Increased serum midkine levels in autism spectrum disorder patients

Background: Midkine (MK) is a heparin binding growth factor and is involved in neurogenesis, neural development and neuroprotection. Additionally, MK may contribute to cancer development and pathogenesis of neurodegenerative disorders and schizophrenia. Considering these effects of MK, this study researched whether MK is involved in autism spectrum disorders (ASD) pathogenesis.

Methods: We evaluated serum MK levels of 38 patients with ASD and 32 healthy control group. MK levels were measured with ELISA, while ASD severity was assessed with Childhood Autism Rating Scale.

Results: Our data showed that the serum MK concentration in ASD patients (mean ± SD, 11.51 ± 8.53 pg/ml) is significantly higher than healthy controls (mean ± SD, 6.19 ± 3.94 pg/ml) (p = 0.007).

Conclusions: According to these results, MK may play a role in ASD pathogenesis.     

Increased CSF levels of nerve growth factor in patients with Alzheimer's disease

The authors quantitated CSF levels of nerve growth factor (NGF) in patients with AD, nondemented control subjects (CTR), and age-matched patients with major depression (DE). CSF levels of NGF were markedly higher in the AD group than in both the CTR and DE groups (p < 0.01 and p < 0.001). Increased CSF levels of NGF in AD patients may reflect reported accumulation of NGF in the AD brain and may constitute a candidate marker for clinical diagnosis and therapeutic monitoring.     

Increased urinary F(2)-isoprostanes levels in the patients with Alzheimer's disease

Isoprostanes, novel markers of oxidative injury, are generated by the free radical-mediated peroxidation of arachidonic acid (AA). They are thought to be important in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD). Using gas chromatography-mass spectrometry (GC-MS), we investigated the alteration of urinary F(2)-isoprostanes in AD patients compared to that of healthy subjects. Our results show that the levels of urinary F(2)-isoprostanes, sum of the prostaglandin F(2 alpha) isomer; prostaglandin F(2 alpha) (PGF(2 alpha)), prostaglandin F(2 beta) (PGF(2 beta)), and 8-isoprostaglandin F(2 alpha) (8-isoPGF(2 alpha)), significantly increased in AD patients (P < 0.05). The concentration of urinary 8-isoPGF(2 alpha), one of the biomarkers of oxidative stress, was not significantly different between 34 AD patients and 20 age-matched controls (P > 0.05). The PGF(2 alpha), formed by endoperoxide reductase from PGH(2), was significantly increased in AD patients, when compared with the levels of the normal controls (P < 0.05). The PGF(2 alpha), an enzymatic product of arachidonic acid, may affect the pathogenesis of AD. In addition, urinary F(2)-isoprostanes can play an important role as a biomarker in AD.     

Increased levels of neuronal thread protein in cerebrospinal fluid of patients with Alzheimer's disease

Neuronal thread protein is a recently characterized, ～20-kd protein that accumulates in brains with Alzheimer's disease (AD) lesions. This study examined whether concentrations of neuronal thread protein (NTP) were also increased in the cerebrospinal fluid (CSF) of individuals with probable (clinically diagnosed) and definite (histopathologically proved) AD. Using a highly sensitive three-site monoclonal antibody–based immunoradiometric assay, we measured NTP concentrations in CSF from 84 patients with probable AD and mild dementia (duration, 4.05 ± 0.36 years), 45 with Parkinson's disease and minimal or no dementia (duration, 4.73 ± 0.78 years), 73 with multiple sclerosis, and 73 nondemented control subjects. NTP concentrations were also measured in postmortem ventricular fluid and temporal lobe neocortex extracts from 31 subjects with histopathologically proved AD and 14 age-matched control subjects. The mean concentration of NTP in the CSF was higher in AD (4.15 ± 0.25 ng/ml; 95% confidence interval [CI] limits, 3.65–4.65) than in Parkinson's disease (1.96 ± 0.16 ng/ml; 95% CI, 1.65–2.27), multiple sclerosis (1.6 0.14 ng/ml; 95% CI limits, 1.33–1.88), or control subjects (1.27 ± 0.06 ng/ml; 95% CI limits, 1.15–1.40) (p < 0.001). In addition, 70% of the patients with probable AD had concentrations of NTP in CSF that were higher than 2.5 ng/ml (> upper 99% CI limit in the control group), compared with 23%of Parkinson's disease patients, 11% of multiple sclerosis patients, and 40% of control subjects. The mean concentrations of NTP in the ventricular fluid and brain tissue from individuals with documented AD and end-stage dementia were threefold higher than the levels detected in the CSF from the remaining patients with probable AD and mild dementia. Moreover, of 9 patients with AD, postmortem brain and CSF manifested 5- to 50-fold higher levels of NTP compared with the CSF samples obtained an average of 6 years earlier. These findings demonstrate that NTP levels are elevated in the CSF of individuals with AD and that NTP levels in the CSF increase strikingly with progression of dementia and neuronal degeneration.     

