Serum heme oxygenase‐1 levels are increased in Parkinson’s disease but not in Alzheimer’s disease

Mateo I, Infante J, Sánchez‐Juan P, García‐Gorostiaga I, Rodríguez‐Rodríguez E, Vázquez‐Higuera JL, Berciano J, Combarros O. Serum heme oxygenase‐1 levels are increased in Parkinson’s disease but not in Alzheimer’s disease.
Acta Neurol Scand: 2010: 121: 136–138.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objective – Oxidative stress is implicated in Parkinson’s disease (PD) and Alzheimer’s disease (AD), and heme oxygenase‐1 (HO‐1) is a potent antioxidant overexpressed in PD substantia nigra and AD cerebral cortex and hippocampus, indicating a possible up‐regulation of antioxidant defenses in both neurodegenerative diseases. The role of HO‐1 in peripheral blood of PD and AD patients remains unresolved. Methods – We measured serum HO‐1 levels in 107 patients with PD, 105 patients with AD, 104 controls for PD and 120 controls for AD. Results – The median serum concentration of HO‐1 was significantly higher in PD patients (2.04 ng/ml) compared with that of PD controls (1.69 ng/ml, P = 0.016), with PD patients predominating over controls in the upper tertile of serum HO‐1 levels, whereas there was more PD controls than PD patients in the lower tertile (P = 0.006). Median serum levels of HO‐1 did not differ significantly between AD patients and AD controls. Conclusion – The increase of serum HO‐1 levels in PD patients could indicate a systemic antioxidant reaction related to a chronic oxidative stress state in PD brain.     

Synergistic effect of two oxidative stress‐related genes (heme oxygenase‐1 and GSK3β) on the risk of Parkinson’s disease

Background: Oxidative stress is a central factor in the pathogenesis of Parkinson’s disease (PD). Heme oxygenase‐1 (HO‐1) is an antioxidant protein expressed in response to oxidative challenge, and its expression levels are inversely correlated with glycogen synthase kinase‐3β (GSK3β) activity. Underexpression of HO‐1 in concert with an upregulation of GSK3β would result in a less effective antioxidant response and might increase the risk of PD. Methods: We examined two functional polymorphism in the promoter regions of HO‐1 (?413, rs2071746) and GSK3β (?157, rs6438552) in a group of 251 Spanish patients with PD and 234 controls. Results: Subjects carrying both the HO‐1 (?413, rs2071746) TT genotype and the GSK3β (?157, rs6438552) TT genotype had a four times higher risk of developing PD than subjects without these genotypes (adjusted by age and sex OR = 4.12; 95% CI = 1.45–11.71; Bonferroni corrected P = 0.024). Conclusions: Considering synergistic effects between polymorphisms in oxidative stress‐related genes may help in determining the risk profile for PD.     

Dietary intake of antioxidant vitamins and risk of Parkinson’s disease: a case–control study in Japan

Background: Antioxidant vitamins are expected to protect cells from oxidative damage by neutralizing the effects of reactive oxygen species. However, epidemiological evidence regarding the associations between antioxidant vitamin intake and Parkinson’s disease (PD) is limited and inconsistent. We investigated the relationship between dietary intake of selected antioxidant vitamins, vegetables and fruit and the risk of PD in Japan using data from a multicenter hospital‐based case–control study. Methods: Included were 249 patients within 6 years of onset of PD. Controls were 368 inpatients and outpatients without a neurodegenerative disease. Information on dietary factors was collected using a validated self‐administered diet history questionnaire. Adjustment was made for sex, age, region of residence, pack‐years of smoking, years of education, body mass index, dietary intake of cholesterol, alcohol, total dairy products, and coffee and the dietary glycemic index. Results: Higher consumption of vitamin E and β‐carotene was significantly associated with a reduced risk of PD after adjustment for confounders under study: the adjusted odds ratio in the highest quartile was 0.45 (95% confidence interval [CI]: 0.25–0.79, P for trend = 0.009) for vitamin E and 0.56 (95% CI: 0.33–0.97, P for trend = 0.03) for β‐carotene. Stratified by sex, such inverse associations were significant only in women. No material relationships were shown between intake of vitamin C, α‐carotene, cryptoxanthin, green and yellow vegetables, other vegetables, or fruit and the risk of PD. Conclusions: Higher intake of vitamin E and β‐carotene may be associated with a decreased risk of PD.     

