Klaus Hager

Protein glycation, oxidation and nitration adduct residues and free adducts of cerebrospinal fluid in Alzheimer's disease and link to cognitive impairment

Increased damage to proteins by glycation, oxidation and nitration has been implicated in neuronal cell death leading to Alzheimers disease (AD). Protein glycation, oxidation and nitration adducts are consequently formed. Quantitative screening of these adducts in CSF may provide a biochemical indicator for the diagnosis of AD. To assess this, we measured 11 glycation adducts, three oxidation adducts and a nitration adduct, determining both protein adduct residues and free adducts, in CSF samples of age‐matched normal healthy subjects (n = 18) and subjects with Alzheimers disease (n = 32). In CSF protein, the concentrations of 3‐nitrotyrosine, Nɛ‐carboxymethyl‐lysine, 3‐deoxyglucosone‐derived hydroimidazolone and N‐formylkynurenine residues were increased in subjects with Alzheimers disease. In CSF ultrafiltrate, the concentrations of 3‐nitrotyrosine, methylglyoxal‐derived hydroimidazolone and glyoxal‐derived hydroimidazolone free adducts were also increased. The Mini‐Mental State Examination (MMSE) score correlated negatively with 3‐nitrotyrosine residue concentration (p < 0.05), and the negative correlation with fructosyl‐lysine residues just failed to reach significance (p = 0.052). Multiple linear regression gave a regression model of the MMSE score on 3‐nitrotyrosine, fructosyl‐lysine and Nɛ‐carboxyethyl‐lysine residues with p‐values of 0.021, 0.031 and 0.052, respectively. These findings indicate that protein glycation, oxidation and nitration adduct residues and free adducts were increased in the CSF of subjects with Alzheimers disease. A combination of nitration and glycation adduct estimates of CSF may provide an indicator for the diagnosis of Alzheimers disease.

Interleukin-6 and selected plasma proteins in healthy persons of different ages

In the present study, interleukin-6 (IL-6) and several acute phase proteins were measured in healthy participants (23-87 years of age). A linear correlation between IL-6 and age was established with an increase of 0.016 pg/ml (0.004) per year of life. Whereas CRP remained below 0.5 mg/dl in all participants, an increase with age for fibrinogen and an inverse relation for albumin as well as transferrin were obtained. However, the increase of IL-6 did not correlate with any of these changes. IL-6 associated diseases may therefore occur more often with advancing age, but in healthy participants IL-6 does not explain the changing plasma protein pattern resembling that of an acute phase reaction.

α-Lipoic acid as a new treatment option for Alzheimer’s disease — a 48 months follow-up analysis

Oxidative stress and neuronal energy depletion are characteristic biochemical hallmarks of Alzheimer’s disease (AD). It is therefore conceivable that pro-energetic and antioxidant drags such as α-lipoic acid might delay the onset or slow down the progression of the disease. In a previous study, 600 mg α-lipoic acid was given daily to nine patients with AD (receiving a standard treatment with choline-esterase inhibitors) in an open-label study over an observation period of 12 months. The treatment led to a stabilization of cognitive functions in the study group, demonstrated by constant scores in two neuropsychological tests (the mini mental state exam, MMSE and the Alzheimer’s disease assessment score cognitive subscale, ADAScog). In this report, we have extended the analysis to 43 patients over an observation period of up to 48 months. In patients with mild dementia (ADAScog < 15), the disease progressed extremely slowly (ADAScog: +1.2 points/year, MMSE:-0.6 points/year), in patients with moderate dementia at approximately twice the rate. However, the progression appears dramatically lower than data reported for untreated patients or patients on choline-esterase inhibitors in the second year of long-term studies. Despite the fact that this study was not double-blinded, placebo-controlled and randomized, our data suggest that treatment with α-lipoic acid might be a successful ‘neuroprotective’ therapy option for AD. However, a state-of-the-art phase II trial is needed urgently.

Fibrin degeneration product concentrations (D-dimers) in the course of ageing.