Increased cerebrospinal fluid cAMP levels in Alzheimer's disease

Since increasing evidence suggests that upregulation of the cAMP-second messenger system may be implicated in Alzheimer's disease neurodegeneration, we have compared the cAMP and cGMP levels in cerebrospinal fluid (CSF) from patients with dementia of the Alzheimer type (DAT, n=10) with those from nondemented age-matched controls (n=10). Our results show that cAMP levels, but not cGMP, are significantly (p<0.01) elevated in CSF from patients with DAT compared to those from nondemented controls. Moreover, a linear regression analysis demonstrated a significant correlation (r=0.62; p<0.01) between cAMP and tau protein levels in CSF when controls and patients with DAT were studied together. These results suggest that upregulation of cAMP-signaling pathway is implicated in Alzheimer's disease physiopathology.     

Increased alpha 7 nicotinic acetylcholine receptor protein levels in Alzheimer's disease patients

We compared the intact alpha7 nicotinic acetylcholine receptor (alpha7nAChR) protein levels in the peripheral blood leukocytes in 15 Alzheimer's disease (AD) patients and 13 normal elderly control subjects. Demographic data and Mini-Mental State Examination (MMSE) scores were obtained. Western blot analysis for alpha7nAChR protein levels in peripheral blood leukocytes was performed. There were no significant differences in sex and age between the AD and control groups. The mean MMSE score of the AD subjects was significantly lower than that of the normal control subjects (15.4 +/- 5.5 vs. 28.5 +/- 1.9 respectively; p < 0.001). The median value of normalized alpha7nAChR protein levels (optical density, arbitrary unit) of the AD group was significantly higher than that of the normal control group (0.6923 vs. 0.4803 respectively; p = 0.045, Mann-Whitney U test). The normalized alpha7nAChR protein levels showed a significant inverse correlation with the MMSE scores (Spearman rho = -0.45; p = 0.016; n = 28). Receiver Operating Characteristic curve analyses showed that the area under curve was 0.72 (95% CI 0.52- 0.87). If the cut-off of the alpha7nAChR protein level was >0.312, the sensitivity, specificity, positive predictive value and negative predictive value would be 80, 39, 60 and 63%, respectively. These findings showed that the alpha7nAChR protein levels would be a potentially useful diagnostic marker for AD.     

Increased levels of magnetic iron compounds in Alzheimer's disease

A study of the magnetic properties of superior temporal gyrus brain tissue from 11 Alzheimer's disease (AD) and 11 age-matched control subjects demonstrates an exponential correlation between the concentrations of the Fe;{2+}-ion-containing iron oxide, magnetite (Fe{3}O{4}), and the fraction of those particles that are smaller than 20 nm in diameter. These data provide circumstantial evidence in favor of their genesis within the 8 nm diameter cores of the iron storage protein ferritin. We also show, for the first time, that the total concentration of biogenic magnetite is generally higher in the AD brain (in some cases as much as 15 times greater than controls) and that there are gender-based differences, with AD female subjects having significantly higher concentrations than all other groups. These results provide insights which may guide current efforts to develop iron-based MRI diagnosis of AD.     

