

Vascular dementia (VaD) and Alzheimer's disease share many pathological and clinical characteristics. Whereas clinical criteria can help differentiate VaD from other types of dementia, neuroimaging is required for confirmation of vascular lesions. Neuroimaging also provides information about location and size of vascular lesions that can lead to a better understanding of symptoms and may help guide therapy.     

Defining dementia: clinical criteria for the diagnosis of vascular dementia

The recognition of cerebrovascular disease (CVD) as a contributing factor and a cause of dementia has led to the development of clinical criteria for vascular dementia (VaD). Due to high specificity, the consensus criteria developed by the National Institute for Neurological and Communicative Disorders and Stroke (NINDS)–Association Internationale pour la Recherche et l'Enseignement en Neurosciences (AIREN) have been used in controlled clinical trials to select patients with pure VaD. VaD is predominantly a subcortical frontal form of dementia with prominent executive dysfunction. In contrast, the criteria of the NINCDS–Alzheimer's Disease and Related Disorders Association (ADRDA) emphasize memory loss as the main feature to distinguish Alzheimer's disease (AD) from VaD and from other forms of dementia. Moreover, CVD may precipitate the clinical expression of AD. Although no criteria have been created specifically for patients having AD with CVD, the ischemic score, the Informant Questionnaire on Cognitive Decline in the Elderly and a history of prestroke mild cognitive impairment (MCI) may be useful for identifying patients with this mixed form of dementia.     

Tau protein concentrations in cerebrospinal fluid of patients with amyotrophic lateral sclerosis

OBJECTIVE: To elucidate whether cerebrospinal fluid (CSF) concentrations of the microtubule-associated tau protein are related to the risk for sporadic amyotrophic lateral sclerosis (SALS). PATIENTS/METHODS: We measured tau concentrations in the CSF of 18 patients with SALS and 75 age- and sex-matched controls, using a specific ELISA method. RESULTS: The mean CSF concentrations of tau protein did not differ significantly between SALS patient and control groups, were not influenced by the clinical form (spinal vs bulbar) of ALS, and were not correlated with age, age at onset, and duration of the disease. CONCLUSIONS: CSF tau concentrations are not a biochemical marker of ALS.     

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.