Serum cholesterol and the progression of Parkinson's disease: results from DATATOP

Background

Recent studies have suggested that higher serum cholesterol may be associated with lower occurrence of Parkinson''s disease (PD). This study is to test the hypothesis that higher serum cholesterol correlates with slower PD progression.

Methods

Baseline non-fasting serum total cholesterol was measured in 774 of the 800 subjects with early PD enrolled between 1987 and 1988 in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) trial. Participants were followed for up to two years, with clinical disability requiring levodopa therapy as the primary endpoint. Hazard ratios (HRs) and 95% confidence intervals (CI) were determined for increasing serum cholesterol concentration (in quintiles) for clinical disability requiring levodopa therapy, after adjusting for confounders. At baseline, only nine subjects reported use of cholesterol-lowering agents (two with statins).

Results

The overall mean cholesterol level was 216 mg/dL (range 100–355). The HR of progressing to the primary endpoint decreased with increasing serum cholesterol concentrations. Compared to the lowest quintile, the HRs (95%CI), for each higher quintile (in ascending order) are 0.83 (0.59–1.16); 0.86 (0.61–1.20); 0.84 (0.60–1.18); and 0.75 (0.52–1.09). The HR for one standard deviation (SD) increase = 0.90 [(0.80–1.01), p for trend = 0.09]. This trend was found in males (HR per SD = 0.88 [(0.77–1.00), p for trend = 0.05], but not in females [HR = 1.03 (0.81–1.32)].

Conclusions

This secondary analysis of the DATATOP trial provides preliminary evidence that higher total serum cholesterol concentrations may be associated with a modest slower clinical progression of PD, and this preliminary finding needs confirmation from larger prospective studies.     

Iron as a vulnerability factor in nigrostriatal degeneration in aging and Parkinson's disease.

Recent findings strengthen the connection between iron accumulation in the basal ganglia, oxidative stress and nigrostriatal degeneration. Oxidative stress appears to be elevated in the normal human substantia nigra in comparison with other brain regions, and further increases occur in Parkinson's disease. Accumulation of iron may contribute to degeneration of nigral dopamine neurons by catalyzing oxidative damage to cell components and also by perturbing the network of interactions that modulate cellular redox status.     

Serum antioxidant enzyme activity in Parkinson's disease

Summary The activities of superoxide dismutase (SOD; EC 1.15.1.1) and glutathione peroxidase (GSHP_x; EC 1.11.1.9.), the enzymes that metabolize the superoxide anion and hydrogen peroxide, respectively, were measured in serum from healthy subjects and patients with Parkinson's disease (PD). The activities of SOD and GSHP_x in patients with PD were higher than those in normal healthy individuals. These results suggest that the increased activities of these enzymes could be due to oxidative stress in the initial stages of this disease.     

Zonisamide reduces nigrostriatal dopaminergic neurodegeneration in a mouse genetic model of Parkinson's disease

Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by the loss of nigrostriatal dopaminergic neurons and consequent motor dysfunction. Zonisamide (1,2‐benzisoxazole‐3‐methanesulfonamide), which was originally developed as an antiepileptic drug, has been found to have therapeutic benefits for PD. However, the pharmacological mechanisms behind the beneficial actions of zonisamide in PD are not fully understood. Here, we investigated the neuroprotective effects of zonisamide on nigrostriatal dopaminergic neurons of the Engrailed mutant mouse, a genetic model of PD. Chronic administration of zonisamide in Engrailed mutant mice was shown to improve the survival of nigrostriatal dopaminergic neurons compared with that under saline treatment. In addition, dopaminergic terminals in the striatum and the motor function were improved in zonisamide‐treated Engrailed mutant mice to the levels of those in control mice. To clarify the mechanism behind the neuroprotective effects of zonisamide, the contents of neurotrophic factors were determined after chronic administration of zonisamide. Brain‐derived neurotrophic factor content was increased in the striatum and ventral midbrain of the zonisamide‐treated mice compared to saline‐treated mice. These findings imply that zonisamide reduces nigrostriatal dopaminergic cell death through brain‐derived neurotrophic factor signaling and may have similar beneficial effects in human parkinsonian patients as well.