Neurotransmission in Parkinson’s disease: beyond dopamine

Parkinson’s disease (PD) is most frequently associated with characteristic motor symptoms that are known to arise with degeneration of dopaminergic neurons. However, patients with this disease also experience a multitude of non‐motor symptoms, such as sleep disturbances, fatigue, apathy, anxiety, depression, cognitive impairment, dementia, olfactory dysfunction, pain, sweating and constipation, some of which can be at least as debilitating as the movement disorders and have a major impact on patients’ quality of life. Many of these non‐motor symptoms may be evident prior to the onset of motor dysfunction. The neuropathology of PD has shown that complex, interconnected neuronal systems, regulated by a number of different neurotransmitters in addition to dopamine, are involved in the aetiology of motor and non‐motor symptoms. This review focuses on the non‐dopaminergic neurotransmission systems associated with PD with particular reference to the effect that their modulation and interaction with dopamine has on the non‐motor symptoms of the disease. PD treatments that focus on the dopaminergic system alone are unable to alleviate both motor and non‐motor symptoms, particularly those that develop at early stages of the disease. The development of agents that interact with several of the affected neurotransmission systems could prove invaluable for the treatment of this disease.     

Genotype–phenotype correlation: Familial Parkinson disease

Kindreds with Mendelian inheritance of Parkinson disease (PD) have been known since a long time ago. Nine loci have been mapped in familial PD by linkage study and four causative genes have been cloned. This paper discusses Park 1 and Park 2, the identification of which has brought about many advances in the studies on pathomechanism of PD. Investigations of these genes in familial PD have expanded their clinical and pathological phenotypes. However, to clarify the effect of mutations on these phenotypes, additional post‐mortem neuropathological studies are required.     

Calbindin‐1 association and Parkinson’s disease

Background and purpose: Calcium levels have been proposed to play an important role in the selective vulnerability of nigrostriatal dopaminergic neurons in Parkinson’s disease (PD). Recently, an association was reported between the calcium buffer, calbindin (rs1805874) and risk of PD in a Japanese patient–control series. Methods: We genotyped rs1805874 in four independent Caucasian patient–control series (1543 PD patients, 1771 controls). Results: There was no evidence of an association between rs1805874 and disease risk in individual populations or in the combined series (odds ratio: 1.04, 95% CI: 0.82–1.31, P = 0.74). Discussion: Our study shows there is no association between rs1805874 and risk for PD in four Caucasian populations. This suggests the effect of calbindin on PD risk displays population specificity.     

Stage‐dependent nigral neuronal loss in incidental Lewy body and Parkinson's disease

To gain a better understanding of the significance of α‐synuclein pathological conditions during disease progression in Parkinson's disease, we investigated whether 1) nigral neuronal loss in incidental Lewy body disease and Parkinson's disease donors is associated with the local burden α‐synuclein pathological conditions during progression of pathological conditions; 2) the burden and distribution of α‐synuclein pathological conditions are related to clinical measures of disease progression. Post‐mortem tissue and medical records of 24 Parkinson's disease patients, 20 incidental Lewy body disease donors, and 12 age‐matched controls were obtained from the Netherlands Brain Bank for morphometric analysis. We observed a 20% decrease in nigral neuronal cell density in incidental Lewy body disease compared with controls. Nigral neuronal loss (12%) was already observed before the appearance α‐synuclein aggregates. The progression from Braak α‐synuclein stage 3 to 4 was associated with a significant decline in neuronal cell density (46%). Nigral neuronal loss increased with later Braak α‐synuclein stages but did not vary across consecutive Braak α‐synuclein stages. We observed a negative correlation between neuronal density and local α‐synuclein burden in the substantia nigra of Parkinson's disease patients (ρ = ?0.54), but no relationship with Hoehn & Yahr stage or disease duration. In conclusion, our findings cast doubt on the pathogenic role of α‐synuclein aggregates in elderly, but do suggest that the severity of neurodegeneration and local burden of α‐synuclein pathological conditions are closely coupled during disease progression in Parkinson's disease. © 2014 International Parkinson and Movement Disorder Society     

Targeting α‐synuclein: Therapeutic options

The discovery of the central role of α‐synuclein (αSyn) in the pathogenesis of Parkinson's disease (PD) has powered, in the last decade, the emergence of novel relevant models of this condition based on viral vector‐mediated expression of the disease‐causing protein or inoculation of toxic species of αSyn. Although the development of these powerful tools and models has provided considerable insights into the mechanisms underlying neurodegeneration in PD, it has also been translated into the expansion of the landscape of preclinical therapeutic strategies. Much attention is now brought to the proteotoxic mechanisms induced by αSyn and how to block them using strategies inspired by intrinsic cellular pathways such as the enhancement of cellular clearance by the lysosomal‐autophagic system, through proteasome‐mediated degradation or through immunization. The important effort undertaken by several laboratories and consortia to tackle these issues and identify novel targets warrants great promise for the discovery not only of neuroprotective approaches but also of restorative strategies for PD and other synucleinopathies. In this viewpoint, we summarize the latest advances in this new area of PD research and will discuss promising approaches and ongoing challenges. © 2016 International Parkinson and Movement Disorder Society     