Increased serum levels of CD95 in Alzheimer's disease

There is growing evidence for a role of apoptosis in Alzheimer's disease (AD). Recent findings suggest an increased susceptibility of lymphocytes to apoptosis in AD. To prove the hypothesis of systemic alterations in the apoptotic balance in AD, serum and cerebrospinal fluid levels of soluble CD95, which is known to mediate apoptosis, were measured. In the serum, AD patients exhibited significantly higher levels of CD95 than the controls (p = 0.017), suggesting an involvement of peripheral markers in AD.     

Circulating immune complexes in sera from patients with Alzheimer's disease and subjects with age-associated memory impairment

Summary Before, we reported a higher frequency of circulating immune complexes (CIC) in the sera from institutionalized Alzheimer's disease (AD), multi-infarct dementia and Down's syndrome patients than from age-matched controls. In this study, we tested the presence of CIC in the sera from an extended series of hospitalized AD patients, AD patients living in the community, from age-associated memory impairment (AAMI) subjects as well as from nursing home and community controls. We used two methods to measure CIC, C1q binding Elisa (C1qB-Elisa) and conglutinin binding (KgB-Elisa). The AD patients showed the highest frequency of positive findings and differed from the controls in KgB (42% vs. 17%) (Chisquare, p=0.01) and C1qB (30% vs. 11%) (p<0.05). In severe AD, 14/19 patients were KgB positive and 11/19 were C1qB positive and differed from controls. The frequency of CIC for the patients with moderate or mild dementia, the AAMI subjects and controls was similar. In the multivariate linear regression analysis, high CIC values of the AD patients significantly associated with a long disease duration and a history of recurrent urinary infections but not with age, sex, hospitalization, or the Mini-Mental Status score. We conclude that AD patients with severe dementia frequently show CIC but those with mild or moderate disease do not. The CIC relate to a long disease duration and a history of recurrent urinary infections.     

Antimicroglia antibodies in sera of Alzheimer's disease patients.

BACKGROUND: Immune mechanisms seem to contribute to the degenerative process in Alzheimer's disease. Antibodies directed against animal brain tissue were found in sera of Alzheimer's patients. METHODS: Antibodies were measured in sera of 25 Alzheimer's patients and a comparison group of 25 age- and sex-matched controls. Sera were tested for their immunological response to various brain structures of postmortem human brain tissue. RESULTS: In 8 patients with Alzheimer's disease perinuclear antibodies directed against microglia were found in amygdala and frontal cortex. In the control group 1 subject showed antibody binding to microglia. CONCLUSIONS: Perinuclear antibodies to microglia may play a role in tissue destruction of Alzheimer's disease. These data add to the evidence that immune mechanisms play a role in the pathophysiology of Alzheimer's disease.     

Cerebrospinal fluid nitrate levels in patients with Alzheimer's disease

It has been suggested that nitric oxide could be implicated in the pathogenesis of Alzheimer's disease (AD). Recently Kuiper et al. reported decreased CSF nitrate levels (oxidation product that provides an indirect estimation of nitric oxide) in AD patients, assessed with a colorimetric method. However other group, using a microplate version of the Griess reaction, did not confirm these findings. We studied the CSF and plasma levels of nitrate with a kinetic cadmium-reduction method in 32 AD patients and 36 matched controls. The CSF and plasma nitrate levels did not differ significantly between the two study groups. CSF and plasma nitrate levels did not correlate with age at onset and duration in the patient group. These data suggest that CSF and plasma levels of nitrate are apparently unrelated with the risk for AD.     