     

LRRK2 pathobiology in Parkinson's disease

Mutations in the catalytic Roc‐COR and kinase domains of leucine‐rich repeat kinase 2 (LRRK2) are a common cause of familial Parkinson's disease (PD). LRRK2 mutations cause PD with age‐related penetrance and clinical features identical to late‐onset sporadic PD. Biochemical studies support an increase in LRRK2 kinase activity and a decrease in GTPase activity for kinase domain and Roc‐COR mutations, respectively. Strong evidence exists that LRRK2 toxicity is kinase dependent leading to extensive efforts to identify selective and brain‐permeable LRRK2 kinase inhibitors for clinical development. Cell and animal models of PD indicate that LRRK2 mutations affect vesicular trafficking, autophagy, protein synthesis, and cytoskeletal function. Although some of these biological functions are affected consistently by most disease‐linked mutations, others are not and it remains currently unclear how mutations that produce variable effects on LRRK2 biochemistry and function all commonly result in the degeneration and death of dopamine neurons. LRRK2 is typically present in Lewy bodies and its toxicity in mammalian models appears to be dependent on the presence of α‐synuclein, which is elevated in human iPS‐derived dopamine neurons from patients harboring LRRK2 mutations. Here, we summarize biochemical and functional studies of LRRK2 and its mutations and focus on aberrant vesicular trafficking and protein synthesis as two leading mechanisms underlying LRRK2‐linked disease.

     

Serum angiotensin converting enzyme values in chronic obstructive pulmonary disease

Angiotensin converting enzyme (ACE) is stored in the endothelium. Its activity depends--among others--on the O2-concentration of the blood. Aim of the study was to examine the serum ACE values in chronic obstructive lung diseases (bronchial asthma, chronic bronchitis, lung fibrosis etc.). At the time of blood sampling, blood-gas tensions and respiratory function parameters of the patients were also determined. On the basis of the blood-gas parameters and SACE x + SD and x--SD values, obtained from the normoxic-normocapnic group, the patients could be divided into sub-groups. In contrast to data in the literature increased enzyme levels in response to hypoxia could be found only in patients suffering from a pulmonary disease associated with severe tissue damage.     

Naringin protects the nigrostriatal dopaminergic projection through induction of GDNF in a neurotoxin model of Parkinson's disease

This study investigated the effect of naringin, a major flavonoid in grapefruit and citrus fruits, on the degeneration of the nigrostriatal dopaminergic (DA) projection in a neurotoxin model of Parkinson's disease (PD) in vivo and the potential underlying mechanisms focusing on the induction of glia-derived neurotrophic factor (GDNF), well known as an important neurotrophic factor involved in the survival of adult DA neurons. 1-Methyl-4-phenylpyridinium (MPP⁺) was unilaterally injected into the medial forebrain bundle of rat brains for a neurotoxin model of PD in the presence or absence of naringin by daily intraperitoneal injection. To ascertain whether naringin-induced GDNF contributes to neuroprotection, we further investigated the effects of intranigral injection of neutralizing antibodies against GDNF in the MPP⁺ rat model of PD. Our observations demonstrate that naringin could increase the level of GDNF in DA neurons, contributing to neuroprotection in the MPP⁺ rat model of PD, with activation of mammalian target of rapamycin complex 1. Moreover, naringin could attenuate the level of tumor necrosis factor-α in microglia increased by MPP⁺-induced neurotoxicity in the substantia nigra. These results indicate that naringin could impart to DA neurons the important ability to produce GDNF as a therapeutic agent against PD with anti-inflammatory effects, suggesting that naringin is a beneficial natural product for the prevention of DA degeneration in the adult brain.     

Ethyl pyruvate rescues nigrostriatal dopaminergic neurons by regulating glial activation in a mouse model of Parkinson's disease

This study examined whether ethyl pyruvate (EP) promotes the survival of nigrostriatal dopaminergic (DA) neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. MPTP induced degeneration of nigrostriatal DA neurons and glial activation as visualized by tyrosine hydroxylase, macrophage Ag complex-1, and/or glial fibrillary acidic protein immunoreactivity. Western blotting and immunohistochemistry showed activation of microglial NADPH oxidase and astroglial myeloperoxidase (MPO) and subsequent reactive oxygen species/reactive nitrogen species production and oxidative DNA damage in the MPTP-treated substantia nigra. Treatment with EP prevented degeneration of nigrostriatal DA neurons, increased striatal dopamine levels, and improved motor function. This neuroprotection afforded by EP was associated with the suppression of astroglial MPO expression, NADPH oxidase-, and/or inducible NO synthase-derived reactive oxygen species/reactive nitrogen species production by activated microglia. Interestingly, EP was found to protect DA neurons from 1-methyl-4-phenyl-pyridinium neurotoxicity in cocultures of mesencephalic neurons and microglia but not in neuron-enriched mesencephalic cultures devoid of microglia. The present findings show that EP may inhibit glial-mediated oxidative stress, suggesting that EP may have therapeutic value in the treatment of aspects of Parkinson's disease related to glia-derived oxidative damage.     