Lewy body variant of Alzheimer’s disease or cerebral type Lewy body disease? Two autopsy cases of presenile onset with minimal involvement of the brainstem

Lewy bodies (LB) usually extend from the brainstem to the cerebrum in patients with Parkinson’s disease. However, whether the patterns of progression of LB and neuronal loss in Parkinson’s disease are identical to those in other Lewy body diseases (LBD) remains unclear. In addition, pathological data on the autonomic nervous system involvement in LBD are limited. We present here the clinicopathological characteristics of two autopsy cases with both Alzheimer’s disease and dementia with Lewy bodies (DLB), possibly diagnosed as having Lewy body variant of Alzheimer’s disease (LBV/AD). Our patients presented clinically with dementia without parkinsonism. Histopathologically, phosphorylated α‐synuclein‐positive LB and Lewy neurites were abundant in the limbic system, especially in the amygdala, and to a lesser degree, in the neocortex, including the primary motor cortex. The amygdala was also most severely affected by neuronal loss, and the other limbic areas and neocortex were affected to a lesser degree. Despite the existence of a small number of LB and many Lewy neurites, neurons in the brainstem nuclei were relatively well preserved. The Braak stages of concurrent neurofibrillary changes and senile plaques were stage V and C, respectively, in both cases. Tyrosine hydroxylase‐positive nerve fibers were relatively well spared in one case examined compared with Parkinson’s disease cases. Furthermore, many Lewy neurites immunopositive for phosphorylated α‐synuclein were found in the nerve fascicles of the epicardium in one case examined and in Parkinson’s disease cases to a lesser degree. These findings suggest that: (i) in at least some LBV/AD cases, the amygdala develops neuronal loss and Lewy‐related pathology prior to the brainstem nuclei; and (ii) the depletion of nerves in the heart tissue of LBV/AD is not necessarily complete despite the development of Lewy‐related pathology.     

Nigral burden of α‐synuclein correlates with striatal dopamine deficit

Aggregated α‐synuclein is the hallmark of Parkinson's disease (PD), diffuse Lewy body disease (DLBD), and multiple system atrophy (MSA). Physiologically, α‐synuclein ensures normal functions of dopamine transporter (DAT) and tyrosine hydoxylase. In α‐synucleinopathies, it accumulates in neuronal cytoplasm and neurites through several stages. It is unclear whether the accumulation of pathological α‐synuclein in the substantia nigra in PD correlates with the dopaminergic deficit in the striatal target. We evaluated the impact of the nigral burden of pathological α‐synuclein immunoreactivity in 27 α‐synucleinopathy brains by morphometric immunohistochemistry. DAT immunoreactivity in the striatum inversely correlates with the total α‐synuclein burden in the substantia nigra but not with cytoplasmic inclusion counts only. This result has implications for imaging, clinicopathological correlative studies, and staging of the disease process. © 2008 Movement Disorder Society     

Nigral iron deposition occurs across motor phenotypes of Parkinson’s disease

Background and purpose: To investigate whether brain iron deposition correlates with motor phenotypic expressions of Parkinson’s disease. Methods: We subtyped patients with Parkinson’s disease according to their main motor symptoms (tremor, rigidity/bradykinesia) into three subgroups: tremor‐dominant subgroup, akinetic/rigid‐dominant subgroup, or mixed subgroup. The iron levels in bilateral substantia nigra, globus pallidus, putamen, the head of caudate, and red nucleus of 87 patients and 50 control subjects were assayed by measuring phase values using susceptibility‐weighted phase imaging in a 3‐tesla magnetic resonance system. The serum ceruloplasmin levels of all subjects were determined. Results: The bilateral average phase values of the substantia nigra and all other brain regions examined did not correlate with the main motor symptoms of Parkinson’s disease in the total patient group or when patients were grouped according to serum ceruloplasmin levels. Significant correlations between serum ceruloplasmin levels and nigral bilateral average phase values were observed in the tremor and akinetic/rigid‐dominant subgroups. Analysis of patients without prior dopaminergic medication exhibited similar results. Increased nigral iron content correlated with disease severity as assayed by the Unified Parkinson’s Disease Rating Scale motor scores in the PD_AR subgroup. Conclusions: These findings suggest that nigral iron deposition, correlating with decreased serum ceruloplasmin levels, is a risk factor in Parkinson’s disease across multiple motor phenotypic expressions.     