D-dimers, cross-linked fibrin split products, have been found to be an indicator of thromboembolic disease and may predict, as fibrinogen or other factors of hemostasis, a higher risk of cerebro- and cardiovascular diseases. D-dimers rose with advancing age in healthy elderly subjects and reached values well above the upper limit of the normal test values. The increase is considered to be the result of several causes, i.e. higher fibrinogen concentrations in the elderly, a slower urinary excretion, more frequent fibrin generation, (occult) diseases, risk factors, inflammatory reactions and degenerative vascular damage. In the elderly, moderately elevated D-dimers are therefore an unspecific finding. The specificity of the D-dimer test for diagnosing thromboembolic diseases can be expected to be lower than in young subjects.

Age dependency of the sialic acid content of fibrinogen. consequences for erythrocyte aggregation

Sialic acid (SA) content of plasma proteins and fibrinogen was investigated in 60 persons of different age and health status. SA/mg fibrin rose with age and morbidity in plasma, rinsed clots of fibrin from plasma and after prothrombin adsorption as well as in fibrin clots prepared from purified fibrinogen. The higher plasma SA is caused by increasing concentrations of glycoproteins like fibrinogen, but also by a higher content of SA/mg protein, as has been shown for fibrinogen. SA is considered to be an unspecific marker of acute phase reactions. Changing SA content of glycoproteins may have functional consequences. An increased red cell aggregation with fibrinogen of healthy elderly correlated with its SA content, but SA is most probably only indicating an altered protein heterogeneity in the aged and not a causative factor that influences erythrocyte aggregation.

Virtual image grasping in patients with Alzheimer-type dementia.

Patients with various neuropsychiatric disorders who confused virtual images with real objects have recently been described. When asked to take objects from an investigators hand while looking in a mirror, these patients reached directly into the mirror for the objects image. To investigate whether the phenomenon occurs in patients with Alzheimers disease, we studied 127 cases, of whom 67 were suspected of having Alzheimer-type dementia (DAT). The phenomenon in question was not observed in either of two control groups, but whereas 38 (57%) of the DAT patients responded correctly, 17 (25%) of them grasped at the mirror image. Characteristically, none of the eight patients who grasped into the mirror and underwent single photon emission computed tomography analysis showed symmetric activity. We also analyzed the behaviour and verbal utterances of the DAT patients in front of the mirror.

Lipoic Acid as a Novel Treatment for Mild Cognitive Impairment and Early-Stage Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive neurodegenerative brain disorder that gradually destroys a patient’s memory and ability to learn, make judgments, communicate within the social environment, and carry out daily activities. In the course of the disease, short-term memory is affected first, caused by neuronal dysfunction and degeneration in the hippocampus and amygdala. As the disease progresses further, neurons also degenerate and die in other cortical regions of the brain. At this stage, sufferers often experience dramatic changes in personality and behavior, such as anxiety, suspiciousness and agitation, as well as delusions and hallucinations. AD prevalence rates are 1% for individuals between 65 and 69 years old, 3% for those between 70 and 74 years old, 6% for those between 75 and 79 years old, 12% for those between 80 and 84 years old, and 25% for those aged 85 years and older. AD is further characterized by two major neuropathological hallmarks: The deposition of neuritic, β-amyloid (Aβ) peptide-containing senile plaques in hippocampal and cerebral cortical regions of AD patients is accompanied by the presence of intracellular neurofibrillary tangles that occupy much of the cytoplasm of pyramidal neurons. Inflammation, as evidenced by the activation of microglia and astroglia, is another hallmark of AD. Inflammation, including superoxide production (“oxidative burst”), is an important source of oxidative stress in AD patients. The inflammatory process occurs mainly around the amyloid plaques and is characterized by proinflammatory substances released from activated microglia and astroglia. Glia-produced cytokines, including interleukin-1β (IL-1β), IL-6, macrophage colony-stimulating factor, and tumor necrosis factor-α (TNF-α), are prominent molecules in the inflammatory process. Besides morphological alterations, AD is also associated with a markedly impaired cerebral glucose metabolism, as detected by reduced cortical F-labeled desoxyglucose utilization in positron emission tomography of AD patients..