Enriched environment protects the nigrostriatal dopaminergic system and induces astroglial reaction in the 6-OHDA rat model of Parkinson's disease

Enriched environment (EE) is neuroprotective in several animal models of neurodegeneration. It stimulates the expression of trophic factors and modifies the astrocyte cell population which has been said to exert neuroprotective effects. We have investigated the effects of EE on 6-hydroxydopamine (6-OHDA)-induced neuronal death after unilateral administration to the medial forebrain bundle, which reaches 85–95% of dopaminergic neurons in the substantia nigra after 3 weeks. Continuous exposure to EE 3 weeks before and after 6-OHDA injection prevents neuronal death (assessed by tyrosine hydroxylase staining), protects the nigrostriatal pathway (assessed by Fluorogold retrograde labeling) and reduces motor impairment. Four days after 6-OHDA injection, EE was associated with a marked increase in glial fibrillary acidic protein staining and prevented neuronal death (assessed by Fluoro Jade-B) but not partial loss of tyrosine hydroxylase staining in the anterior substantia nigra. These results robustly demonstrate that EE preserves the entire nigrostriatal system against 6-OHDA-induced toxicity, and suggests that an early post-lesion astrocytic reaction may participate in the neuroprotective mechanism.     

Influences of dopaminergic lesion on epidermal growth factor-ErbB signals in Parkinson's disease and its model: neurotrophic implication in nigrostriatal neurons

Epidermal growth factor (EGF) is a member of a structurally related family containing heparin-binding EGF-like growth factor (HB-EGF) and transforming growth factor alpha (TGFalpha) that exerts neurotrophic activity on midbrain dopaminergic neurons. To examine neurotrophic abnormality in Parkinson's disease (PD), we measured the protein content of EGF, TGFalpha, and HB-EGF in post-mortem brains of patients with Parkinson's disease and age-matched control subjects. Protein levels of EGF and tyrosine hydroxylase were decreased in the prefrontal cortex and the striatum of patients. In contrast, HB-EGF and TGFalpha levels were not significantly altered in either region. The expression of EGF receptors (ErbB1 and ErbB2, but not ErbB3 or ErbB4) was down-regulated significantly in the same forebrain regions. The same phenomenon was mimicked in rats by dopaminergic lesions induced by nigral 6-hydroxydopamine infusion. EGF and ErbB1 levels in the striatum of the PD model were markedly reduced on the lesioned side, compared with the control hemisphere. Subchronic supplement of EGF in the striatum of the PD model locally prevented the dopaminergic neurodegeration as measured by tyrosine hydroxylase immunoreactivity. These findings suggest that the neurotrophic activity of EGF is maintained by afferent signals of midbrain dopaminergic neurons and is impaired in patients with Parkinson's disease.     

Urinary 8-OHdG elevations in a partial lesion rat model of Parkinson's disease correlate with behavioral symptoms and nigrostriatal dopaminergic depletion

Increased oxidative stress contributes to pathogenesis of Parkinson's disease (PD). 8-hydroxy-2'-deoxyguanosine (8-OHdG) is the oxidation product most frequently measured as an indicator of oxidative DNA damage. Several studies have shown increased 8-OHdG in PD patients. There are few basic laboratory data examining 8-OHdG levels in animal models of PD. In this study, we utilized hemiparkinsonian model of rats induced by intrastriatal injection of 6-hydroxydopamine (6-OHDA). The urinary 8-OHdG level was measured in relation to behavioral and pathological deficits arising from 6-OHDA-induced neurotoxic effects on the nigrostriatal dopaminergic pathway. All rats were subjected to a series of behavioral tests for 42 days after 6-OHDA injection. We collected urine samples with subsequent measurement of 8-OHdG level using ELISA kits. For immunohistochemical evaluation, tyrosine hydroxylase (TH) staining was performed. Significant increments in urinary 8-OHdG level were observed continuously from day 7 until day 35 compared to control group, which showed a trend of elevation as early as day 3. Such elevated urinary 8-OHdG level significantly correlated with all of the behavioral deficits measured here, suggesting that urinary 8-OHdG level provides a good index of severity of parkinsonism. Urinary 8-OHdG level also had a significant positive correlation with the survival rate of dopaminergic fibers or neurons, advancing the concept that oxidative stress during the early phase of 6-OHDA neurotoxicity may correspond to disease progression closely approximating neuronal degeneration in the nigrostriatal dopaminergic system. The present results demonstrate that alterations in urinary 8-OHdG level closely approximate onset and disease progression in PD.     