Increased plasma levels of BDNF and inflammatory markers in Alzheimer's disease

Alzheimer's disease (AD) is the most common cause of dementia in the elderly. Neurotrophic factors and inflammatory markers may play considerable roles in AD. In this study we measured, through Enzyme-Linked Immunosorbent Assay, the plasma levels of brain derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF) and neuronal growth factor (NGF), as well as tumor necrosis factor-alpha soluble receptors, sTNFR1 and sTNFR2, and soluble intercellular adhesion molecule 1 (sICAM-1), in 50 AD patients, 37 patients with mild cognitive impairment (MCI) and 56 healthy elderly controls. BDNF levels, expressed as median and interquartile range, were higher for AD patients (2545.3, 1497.4–4153.4 pg/ml) compared to controls (1503.8, 802.3–2378.4 pg/ml), P < 0.001. sICAM-1 was also higher in AD patients. sTNFR1 levels were increased in AD when compared to controls and also to MCI. GDNF, NGF and sTNFR2 levels showed no significant differences among the studied groups. The increase in BDNF might reflect a compensatory mechanism against early neurodegeneration and seems to be related to inflammation. sTNFR1 appears to mark not only the inflammatory state but also differentiates between MCI and AD, which may be an additional tool for differentiating degrees of cognitive impairment.     

Cerebrospinal fluid levels of selenium in patients with Alzheimer's disease

Summary. We compared CSF and serum selenium levels, measured by atomic absorption spectrophotometry, in 27 patients with Alzheimer's disease (AD) (13 females, 14 males, mean ± SD age 73.6 ± 7.4 years) without major clinical signs of undernutrition, and 34 matched controls (18 females, 16 males, mean ± SD age 70.7 ± 7.8 years). CSF and serum selenium levels did not differ significantly between AD-patient (11.4 ± 7.8 ng/ml and 28.5 ± 13.0 ng/ml, respectively) and control groups (13.3 ± 7.0 ng/ml and 22.5 ± 17.5 ng/ml). These values were not correlated with age, age at onset, duration of the disease, and scores of the MiniMental State Examination in the AD group. Weight and body mass index were significantly lower in AD patients than in controls. These results suggest that CSF selenium concentrations are apparently unrelated with the reported oxidative stress processes in patients with AD. Received May 5, 1998; accepted September 9, 1998     

Cerebrospinal fluid levels of thiamine in patients with Alzheimer's disease

Summary. Thiamine is an essential cofactor for several important enzymes involved in brain oxidative metabolism, such as the alpha-ketoglutarate dehydrogenase complex (KGDHC), pyruvate-dehydrogenase complex (PDHC), and transketolase. Some investigators reported decreased thiamine-diphosphate levels and decreased activities of KGDHC, pyruvate-dehydrogenase complex and transketolase in the brain tissue of Alzheimer's disease (AD) patients. We measured cerebrospinal (CSF) levels of thiamine-diphosphate, thiamine-monophosphate, free thiamine, and total thiamine, using ion-pair reversed phase high performance liquid chromatography, in 33 patients with sporadic AD and 32 matched controls. The mean CSF levels of thiamine-derivatives did not differ significantly from those of controls, while the mean plasma levels of thiamine-diphosphate, free and total thiamine were significantly lower in the AD-patient group. CSF and plasma thiamine levels were not correlated with age, age at onset, duration of the disease, and scores of the MiniMental State Examination, with the exception of plasma thiamine-diphosphate with MiniMental State Examination (r = 0.41, p < 0.05) in the AD-patients group. CSF and plasma values did not predict dementia progression, assessed with the Minimental State Examination scores. These results suggest that CSF thiamine levels are not related with the risk for and the progression of AD. Received May 19, 2001; accepted January 8, 2002     

Cerebrospinal fluid levels of insulin in patients with Alzheimer's disease

OBJECTIVES: Some previous reports suggested a potential role of insulin in memory and in the pathophysiology of Alzheimer's disease (AD). We assessed the cerebrospinal fluid (CSF) levels of insulin in patients with AD and in age and sex-matched controls trying to elucidate whether this value could be related with the risk or severity of AD. PATIENTS AND METHODS: We measured the CSF insulin levels in 27 patients with AD and 16 matched controls using a RadioImmunoanalysis method. RESULTS: CSF insulin levels did not differ significantly between AD-patient and control groups. These values were not correlated with age, age at onset, duration of the disease, and scores of the MiniMental State Examination in the AD group. CONCLUSION: These results suggest that CSF insulin concentrations are not related with the risk or severity of AD.     