Characterization of Lewy body pathology in 12‐ and 16‐year‐old intrastriatal mesencephalic grafts surviving in a patient with Parkinson's disease

We previously reported the occurrence of Lewy bodies in grafted human fetal mesencephalic neurons in two patients with Parkinson's disease. Here, we have used immunohistochemistry and electron microscopy to characterize the development of Lewy bodies in one of these cases. This patient was operated in putamen on both sides at 12 or 16 years before death, respectively. We demonstrate that 2% of the 12‐year‐old and 5% of the 16‐year‐old grafted, presumed dopaminergic neurons contained Lewy bodies immunoreactive for α‐synuclein. Based on morphological analysis, two forms of α‐synuclein‐positive aggregates were distinguished in the grafts, the first a classical and compact Lewy body, the other a loose meshwork aggregate. Lewy bodies in the grafts stained positively for ubiquitin and thioflavin‐S, and contained characteristic α‐synuclein immunoreactive electron dense fibrillar structures on electron microscopy. Our data indicate that Lewy bodies develop gradually in transplanted dopaminergic neurons in a fashion similar to that in dopaminergic neurons in the host substantia nigra. © 2010 Movement Disorder Society     

Prevalence of Parkinson’s disease in Korea

The prevalence of neurodegenerative disorders is not well documented in Korea. We assessed the prevalence of Parkinson's disease in an elderly population in a newly industrialized city in a rural region. Subjects for this study were randomly selected from a community-based cohort study. The sample in the cohort represented approximately 1.3% (4700) of 362 625 adults (age>18 years) listed in the city register in 1998. Among this group, 4218 subjects (1086 subjects aged>60 years) agreed to be interviewed and underwent a physical examination and neuropsychological tests administered by a neurologist and neuropsychologist. All participants were examined. Participants who had bradykinesia and at least one other possible cardinal sign of parkinsonism at the neurologic screening, and those who reported that they had Parkinson's disease, or were taking antiparkinsonian drugs were identified. In our study, 16 subjects showed evidence of Parkinson's disease. The prevalence in this population was 0.37%. Prevalence increased with age, and prevalence was 1.47% for those aged older than 60 years. Postural instability and gait disturbance were more common in the older age group. The results of neuropsychological tests were as follows: (1) only two subjects had low scores (<20) in the Korea-version mini-mental status examination; (2) seven subjects scored 0.5, one subject scored 2 and the other eight subjects scored 0 in the clinical dementia rating. The results of our prevalence study are similar to those of studies carried out in Western countries. Age is a risk factor for Parkinson's disease in Korea.     

Overexpression of α‐synuclein in an astrocyte cell line promotes autophagy inhibition and apoptosis

α‐Synuclein is the major component of neuronal cytoplasmic aggregates called Lewy bodies, the main pathological hallmark of Parkinson disease. Although neurons are the predominant cells expressing α‐synuclein in the brain, recent studies have demonstrated that primary astrocytes in culture also express α‐synuclein and regulate α‐synuclein trafficking. Astrocytes have a neuroprotective role in several detrimental brain conditions; we therefore analyzed the effects of the overexpression of wild‐type α‐synuclein and its A30P and A53T mutants on autophagy and apoptosis. We observed that in immortalized astrocyte cell lines, overexpression of α‐synuclein proteins promotes the decrease of LC3‐II and the increase of p62 protein levels, suggesting the inhibition of autophagy. When these cells were treated with rotenone, there was a loss of mitochondrial membrane potential, especially in cells expressing mutant α‐synuclein. The level of this decrease was related to the toxicity of the mutants because they show a more intense and sustained effect. The decrease in autophagy and the mitochondrial changes in conjunction with parkin expression levels may sensitize astrocytes to apoptosis.     

Glial reactions in Parkinson's disease

Dopaminergic neurons of the substantia nigra are particularly vulnerable to oxidative and inflammatory attack. Such processes may play a crucial role in the etiology of Parkinson disease (PD). Since glia are the main generators of these processes, the possibility that PD may be caused by glial dysfunction needs to be considered. This review concentrates on glial reactions in PD. Reactive astrocytes and reactive microglia are abundant in the substantia nigra (SN) of PD cases indicating a robust inflammatory state. Glia normally serve neuroprotective roles but, given adverse stimulation, they may contribute to damaging chronic inflammation. Microglia, the phagocytes of brain, may be the main contributors since they can produce large numbers of superoxide anions and other neurotoxins. Their toxicity towards dopaminergic neurons has been demonstrated in tissue culture and various animal models of PD. The MPTP and α‐synuclein models are of particular interest. Years after exposure to MPTP, inflammation has been observed in the SN. This has established that an acute insult to the SN can result in a sustained local inflammation. The α‐synuclein model indicates that an endogenous protein can induce inflammation, and, when overexpressed, can lead to autosomal dominant PD. Less is known about the role of astrocytes than microglia, but they are known to secrete both inflammatory and anti‐inflammatory molecules and may play a role in modulating microglial activity. Oligodendrocytes do not seem to play a role in promoting inflammation although, like neurons, they may be damaged by inflammatory processes. Further research concerning glial reactions in PD may lead to disease‐modifying therapeutic approaches. © 2007 Movement Disorder Society