Serum cholesterol esterification in hyperthyroidism and hypothyroidism

The rate of serum cholesterol esterification was measured in twenty healthy subjects and compared to similar data obtained with seventeen hyperthyroid and ten hypothyroid subjects. No significant differences were noted in the rate of cholesterol esterification while differences in the fractional rates were highly significant (p less than 0.001); the hyperthyroid group being higher and the hypothyroid group lower than normal. There were no clear trends observed in the changes of the rate of cholesterol esterification upon therapy. However, the fractional rates always increased when hypothyroid patients became euthyroid and always decreased in hyperthyroid patients as the result of therapy.     

Simultaneous quantification of hepatic MRI-PDFF and R2* in a rabbit model with nonalcoholic fatty liver disease

Quantification of hepatic fat and iron content is important for early detection and monitoring of nonalcoholic fatty liver disease(NAFLD) patients. This study evaluated quantification efficiency of hepatic proton density fat fraction(PDFF) by MRI using NAFLD rabbits. R2* was also measured to investigate whether it correlates with fat levels in NAFLD. NAFLD rabbit model was successfully established by high fat and cholesterol diet. Rabbits underwent MRI examination for fat and iron analyses,compared with liver histological findings. MR examinations were performed on a 3.0 T MR system using multi-echo 3 D gradient recalled echo(GRE) sequence. MRI-PDFF showed significant differences between different steatosis grades with medians of3.72%(normal), 5.43%(mild), 9.11%(moderate) and 11.17%(severe), whereas this was not observed in R2*. Close correlation between MRI-PDFF and histological steatosis was observed(r=0.78, P=0.000). Hepatic iron deposit was not found in any rabbits. There was no correlation between R2* and either liver MRI-PDFF or histological steatosis. MR measuring MRI-PDFF and R2* simultaneously provides promising quantification of steatosis and iron. Rabbit NAFLD model confirmed accuracy of MRI-PDFF for liver fat quantification. R2* measurement and relationship between fat and iron of NAFLD liver need further experimental investigation.     

Serum trace element levels and the complexity of inter-element relations in patients with Parkinson's disease

Trace elements have been postulated to play a role in Parkinson's disease (PD). In order to elucidate whether changes in the serum levels of trace elements reflect the progression of PD, we assessed serum levels of 12 elements (Na, K, Fe, Al, Cu, Zn, Ca, Mg, Mn, Si, P and S) in early PD, severe PD and normal subjects, using inductively coupled plasma atomic emission spectrometry. The concentrations in μmol/ml, the relative mole percentage distribution and inter-element relations were computed. Statistical analysis of these data showed a definite pattern of variation among certain elements in early and severe PD compared to controls. In both early and severe PD serum, Al and S concentrations were significantly decreased (p<0.05) compared to the controls. Fe (p<0.01) and Zn (p<0.05) concentrations were significantly lower in severe PD, while K, Mg, Cu (p<0.01) and P (p<0.05) concentrations were higher in early and severe PD compared to the controls. The data revealed an imbalance in the inter-element relations in both early and severe PD serum compared to controls, as shown by the direct and inverse correlations. These results suggest a disturbance in the element homeostasis during the progression of PD.     

Serum amylase values in callitrichids.

We determined the amylase levels in serum samples from six callitrichid species. The normal serum amylase values for all of these species was within or higher than the normal human range. Amylase values higher than the normal range occurred not only in association with pancreatitis but also pyometra, bone fracture, abscesses, diabetes mellitus and gastrointestinal conditions leading to diarrhea. We concluded that although serum amylase activity may be helpful in diagnosing pancreatitis, it is, as in humans, not specific for this condition in callitrichids.