Uric acid levels in sera from patients with multiple sclerosis

The levels of uric acid (UA), a natural peroxynitrite scavenger, were measured in sera from 240 patients with multiple sclerosis (MS) and 104 sex- and age-matched control patients with other neurological diseases (OND). The mean serum UA concentration was lower in the MS than in the OND group, but the difference did not reach the level of statistical significance (P=0.068). However, the mean serum UA level from patients with active MS (202.6+67.1 μmol/l) was significantly lower than that in inactive MS patients (226.5+78.6 μmol/l; P=0.046) and OND controls (P=0.007). We found a significant inverse correlation of serum UA concentration with female gender (P=0.0001), disease activity (P=0.012) and duration (P=0.017), and a trend towards an inverse correlation with disability as assessed by EDSS score, which did not reach statistical significance (P=0.067). Finally, multivariate linear regression analyses showed that UA concentration was independently correlated with gender (P=0.0001), disease activity (P=0.014) and duration of the disease (P=0.043) in MS patients. These findings suggest that serum UA might serve as a possible marker of disease activity in MS. They also provide support to the potential beneficial therapeutic effect of radical-scavenging substances in MS. Received: 8 March 2000 / Received in revised form: 20 July 2000 / Accepted: 13 August 2000     

Cerebrospinal fluid levels of transition metals in patients with Alzheimer's disease

Summary. We compared CSF and serum levels of iron, copper, manganese, and zinc, measured by atomic absorption spectrophotometry, in 26 patients patients with Alzheimer's disease (AD) without major clinical signs of undernutrition, and 28 matched controls. CSF zinc levels were significantly decreased in AD patients as compared with controls (p < 0.05). The serum levels of zinc, and the CSF and serum levels of iron, copper, and manganese, did not differ significantly between AD-patient and control groups. These values were not correlated with age, age at onset, duration of the disease, and scores of the MiniMental State Examination in the AD group. Weight and body mass index were significantly lower in AD patients than in controls. Because serum zinc levels were normal, the possibility that low CSF zinc levels were due to a deficiency of dietary intake seems unlikely. However, it is possible that they might be related to the interaction of beta-amyloid and/or amyloid precursor protein with zinc, that could result in a depletion of zinc levels. Accepted February 17, 1998; received November 17, 1997     

Serum levels of coenzyme Q10 in patients with Alzheimer's disease

Summary. We compared serum levels of coenzyme Q₁₀ and the coenzyme Q₁₀/cholesterol ratio in 44 patients with Alzheimer's disease (AD), 17 patients with vascular dementia (VD), and 21 matched controls. The mean serum coenzyme Q₁₀ and cholesterol levels and the coenzyme Q₁₀/cholesterol ratio of patients with AD or VD did not differ significantly from those of controls. Coenzyme Q₁₀ levels and coenzyme Q₁₀/cholesterol ratio of AD or VD patients were not correlated with age, age at onset, duration of the disease or scores of the MiniMental State Examination. These results suggest that these values are not related with the risk for AD or VD. Received July 19, 1999; accepted October 14, 1999     

Altered phosphofructokinase mRNA levels but unchanged isoenzyme pattern in brains from patients with Alzheimer's disease

In order to find out whether the increased phosphofructokinase (PFK) activities observed in brains from Alzheimer's disease (AD) patients are associated with alterations in PFK mRNA levels, we determined total PFK mRNA and the three different PFK isoenzyme mRNAs in AD and control patients by ribonuclease protection assay (RPA) and quantitative RT-PCR. PFK mRNA levels were found increased in some brain areas in AD patients. While all three PFK isoenzyme mRNAs were detectable in every studied brain sample, no changes of the PFK isoenzyme pattern were observed in patients with AD.